🏷

Classifications

Harrison's Chapter

ICD-O Morphology

🔗

Mappings

MONDO

MONDO:0006468 thyroid gland undifferentiated (anaplastic) carcinoma

MONDO provides an exact disease term for anaplastic thyroid carcinoma.

NCIT

NCIT:C3878 Thyroid Gland Anaplastic Carcinoma

NCIT provides an exact neoplasm term for anaplastic thyroid carcinoma; cross-referenced from MONDO:0006468.

NCIT

NCIT:C3878 Thyroid Gland Anaplastic Carcinoma

NCIT provides an exact neoplasm term for anaplastic thyroid carcinoma; cross-referenced from MONDO:0006468.

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Pathophysiology

9

MAPK-Activating Truncal Driver Alteration

ATC commonly arises from a pre-existing follicular-cell-derived thyroid carcinoma that already carries a truncal MAPK-pathway driver alteration. This initiating event establishes the core oncogenic signaling axis that is later exploited therapeutically in molecularly selected tumors.

thyroid follicular cell CL:0002258

MAPK cascade GO:0000165 ↑ INCREASED

thyroid gland UBERON:0002046

Downstream

TP53 Loss and p53-Mediated DNA Damage Response Failure TP53 alteration permits genomically unstable progression to high-grade disease

TERT Reactivation and Telomere Maintenance TERT promoter mutation supports immortalization during tumor progression

PI3K-AKT Survival Signaling PI3K pathway activation adds a parallel survival and growth program

Dedifferentiation and Loss of Thyroid Identity MAPK-driven tumor evolution culminates in loss of differentiated thyroid functions

Adaptive Immune Resistance and Immunosuppressive Microenvironment BRAF V600E-mutant tumors show higher tumor-cell PD-L1 positivity, coupling MAPK driver status to adaptive immune resistance

Show evidence (1 reference)

PMID:40396891 SUPPORT Other

"The sequence of events leading to the development of ATC commonly begins with a tumorigenic mutation that constitutively activates the mitogen-activated protein kinase (MAPK) pathway, giving rise to indolent entities such as well-differentiated papillary or follicular thyroid carcinomas."

Supports ATC initiation from MAPK-activating precursor lesions derived from follicular thyroid carcinoma.

TP53 Loss and p53-Mediated DNA Damage Response Failure

Progression to ATC commonly includes late TP53 alteration, which weakens p53-mediated DNA damage control and permits genomically unstable evolution toward highly aggressive undifferentiated disease.

DNA damage response, signal transduction by p53 class mediator GO:0030330 ↓ DECREASED

Downstream

Dedifferentiation and Loss of Thyroid Identity TP53 loss facilitates progression into less-differentiated undifferentiated disease

Show evidence (1 reference)

PMID:41175860 SUPPORT Other

"Progression of thyroid tumors to advanced and less-differentiated carcinomas requires additional oncogenic alterations, including TP53 and TERT promoter mutation, and aberrant PI3K-PTEN-AKT signaling."

Supports TP53 mutation as a late event required for progression to advanced less-differentiated thyroid carcinoma.

TERT Reactivation and Telomere Maintenance

TERT promoter mutation is a late progression event that reactivates telomerase, enabling telomere maintenance and sustained clonal expansion in advanced follicular-cell-derived thyroid carcinoma.

telomere maintenance via telomerase GO:0007004 ↑ INCREASED

Downstream

Dedifferentiation and Loss of Thyroid Identity TERT activation sustains clonal expansion of less-differentiated tumor cells

Show evidence (1 reference)

PMID:41175860 SUPPORT Other

"Progression of thyroid tumors to advanced and less-differentiated carcinomas requires additional oncogenic alterations, including TP53 and TERT promoter mutation, and aberrant PI3K-PTEN-AKT signaling."

Supports TERT promoter mutation as a late progression event in advanced less-differentiated thyroid carcinoma.

PI3K-AKT Survival Signaling

Aberrant PI3K-PTEN-AKT signaling provides a parallel survival and growth pathway during ATC progression, helping aggressive clones persist despite loss of differentiated thyroid-cell features.

phosphatidylinositol 3-kinase/protein kinase B signal transduction GO:0043491 ↑ INCREASED

Downstream

Matrix Metalloproteinase Dysregulation and Invasion PI3K-AKT signaling supports invasive and metastatic behavior

Show evidence (1 reference)

PMID:41175860 SUPPORT Other

"Progression of thyroid tumors to advanced and less-differentiated carcinomas requires additional oncogenic alterations, including TP53 and TERT promoter mutation, and aberrant PI3K-PTEN-AKT signaling."

Supports aberrant PI3K-PTEN-AKT signaling as a distinct late survival pathway in advanced less-differentiated thyroid carcinoma.

SWI/SNF Chromatin Remodeling Complex Inactivation

A substantial subset of anaplastic thyroid carcinomas acquires inactivating mutations in subunits of the SWI/SNF ATP-dependent chromatin remodeling complex, most often ARID1A, ARID2, or SMARCB1. These mutations are enriched in ATC relative to less advanced thyroid cancers and collapse chromatin accessibility at thyroid lineage-specification genes, reinforcing the dedifferentiated, radioiodine-refractory state and rendering tumors insensitive to MAPK-inhibitor-based redifferentiation.

thyroid follicular cell CL:0002258

chromatin remodeling GO:0006338 ↓ DECREASED

thyroid gland UBERON:0002046

Downstream

Dedifferentiation and Loss of Thyroid Identity SWI/SNF loss closes chromatin at thyroid lineage transcription-factor target sites, impairing thyroid-differentiated gene expression and locking tumors in a radioiodine-refractory dedifferentiated state.

Show evidence (2 references)

PMID:26878173 SUPPORT Human Clinical

"Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases."

Next-generation sequencing of 117 patient-derived poorly differentiated and anaplastic thyroid cancers shows SWI/SNF subunit mutations are enriched in ATC relative to poorly differentiated thyroid cancer, establishing SWI/SNF inactivation as a recurrent ATC-associated genomic alteration.

PMID:33318036 SUPPORT Model Organism

"thyroid-specific loss of Arid1a, Arid2, or Smarcb1 in mouse BRAFV600E-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation."

A genetically engineered mouse model demonstrates that loss of individual SWI/SNF subunits in BRAF-mutant thyroid tumors drives progression and impairs differentiation, supporting a causal role for SWI/SNF inactivation in ATC-like dedifferentiation.

Dedifferentiation and Loss of Thyroid Identity

As follicular-cell-derived thyroid carcinoma dedifferentiates into ATC, it loses thyroid-specific transcriptional programs and iodide-handling functions. This transition is a major reason ATC is radioiodine refractory and clinically far more aggressive than differentiated thyroid cancer.

cell differentiation GO:0030154 ↓ DECREASED

Downstream

Epithelial-Mesenchymal Transition Dedifferentiation activates the epithelial-mesenchymal transition program as follicular-cell-derived tumors progress to ATC.

Matrix Metalloproteinase Dysregulation and Invasion Dedifferentiated tumors acquire a more invasive and metastatic phenotype

Show evidence (2 references)

PMID:41462994 SUPPORT Other

"Follicular-cell-derived thyroid carcinoma, while typically associated with a favorable prognosis, can undergo dedifferentiation into poorly differentiated (PDTC) or anaplastic thyroid carcinoma (ATC), leading to enhanced aggressiveness and radioiodine resistance."

Supports dedifferentiation into ATC as the mechanistic basis for aggressiveness and radioiodine refractoriness.

PMID:41462994 SUPPORT Other

"These alterations promote the loss of thyroid-specific functions, including iodide metabolism, and correlate with poor clinical outcomes."

Directly supports loss of thyroid identity and impaired iodide handling in dedifferentiated disease.

Epithelial-Mesenchymal Transition

During progression to ATC, tumor cells activate an epithelial-mesenchymal transition (EMT) program: they lose the epithelial adhesion molecule E-cadherin and gain mesenchymal markers such as vimentin together with the EMT transcription factor ZEB1. This phenotypic switch underlies the migratory, invasive, and metastatic behavior that characterizes anaplastic thyroid carcinoma.

epithelial to mesenchymal transition GO:0001837 ↑ INCREASED

Downstream

Matrix Metalloproteinase Dysregulation and Invasion The EMT program confers a migratory, invasive phenotype that, together with matrix-remodeling proteases, drives local invasion and metastatic spread.

Show evidence (1 reference)

PMID:32774477 SUPPORT In Vitro

"In ATC tissues and cell lines, the mesenchymal marker ZEB1 was significantly upregulated and the epithelial marker E-cadherin was significantly downregulated. Additionally, the mesenchymal marker vimentin was significantly upregulated in ATC tissues and in one ATC cell line."

Immunohistochemistry of human ATC tissues and expression analysis of ATC cell lines demonstrate loss of epithelial E-cadherin with gain of mesenchymal ZEB1 and vimentin, the molecular hallmark of EMT.

Matrix Metalloproteinase Dysregulation and Invasion

ATC exhibits marked dysregulation of matrix metalloproteinase-related programs, remodeling the extracellular environment to support migration, local tissue destruction, and distant spread.

positive regulation of cell migration GO:0030335 ↑ INCREASED

Downstream

Rapidly enlarging thyroid mass Aggressive tumor growth and local invasion present as a rapidly enlarging anterior thyroid or neck mass.

Dysphagia Local invasion and compressive neck disease can impair swallowing.

Dyspnea Pulmonary metastases or compressive neck disease can produce shortness of breath.

Stridor Critical upper-airway narrowing from local tumor invasion or compression can produce stridor.

Hoarse voice Invasion or compression of laryngeal structures can cause hoarseness.

Cervical lymphadenopathy Invasive ATC frequently spreads to regional cervical lymph nodes.

Show evidence (1 reference)

PMID:25887408 SUPPORT Computational

"Inhibition of matrix metalloproteinases pathway is a major event involved in thyroid cancer progression and its dysregulation may result crucial for invasiveness, migration and metastasis."

Transcriptomic analysis supports dysregulated matrix metalloproteinase biology as a mechanism for ATC invasion and metastasis, although the abstract does not independently resolve the exact direction of that dysregulation.

Adaptive Immune Resistance and Immunosuppressive Microenvironment

ATC frequently upregulates tumor-cell PD-L1 within an immune-infiltrated microenvironment. The majority of ATCs are PD-L1-positive and contain abundant CD3+/CD8+ tumor-infiltrating lymphocytes and tumor-associated macrophages, indicating an "immune-adapted" tumor in which pre-existing anti-tumor immunity is actively suppressed through the PD-1/PD-L1 axis. PD-L1 positivity is enriched in BRAF V600E-mutant ATC and is considered predictive of response to anti-PD-1/PD-L1 therapy.

CD8+ tumor-infiltrating lymphocyte CL:0000625 tumor-associated macrophage CL:0000235

Negative Regulation of T Cell Mediated Immunity GO:0002710 ↑ INCREASED

Show evidence (3 references)

PMID:39004795 SUPPORT Human Clinical

"Most ATCs (73.2%) were PD-L1-positive."

A multi-institutional study of 179 ATCs establishes that the majority of ATCs express tumor-cell PD-L1, the central effector of adaptive immune resistance.

PMID:39004795 SUPPORT Human Clinical

"Tumor cell surface PD-L1 expression is considered predictive of therapeutic response."

Links tumor-cell PD-L1 expression to predicted responsiveness to anti-PD checkpoint blockade, the therapeutic corollary of adaptive immune resistance.

PMID:34093774 SUPPORT Human Clinical

"In addition to increased PD-L1 expression, all ATC cases exhibited significantly increased CD3+ and CD8+ T cells, CD68+ and CD163+ macrophages, and S100+ dendritic cells compared with the PDTC cases."

Demonstrates that PD-L1 upregulation in ATC co-occurs with a brisk T cell and macrophage infiltrate, the hallmark "immune-adapted" state of adaptive immune resistance rather than an immune-desert tumor.

✶

Histopathology

2

Anaplastic Thyroid Carcinoma

Undifferentiated thyroid carcinoma composed of pleomorphic epithelioid, spindle, and/or giant cells with highly aggressive morphology.

Show evidence (1 reference)

PMID:25214840 SUPPORT Other

"Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. It shows a wide spectrum of morphological presentations and the diagnosis could be challenging due to its high degree of dedifferentiation."

Supports ATC as an undifferentiated aggressive thyroid carcinoma with a morphologically heterogeneous diagnostic appearance.

Spindle Cell Pattern

Sarcomatoid spindle-cell morphology is a common microscopic pattern in ATC.

Show evidence (1 reference)

PMID:22783225 SUPPORT Other

"The three different morphologic patterns identifiable at histologic analysis (squamoid, spindle cell, and giant cell) present similar biological and clinical features and none influences the prognosis (Hundahl et al., 1998)."

Directly identifies spindle-cell morphology as one of the recognized histologic patterns of anaplastic thyroid carcinoma.

⬡

Pathograph

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Phenotypes

6

Cardiovascular 1

Cervical lymphadenopathy Lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:30844206 SUPPORT Other

"anaplastic thyroid cancer is highly locally invasive, with a propensity for early lymph node positivity and distant metastatic disease."

Directly supports early cervical/regional lymph node involvement as a characteristic pattern in ATC.

Digestive 1

Dysphagia Dysphagia HP:0002015

Show evidence (1 reference)

PMID:38179406 SUPPORT Other

"It is the most aggressive form of thyroid carcinoma, with a median survival of 5 mo and poor quality of life (airway obstruction, dysphagia, hoarseness, persistent pain)."

Directly lists dysphagia among the characteristic symptoms of anaplastic thyroid carcinoma.

Endocrine 1

Rapidly enlarging thyroid mass Thyroid carcinoma HP:0002890

Show evidence (1 reference)

PMID:30844206 SUPPORT Other

"Anaplastic thyroid cancer typically presents as a rapidly growing anterior neck mass and may have compressive symptoms early in the disease."

Directly supports a rapidly enlarging anterior neck/thyroid mass as the typical clinical presentation of ATC.

Respiratory 2

Dyspnea Dyspnea HP:0002094

Show evidence (1 reference)

PMID:22783225 SUPPORT Other

"Systemic symptoms include anorexia, weight loss, and shortness of breath with pulmonary metastases."

Directly lists shortness of breath as a systemic symptom of ATC with pulmonary metastatic disease.

Stridor Stridor HP:0010307

Show evidence (1 reference)

PMID:22783225 SUPPORT Other

"Locally, ATC shows a rapidly enlarging anterior neck mass, with accompanying dysphagia (40%), voice change or hoarseness (40%), and stridor (24%)."

Directly lists stridor among local symptoms accompanying ATC neck masses.

Voice 1

Hoarse voice Hoarse voice HP:0001609

Show evidence (1 reference)

PMID:38179406 SUPPORT Other

"It is the most aggressive form of thyroid carcinoma, with a median survival of 5 mo and poor quality of life (airway obstruction, dysphagia, hoarseness, persistent pain)."

Directly lists hoarseness as a characteristic quality-of-life impairing symptom of ATC, reflecting laryngeal involvement.

🧬

Genetic Associations

4

BRAF (Somatic activating mutation)

Show evidence (1 reference)

PMID:38044137 SUPPORT Human Clinical

"Of ATC cases, 52.9% had BRAF mutations, and 5.9% had RET fusion."

Supports frequent BRAF alteration in advanced ATC and its therapeutic relevance.

TP53 (Somatic loss-of-function alteration)

Show evidence (1 reference)

PMID:38044137 SUPPORT Human Clinical

"ATC cases had a significantly higher prevalence of TP53 alterations than the other cases (82.3% vs. 11.8%)"

Supports TP53 alteration as a characteristic high-frequency event in ATC.

TERT (Somatic promoter mutation)

Show evidence (1 reference)

PMID:38044137 SUPPORT Human Clinical

"whereas the frequencies of TERT promoter mutations were 88.2% in ATC cases and 64.7% in the other cases, albeit without a significant difference."

Supports the high prevalence of TERT promoter mutations in ATC.

RET (Rare somatic gene fusion)

Show evidence (1 reference)

PMID:38044137 SUPPORT Human Clinical

"Of ATC cases, 52.9% had BRAF mutations, and 5.9% had RET fusion."

Supports RET fusion as an uncommon but actionable genomic alteration in ATC.

💊

Medical Actions

4

Surgery and Airway Stabilization

Action: surgical procedure MAXO:0000004

Selected localized tumors may undergo aggressive resection, but airway preservation or tracheostomy is often the more urgent intervention because many patients present with compressive neck disease.

Show evidence (1 reference)

PMID:38179406 SUPPORT Other

"Recent management policy is based on surgery, even debulking, chemotherapy (cisplatin or doxorubicin), radiotherapy (adjuvant or definitive), targeted biological agents and immunotherapy."

Supports surgery (including debulking resection) as a core component of current ATC management alongside radiotherapy and systemic therapy.

External Beam Radiation Therapy

Action: radiation therapy MAXO:0000014

External beam radiation is used for locoregional control, palliation of compressive symptoms, and as part of multimodality treatment when feasible.

Show evidence (1 reference)

PMID:38179406 SUPPORT Other

"Recent management policy is based on surgery, even debulking, chemotherapy (cisplatin or doxorubicin), radiotherapy (adjuvant or definitive), targeted biological agents and immunotherapy."

Directly supports adjuvant or definitive radiotherapy as a component of current ATC management strategy.

Dabrafenib Plus Trametinib

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: dabrafenib CHEBI:75045 trametinib CHEBI:75998

Combined BRAF and MEK inhibition provides substantial clinical benefit in BRAF V600E-mutant ATC and is a core systemic option for molecularly selected patients.

Mechanism Target:

INHIBITS MAPK-Activating Truncal Driver Alteration — Combined BRAF and MEK inhibition suppresses the MAPK-dependent oncogenic program that persists in BRAF V600E-mutant ATC.

Show evidence (1 reference)

PMID:40396891 SUPPORT Other

"Indeed, genotype-guided targeting of the MAPK pathway is now the standard of care for subgroups of ATC patients"

Review supports genotype-guided MAPK inhibition as standard treatment strategy for molecularly defined ATC subsets.

Show evidence (2 references)

PMID:35026411 SUPPORT Human Clinical

"The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%."

The updated ROAR ATC cohort showed meaningful response and durability with dabrafenib plus trametinib in BRAF V600E-mutant disease.

PMID:35026411 SUPPORT Human Clinical

"These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC."

Directly supports dabrafenib plus trametinib as a clinically useful targeted treatment in ATC.

Lenvatinib Plus Pembrolizumab

Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262

Agent: lenvatinib CHEBI:85994 pembrolizumab NCIT:C106432

Combination of the multikinase inhibitor lenvatinib with the anti-PD-1 immune checkpoint inhibitor pembrolizumab is an emerging systemic option for anaplastic and poorly differentiated thyroid carcinoma. It exploits the high tumor mutational burden and elevated PD-L1 expression characteristic of these dedifferentiated tumors, with the most durable responses seen in tumors with increased TMB or a high PD-L1 tumor proportion score.

Mechanism Target:

INHIBITS Adaptive Immune Resistance and Immunosuppressive Microenvironment — Pembrolizumab blocks PD-1/PD-L1 engagement, reversing the adaptive immune resistance program that shields PD-L1-high ATC cells from cytotoxic T cell killing, while lenvatinib provides concurrent antiangiogenic pressure.

Show evidence (1 reference)

PMID:35347921 SUPPORT Other

"The immune checkpoint inhibitor pembrolizumab can be applied to treat thyroid cancer with high tumor mutational load and may be considered as the preferred modality for the treatment of ATC patients with high programmed death ligand-1 expression."

Review supports pembrolizumab targeting the PD-L1-driven immune resistance program, with greatest benefit in PD-L1-high ATC.

Show evidence (2 references)

PMID:33509020 SUPPORT Human Clinical

"These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab."

The biological rationale links ATC's high tumor mutational burden and elevated PD-L1 to responsiveness to combined lenvatinib and pembrolizumab.

PMID:33509020 SUPPORT Human Clinical

"Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions."

The retrospective ATC/PDTC series reported complete and durable remissions, supporting the combination as an effective systemic treatment option.

🔬

Biochemical Markers

2

Comprehensive genomic profiling

Show evidence (1 reference)

PMID:38044137 SUPPORT Human Clinical

"In conclusion, 58.8% of ATC, 93.8% of PTC, and 42.9% of PDTC had genetic alterations linked to therapeutic agents. Active gene panel testing is required to increase treatment options."

Supports routine genomic profiling in advanced ATC because actionable alterations are common enough to change treatment selection.

Radioiodine avidity

Show evidence (1 reference)

PMID:41462994 SUPPORT Other

"These alterations promote the loss of thyroid-specific functions, including iodide metabolism, and correlate with poor clinical outcomes."

Supports loss of iodide handling (i.e. loss of radioiodine avidity) as a functional consequence of ATC dedifferentiation.

🔬

Clinical Trials

2

NCT02034110 PHASE_II COMPLETED

ROAR basket study of dabrafenib plus trametinib in BRAF V600E-mutant rare cancers, including the anaplastic thyroid carcinoma cohort whose updated analysis (PMID:35026411) anchors the targeted-therapy treatment block in this entry.

Target Phenotypes: thyroid carcinoma HP:0002890

Show evidence (1 reference)

clinicaltrials:NCT02034110 SUPPORT Human Clinical

"This was a Phase II, open-label, non-randomized, multi-center study of oral dabrafenib in combination with oral trametinib in subjects with rare cancers harboring the BRAF V600E mutation including anaplastic thyroid cancer (ATC)"

Directly establishes the ROAR study design and the inclusion of an anaplastic thyroid carcinoma cohort treated with combined BRAF/MEK inhibition, the trial whose ATC cohort underpins the current genotype-guided systemic therapy standard.

NCT04171622 PHASE_II ACTIVE_NOT_RECRUITING

Phase II trial of the multikinase inhibitor lenvatinib combined with the anti-PD-1 antibody pembrolizumab in stage IVB locally advanced/unresectable or stage IVC metastatic anaplastic thyroid cancer. It prospectively tests the lenvatinib-plus-pembrolizumab combination that is curated as a treatment in this entry, exploiting ATC's high tumor mutational burden and PD-L1 expression.

Target Phenotypes: thyroid carcinoma HP:0002890

Show evidence (1 reference)

clinicaltrials:NCT04171622 SUPPORT Human Clinical

"This phase II trial studies how well lenvatinib and pembrolizumab work in treating patients with anaplastic thyroid cancer that is stage IVB and has spread to nearby tissue or lymph nodes (locally advanced) and cannot be removed by surgery (unresectable), or stage IVC that has spread to other..."

Registers a prospective phase II evaluation of the lenvatinib plus pembrolizumab combination in advanced/metastatic ATC, complementing the Lenvatinib Plus Pembrolizumab treatment block whose supporting evidence is currently a retrospective series.

{ }

Source YAML

click to show

name: Anaplastic Thyroid Carcinoma
creation_date: '2026-04-12T05:11:48Z'
updated_date: '2026-05-17T00:00:00Z'
description: >-
  Anaplastic thyroid carcinoma (ATC) is a highly aggressive undifferentiated
  follicular-cell-derived thyroid malignancy that typically emerges through
  stepwise dedifferentiation of papillary or follicular thyroid carcinoma. Its
  biology is defined by MAPK-pathway driver alterations with superimposed TP53,
  TERT, and PI3K/AKT pathway abnormalities, leading to rapid local invasion,
  airway and esophageal compression, early distant metastasis, and loss of
  radioiodine avidity.
categories:
- Endocrine Cancer
- Solid Tumor
parents:
- thyroid carcinoma
pathophysiology:
- name: MAPK-Activating Truncal Driver Alteration
  conforms_to: "sustaining_proliferative_signaling#Oncogenic Growth-Signal Lesion"
  description: >-
    ATC commonly arises from a pre-existing follicular-cell-derived thyroid
    carcinoma that already carries a truncal MAPK-pathway driver alteration.
    This initiating event establishes the core oncogenic signaling axis that is
    later exploited therapeutically in molecularly selected tumors.
  evidence:
  - reference: PMID:40396891
    reference_title: >-
      NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO
      TREATMENTS: Molecular insights into the origin, biology, and treatment of
      anaplastic thyroid carcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The sequence of events leading to the development of ATC commonly begins
      with a tumorigenic mutation that constitutively activates the
      mitogen-activated protein kinase (MAPK) pathway, giving rise to indolent
      entities such as well-differentiated papillary or follicular thyroid
      carcinomas.
    explanation: >-
      Supports ATC initiation from MAPK-activating precursor lesions derived
      from follicular thyroid carcinoma.
  cell_types:
  - preferred_term: thyroid follicular cell
    term:
      id: CL:0002258
      label: thyroid follicular cell
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  locations:
  - preferred_term: thyroid gland
    term:
      id: UBERON:0002046
      label: thyroid gland
  downstream:
  - target: TP53 Loss and p53-Mediated DNA Damage Response Failure
    description: TP53 alteration permits genomically unstable progression to high-grade disease
    evidence:
    - reference: PMID:40396891
      reference_title: >-
        NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO
        TREATMENTS: Molecular insights into the origin, biology, and treatment of
        anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This is followed by recurring alterations that drive oncogenic
        properties such as enhanced proliferation, genomic instability,
        replicative immortality, and dedifferentiation, culminating in the
        emergence of highly aggressive ATC tumors.
      explanation: >-
        Supports the truncal MAPK driver being followed by recurring alterations
        that drive genomic instability, the consequence of TP53 loss and
        p53-mediated DNA damage response failure.
  - target: TERT Reactivation and Telomere Maintenance
    description: TERT promoter mutation supports immortalization during tumor progression
    evidence:
    - reference: PMID:40396891
      reference_title: >-
        NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO
        TREATMENTS: Molecular insights into the origin, biology, and treatment of
        anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This is followed by recurring alterations that drive oncogenic
        properties such as enhanced proliferation, genomic instability,
        replicative immortality, and dedifferentiation, culminating in the
        emergence of highly aggressive ATC tumors.
      explanation: >-
        Supports the truncal MAPK driver being followed by recurring alterations
        that confer replicative immortality, the consequence of TERT
        reactivation and telomere maintenance.
  - target: PI3K-AKT Survival Signaling
    description: PI3K pathway activation adds a parallel survival and growth program
    evidence:
    - reference: PMID:40396891
      reference_title: >-
        NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO
        TREATMENTS: Molecular insights into the origin, biology, and treatment of
        anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This is followed by recurring alterations that drive oncogenic
        properties such as enhanced proliferation, genomic instability,
        replicative immortality, and dedifferentiation, culminating in the
        emergence of highly aggressive ATC tumors.
      explanation: >-
        Supports the truncal MAPK driver being followed by recurring alterations
        that drive enhanced proliferation, consistent with PI3K-AKT survival
        signaling as a parallel growth program acquired during progression.
  - target: Dedifferentiation and Loss of Thyroid Identity
    description: MAPK-driven tumor evolution culminates in loss of differentiated thyroid functions
    evidence:
    - reference: PMID:40396891
      reference_title: >-
        NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO
        TREATMENTS: Molecular insights into the origin, biology, and treatment of
        anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This is followed by recurring alterations that drive oncogenic
        properties such as enhanced proliferation, genomic instability,
        replicative immortality, and dedifferentiation, culminating in the
        emergence of highly aggressive ATC tumors.
      explanation: >-
        Supports the truncal MAPK driver being followed by recurring alterations
        that culminate in dedifferentiation and the emergence of highly
        aggressive ATC.
  - target: Adaptive Immune Resistance and Immunosuppressive Microenvironment
    description: BRAF V600E-mutant tumors show higher tumor-cell PD-L1 positivity, coupling MAPK driver status to adaptive immune resistance
    evidence:
    - reference: PMID:39004795
      reference_title: >-
        PD-L1 Expression and Its Modulating Factors in Anaplastic Thyroid
        Carcinoma: A Multi-institutional Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        BRAF V600E, but not TERT promoter mutations, correlated significantly
        with PD-L1-positivity rate
      explanation: >-
        A multi-institutional study of 179 ATCs found BRAF V600E mutation status
        correlated significantly with tumor-cell PD-L1 positivity, linking the
        MAPK truncal driver to adaptive immune resistance.
- name: TP53 Loss and p53-Mediated DNA Damage Response Failure
  description: >-
    Progression to ATC commonly includes late TP53 alteration, which weakens
    p53-mediated DNA damage control and permits genomically unstable evolution
    toward highly aggressive undifferentiated disease.
  evidence:
  - reference: PMID:41175860
    reference_title: >-
      Somatic genetic alterations in the development and progression in thyroid
      tumors of follicular cells.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Progression of thyroid tumors to advanced and less-differentiated
      carcinomas requires additional oncogenic alterations, including TP53 and
      TERT promoter mutation, and aberrant PI3K-PTEN-AKT signaling.
    explanation: >-
      Supports TP53 mutation as a late event required for progression to
      advanced less-differentiated thyroid carcinoma.
  biological_processes:
  - preferred_term: DNA damage response, signal transduction by p53 class mediator
    modifier: DECREASED
    term:
      id: GO:0030330
      label: DNA damage response, signal transduction by p53 class mediator
  downstream:
  - target: Dedifferentiation and Loss of Thyroid Identity
    description: TP53 loss facilitates progression into less-differentiated undifferentiated disease
    evidence:
    - reference: PMID:41462994
      reference_title: >-
        Dedifferentiation and Redifferentiation of Follicular-Cell-Derived
        Thyroid Carcinoma: Mechanisms and Therapeutic Implications.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        highlighting the roles of key mutations-such as BRAF, RAS, TERT, and
        TP53-and the disregulation of signaling pathways, including MAPK and
        PI3K/AKT
      explanation: >-
        Identifies TP53 among the key mutations driving dedifferentiation of
        follicular-cell-derived thyroid carcinoma into poorly differentiated and
        anaplastic disease.
- name: TERT Reactivation and Telomere Maintenance
  description: >-
    TERT promoter mutation is a late progression event that reactivates
    telomerase, enabling telomere maintenance and sustained clonal expansion in
    advanced follicular-cell-derived thyroid carcinoma.
  evidence:
  - reference: PMID:41175860
    reference_title: >-
      Somatic genetic alterations in the development and progression in thyroid
      tumors of follicular cells.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Progression of thyroid tumors to advanced and less-differentiated
      carcinomas requires additional oncogenic alterations, including TP53 and
      TERT promoter mutation, and aberrant PI3K-PTEN-AKT signaling.
    explanation: >-
      Supports TERT promoter mutation as a late progression event in advanced
      less-differentiated thyroid carcinoma.
  biological_processes:
  - preferred_term: telomere maintenance via telomerase
    modifier: INCREASED
    term:
      id: GO:0007004
      label: telomere maintenance via telomerase
  downstream:
  - target: Dedifferentiation and Loss of Thyroid Identity
    description: TERT activation sustains clonal expansion of less-differentiated tumor cells
    evidence:
    - reference: PMID:41462994
      reference_title: >-
        Dedifferentiation and Redifferentiation of Follicular-Cell-Derived
        Thyroid Carcinoma: Mechanisms and Therapeutic Implications.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        highlighting the roles of key mutations-such as BRAF, RAS, TERT, and
        TP53-and the disregulation of signaling pathways, including MAPK and
        PI3K/AKT
      explanation: >-
        Identifies TERT among the key mutations driving dedifferentiation of
        follicular-cell-derived thyroid carcinoma into poorly differentiated and
        anaplastic disease.
- name: PI3K-AKT Survival Signaling
  description: >-
    Aberrant PI3K-PTEN-AKT signaling provides a parallel survival and growth
    pathway during ATC progression, helping aggressive clones persist despite
    loss of differentiated thyroid-cell features.
  evidence:
  - reference: PMID:41175860
    reference_title: >-
      Somatic genetic alterations in the development and progression in thyroid
      tumors of follicular cells.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Progression of thyroid tumors to advanced and less-differentiated
      carcinomas requires additional oncogenic alterations, including TP53 and
      TERT promoter mutation, and aberrant PI3K-PTEN-AKT signaling.
    explanation: >-
      Supports aberrant PI3K-PTEN-AKT signaling as a distinct late survival
      pathway in advanced less-differentiated thyroid carcinoma.
  biological_processes:
  - preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  downstream:
  - target: Matrix Metalloproteinase Dysregulation and Invasion
    description: PI3K-AKT signaling supports invasive and metastatic behavior
    evidence:
    - reference: PMID:21196242
      reference_title: Contribution of PKB/AKT signaling to thyroid cancer.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        regulate several processes including cell proliferation and survival,
        growth and response to nutrient availability, migration, tissue invasion
        and angiogenesis. Aberrant activation of Akt is involved in a variety of
        human cancers including those arising in the thyroid gland.
      explanation: >-
        Akt signaling regulates migration and tissue invasion and is aberrantly
        activated in thyroid cancers, supporting the causal link from PI3K-AKT
        survival signaling to invasive and metastatic behavior.
- name: SWI/SNF Chromatin Remodeling Complex Inactivation
  description: >-
    A substantial subset of anaplastic thyroid carcinomas acquires inactivating
    mutations in subunits of the SWI/SNF ATP-dependent chromatin remodeling
    complex, most often ARID1A, ARID2, or SMARCB1. These mutations are enriched
    in ATC relative to less advanced thyroid cancers and collapse chromatin
    accessibility at thyroid lineage-specification genes, reinforcing the
    dedifferentiated, radioiodine-refractory state and rendering tumors
    insensitive to MAPK-inhibitor-based redifferentiation.
  evidence:
  - reference: PMID:26878173
    reference_title: >-
      Genomic and transcriptomic hallmarks of poorly differentiated and
      anaplastic thyroid cancers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to PDTCs, ATCs had a greater mutation burden, including a higher
      frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway
      effectors, SWI/SNF subunits, and histone methyltransferases.
    explanation: >-
      Next-generation sequencing of 117 patient-derived poorly differentiated
      and anaplastic thyroid cancers shows SWI/SNF subunit mutations are
      enriched in ATC relative to poorly differentiated thyroid cancer,
      establishing SWI/SNF inactivation as a recurrent ATC-associated genomic
      alteration.
  - reference: PMID:33318036
    reference_title: >-
      SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and
      Insensitivity to Redifferentiation Therapies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      thyroid-specific loss of Arid1a, Arid2, or Smarcb1 in mouse
      BRAFV600E-mutant tumors promotes disease progression and decreased
      survival, associated with lesion-specific effects on chromatin
      accessibility and differentiation.
    explanation: >-
      A genetically engineered mouse model demonstrates that loss of individual
      SWI/SNF subunits in BRAF-mutant thyroid tumors drives progression and
      impairs differentiation, supporting a causal role for SWI/SNF inactivation
      in ATC-like dedifferentiation.
  cell_types:
  - preferred_term: thyroid follicular cell
    term:
      id: CL:0002258
      label: thyroid follicular cell
  biological_processes:
  - preferred_term: chromatin remodeling
    modifier: DECREASED
    term:
      id: GO:0006338
      label: chromatin remodeling
  locations:
  - preferred_term: thyroid gland
    term:
      id: UBERON:0002046
      label: thyroid gland
  downstream:
  - target: Dedifferentiation and Loss of Thyroid Identity
    description: >-
      SWI/SNF loss closes chromatin at thyroid lineage transcription-factor
      target sites, impairing thyroid-differentiated gene expression and locking
      tumors in a radioiodine-refractory dedifferentiated state.
    evidence:
    - reference: PMID:33318036
      reference_title: >-
        SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and
        Insensitivity to Redifferentiation Therapies.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results show that SWI/SNF complexes are central to the maintenance
        of differentiated function in thyroid cancers, and their loss confers
        radioiodine refractoriness and resistance to MAPK inhibitor-based
        redifferentiation therapies.
      explanation: >-
        The study concludes that SWI/SNF complexes maintain thyroid
        differentiated function and that their loss confers radioiodine
        refractoriness, supporting the causal edge from SWI/SNF inactivation to
        loss of thyroid identity.
- name: Dedifferentiation and Loss of Thyroid Identity
  description: >-
    As follicular-cell-derived thyroid carcinoma dedifferentiates into ATC, it
    loses thyroid-specific transcriptional programs and iodide-handling
    functions. This transition is a major reason ATC is radioiodine refractory
    and clinically far more aggressive than differentiated thyroid cancer.
  evidence:
  - reference: PMID:41462994
    reference_title: >-
      Dedifferentiation and Redifferentiation of Follicular-Cell-Derived
      Thyroid Carcinoma: Mechanisms and Therapeutic Implications.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Follicular-cell-derived thyroid carcinoma, while typically associated
      with a favorable prognosis, can undergo dedifferentiation into poorly
      differentiated (PDTC) or anaplastic thyroid carcinoma (ATC), leading to
      enhanced aggressiveness and radioiodine resistance.
    explanation: >-
      Supports dedifferentiation into ATC as the mechanistic basis for
      aggressiveness and radioiodine refractoriness.
  - reference: PMID:41462994
    reference_title: >-
      Dedifferentiation and Redifferentiation of Follicular-Cell-Derived
      Thyroid Carcinoma: Mechanisms and Therapeutic Implications.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These alterations promote the loss of thyroid-specific functions,
      including iodide metabolism, and correlate with poor clinical outcomes.
    explanation: >-
      Directly supports loss of thyroid identity and impaired iodide handling in
      dedifferentiated disease.
  biological_processes:
  - preferred_term: cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030154
      label: cell differentiation
  downstream:
  - target: Epithelial-Mesenchymal Transition
    description: >-
      Dedifferentiation activates the epithelial-mesenchymal transition program
      as follicular-cell-derived tumors progress to ATC.
    evidence:
    - reference: PMID:31378850
      reference_title: >-
        Epithelial-to-mesenchymal transition in thyroid cancer: a comprehensive
        review.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Current understanding on the role of epithelial-mesenchymal transition
        (EMT) in thyroid carcinomas suggests that EMT is implicated in the
        progression from follicular thyroid cancer (FTC) and papillary thyroid
        cancer (PTC) to poorly differentiated thyroid carcinoma (PDTC) and
        anaplastic thyroid cancer (ATC).
      explanation: >-
        A comprehensive review links activation of the EMT program to the
        dedifferentiating progression of differentiated thyroid cancer to ATC.
  - target: Matrix Metalloproteinase Dysregulation and Invasion
    description: Dedifferentiated tumors acquire a more invasive and metastatic phenotype
    evidence:
    - reference: PMID:25887408
      reference_title: >-
        Genome-wide expression analysis suggests a crucial role of dysregulation
        of matrix metalloproteinases pathway in undifferentiated thyroid
        carcinoma.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        This pathway is drastically altered in ATC while in FTC and PTC, the
        most important pathways are related to DNA-repair activation or cell to
        cell signaling events.
      explanation: >-
        Genome-wide expression analysis shows the matrix metalloproteinase
        pathway is drastically altered specifically in undifferentiated ATC and
        not in differentiated FTC/PTC, linking dedifferentiation to MMP
        dysregulation and invasion.
- name: Epithelial-Mesenchymal Transition
  description: >-
    During progression to ATC, tumor cells activate an epithelial-mesenchymal
    transition (EMT) program: they lose the epithelial adhesion molecule
    E-cadherin and gain mesenchymal markers such as vimentin together with the
    EMT transcription factor ZEB1. This phenotypic switch underlies the
    migratory, invasive, and metastatic behavior that characterizes anaplastic
    thyroid carcinoma.
  evidence:
  - reference: PMID:32774477
    reference_title: >-
      MicroRNA 200b promotes mesenchymal-to-epithelial transition in anaplastic
      thyroid carcinoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In ATC tissues and cell lines, the mesenchymal marker ZEB1 was
      significantly upregulated and the epithelial marker E-cadherin was
      significantly downregulated. Additionally, the mesenchymal marker vimentin
      was significantly upregulated in ATC tissues and in one ATC cell line.
    explanation: >-
      Immunohistochemistry of human ATC tissues and expression analysis of ATC
      cell lines demonstrate loss of epithelial E-cadherin with gain of
      mesenchymal ZEB1 and vimentin, the molecular hallmark of EMT.
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    modifier: INCREASED
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  downstream:
  - target: Matrix Metalloproteinase Dysregulation and Invasion
    description: >-
      The EMT program confers a migratory, invasive phenotype that, together
      with matrix-remodeling proteases, drives local invasion and metastatic
      spread.
    evidence:
    - reference: PMID:31378850
      reference_title: >-
        Epithelial-to-mesenchymal transition in thyroid cancer: a comprehensive
        review.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        the initiation of the EMT program in thyroid epithelial cells elevates
        the number of stem cells, which contribute to recurrent and metastatic
        diseases.
      explanation: >-
        EMT initiation in thyroid epithelial cells is linked to recurrent and
        metastatic disease, supporting EMT as an upstream driver of the invasive
        and metastatic phenotype.
- name: Matrix Metalloproteinase Dysregulation and Invasion
  description: >-
    ATC exhibits marked dysregulation of matrix metalloproteinase-related
    programs, remodeling the extracellular environment to support migration,
    local tissue destruction, and distant spread.
  evidence:
  - reference: PMID:25887408
    reference_title: >-
      Genome-wide expression analysis suggests a crucial role of dysregulation
      of matrix metalloproteinases pathway in undifferentiated thyroid
      carcinoma.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Inhibition of matrix metalloproteinases pathway is a major event involved
      in thyroid cancer progression and its dysregulation may result crucial for
      invasiveness, migration and metastasis.
    explanation: >-
      Transcriptomic analysis supports dysregulated matrix metalloproteinase
      biology as a mechanism for ATC invasion and metastasis, although the
      abstract does not independently resolve the exact direction of that
      dysregulation.
  biological_processes:
  - preferred_term: positive regulation of cell migration
    modifier: INCREASED
    term:
      id: GO:0030335
      label: positive regulation of cell migration
  downstream:
  - target: Rapidly enlarging thyroid mass
    description: Aggressive tumor growth and local invasion present as a rapidly enlarging anterior thyroid or neck mass.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - explosive local tumor growth
    evidence:
    - reference: PMID:30844206
      reference_title: Anaplastic Thyroid Cancer.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Anaplastic thyroid cancer typically presents as a rapidly growing
        anterior neck mass and may have compressive symptoms early in the
        disease.
      explanation: >-
        The review directly connects aggressive ATC growth to the rapidly
        enlarging anterior neck mass phenotype.
  - target: Dysphagia
    description: Local invasion and compressive neck disease can impair swallowing.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - esophageal compression or invasion
    evidence:
    - reference: PMID:38179406
      reference_title: Update on current diagnosis and management of anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It is the most aggressive form of thyroid carcinoma, with a median
        survival of 5 mo and poor quality of life (airway obstruction,
        dysphagia, hoarseness, persistent pain).
      explanation: >-
        The review lists dysphagia among quality-of-life-limiting ATC
        manifestations caused by locally aggressive disease.
  - target: Dyspnea
    description: Pulmonary metastases or compressive neck disease can produce shortness of breath.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - pulmonary metastatic disease
    - airway compression
    evidence:
    - reference: PMID:22783225
      reference_title: Anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Systemic symptoms include anorexia, weight loss, and shortness of
        breath with pulmonary metastases.
      explanation: >-
        The review connects metastatic ATC progression to shortness of breath.
  - target: Stridor
    description: Critical upper-airway narrowing from local tumor invasion or compression can produce stridor.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - upper-airway compression
    evidence:
    - reference: PMID:22783225
      reference_title: Anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Locally, ATC shows a rapidly enlarging anterior neck mass, with
        accompanying dysphagia (40%), voice change or hoarseness (40%), and
        stridor (24%).
      explanation: >-
        The review lists stridor as a local manifestation of the rapidly
        enlarging ATC neck mass.
  - target: Hoarse voice
    description: Invasion or compression of laryngeal structures can cause hoarseness.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - laryngeal or recurrent laryngeal nerve involvement
    evidence:
    - reference: PMID:38179406
      reference_title: Update on current diagnosis and management of anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It is the most aggressive form of thyroid carcinoma, with a median
        survival of 5 mo and poor quality of life (airway obstruction,
        dysphagia, hoarseness, persistent pain).
      explanation: >-
        The review lists hoarseness among characteristic symptoms of locally
        aggressive ATC.
  - target: Cervical lymphadenopathy
    description: Invasive ATC frequently spreads to regional cervical lymph nodes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30844206
      reference_title: Anaplastic Thyroid Cancer.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        anaplastic thyroid cancer is highly locally invasive, with a propensity
        for early lymph node positivity and distant metastatic disease.
      explanation: >-
        The review directly supports early regional lymph-node involvement as a
        downstream manifestation of invasive ATC.
- name: Adaptive Immune Resistance and Immunosuppressive Microenvironment
  conforms_to: "immune_checkpoint_blockade#Adaptive Immune Resistance"
  description: >-
    ATC frequently upregulates tumor-cell PD-L1 within an immune-infiltrated
    microenvironment. The majority of ATCs are PD-L1-positive and contain
    abundant CD3+/CD8+ tumor-infiltrating lymphocytes and tumor-associated
    macrophages, indicating an "immune-adapted" tumor in which pre-existing
    anti-tumor immunity is actively suppressed through the PD-1/PD-L1 axis.
    PD-L1 positivity is enriched in BRAF V600E-mutant ATC and is considered
    predictive of response to anti-PD-1/PD-L1 therapy.
  cell_types:
  - preferred_term: CD8+ tumor-infiltrating lymphocyte
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: tumor-associated macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Negative Regulation of T Cell Mediated Immunity
    modifier: INCREASED
    term:
      id: GO:0002710
      label: negative regulation of T cell mediated immunity
  evidence:
  - reference: PMID:39004795
    reference_title: >-
      PD-L1 Expression and Its Modulating Factors in Anaplastic Thyroid
      Carcinoma: A Multi-institutional Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most ATCs (73.2%) were PD-L1-positive.
    explanation: >-
      A multi-institutional study of 179 ATCs establishes that the majority of
      ATCs express tumor-cell PD-L1, the central effector of adaptive immune
      resistance.
  - reference: PMID:39004795
    reference_title: >-
      PD-L1 Expression and Its Modulating Factors in Anaplastic Thyroid
      Carcinoma: A Multi-institutional Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tumor cell surface PD-L1 expression is considered predictive of
      therapeutic response.
    explanation: >-
      Links tumor-cell PD-L1 expression to predicted responsiveness to anti-PD
      checkpoint blockade, the therapeutic corollary of adaptive immune
      resistance.
  - reference: PMID:34093774
    reference_title: >-
      PD-L1 expression and immune cells in anaplastic carcinoma and poorly
      differentiated carcinoma of the human thyroid gland: A retrospective
      study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to increased PD-L1 expression, all ATC cases exhibited
      significantly increased CD3+ and CD8+ T cells, CD68+ and CD163+
      macrophages, and S100+ dendritic cells compared with the PDTC cases.
    explanation: >-
      Demonstrates that PD-L1 upregulation in ATC co-occurs with a brisk T cell
      and macrophage infiltrate, the hallmark "immune-adapted" state of adaptive
      immune resistance rather than an immune-desert tumor.
histopathology:
- name: Anaplastic Thyroid Carcinoma
  diagnostic: true
  finding_term:
    preferred_term: anaplastic thyroid carcinoma
    term:
      id: NCIT:C3878
      label: Thyroid Gland Anaplastic Carcinoma
  description: >-
    Undifferentiated thyroid carcinoma composed of pleomorphic epithelioid,
    spindle, and/or giant cells with highly aggressive morphology.
  evidence:
  - reference: PMID:25214840
    reference_title: >-
      Update on anaplastic thyroid carcinoma: morphological, molecular, and
      genetic features of the most aggressive thyroid cancer.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Anaplastic thyroid carcinoma (ATC) is the most aggressive form of
      thyroid cancer. It shows a wide spectrum of morphological
      presentations and the diagnosis could be challenging due to its high
      degree of dedifferentiation.
    explanation: >-
      Supports ATC as an undifferentiated aggressive thyroid carcinoma with
      a morphologically heterogeneous diagnostic appearance.
- name: Spindle Cell Pattern
  finding_term:
    preferred_term: spindle cell pattern
    term:
      id: NCIT:C53643
      label: Spindle Cell Pattern
  description: >-
    Sarcomatoid spindle-cell morphology is a common microscopic pattern in ATC.
  evidence:
  - reference: PMID:22783225
    reference_title: Anaplastic thyroid carcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The three different morphologic patterns identifiable at histologic
      analysis (squamoid, spindle cell, and giant cell) present similar
      biological and clinical features and none influences the prognosis
      (Hundahl et al., 1998).
    explanation: >-
      Directly identifies spindle-cell morphology as one of the recognized
      histologic patterns of anaplastic thyroid carcinoma.
phenotypes:
- category: Endocrine
  name: Rapidly enlarging thyroid mass
  diagnostic: true
  description: >-
    Patients frequently present with a rapidly enlarging fixed thyroid or neck
    mass reflecting explosive local growth.
  phenotype_term:
    preferred_term: thyroid carcinoma
    term:
      id: HP:0002890
      label: Thyroid carcinoma
  evidence:
  - reference: PMID:30844206
    reference_title: Anaplastic Thyroid Cancer.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Anaplastic thyroid cancer typically presents as a rapidly growing
      anterior neck mass and may have compressive symptoms early in the
      disease.
    explanation: >-
      Directly supports a rapidly enlarging anterior neck/thyroid mass as
      the typical clinical presentation of ATC.
- category: Gastrointestinal
  name: Dysphagia
  description: >-
    Esophageal compression or invasion commonly produces difficulty swallowing.
  phenotype_term:
    preferred_term: dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:38179406
    reference_title: Update on current diagnosis and management of anaplastic thyroid carcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is the most aggressive form of thyroid carcinoma, with a median
      survival of 5 mo and poor quality of life (airway obstruction,
      dysphagia, hoarseness, persistent pain).
    explanation: >-
      Directly lists dysphagia among the characteristic symptoms of
      anaplastic thyroid carcinoma.
- category: Respiratory
  name: Dyspnea
  description: >-
    Tracheal compression, airway narrowing, or pulmonary metastatic disease may
    cause shortness of breath.
  phenotype_term:
    preferred_term: dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:22783225
    reference_title: Anaplastic thyroid carcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Systemic symptoms include anorexia, weight loss, and shortness of
      breath with pulmonary metastases.
    explanation: >-
      Directly lists shortness of breath as a systemic symptom of ATC with
      pulmonary metastatic disease.
- category: Respiratory
  name: Stridor
  description: >-
    Critical upper-airway narrowing can produce inspiratory stridor and mandate
    urgent airway intervention.
  phenotype_term:
    preferred_term: stridor
    term:
      id: HP:0010307
      label: Stridor
  evidence:
  - reference: PMID:22783225
    reference_title: Anaplastic thyroid carcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Locally, ATC shows a rapidly enlarging anterior neck mass, with
      accompanying dysphagia (40%), voice change or hoarseness (40%), and
      stridor (24%).
    explanation: >-
      Directly lists stridor among local symptoms accompanying ATC neck
      masses.
- category: Head and Neck
  name: Hoarse voice
  description: >-
    Recurrent laryngeal nerve involvement or laryngeal invasion often causes
    dysphonia.
  phenotype_term:
    preferred_term: hoarse voice
    term:
      id: HP:0001609
      label: Hoarse voice
  evidence:
  - reference: PMID:38179406
    reference_title: Update on current diagnosis and management of anaplastic thyroid carcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is the most aggressive form of thyroid carcinoma, with a median
      survival of 5 mo and poor quality of life (airway obstruction,
      dysphagia, hoarseness, persistent pain).
    explanation: >-
      Directly lists hoarseness as a characteristic quality-of-life impairing
      symptom of ATC, reflecting laryngeal involvement.
- category: Systemic
  name: Cervical lymphadenopathy
  description: >-
    Regional nodal involvement is common in locoregionally advanced disease.
  phenotype_term:
    preferred_term: lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:30844206
    reference_title: Anaplastic Thyroid Cancer.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      anaplastic thyroid cancer is highly locally invasive, with a propensity
      for early lymph node positivity and distant metastatic disease.
    explanation: >-
      Directly supports early cervical/regional lymph node involvement as
      a characteristic pattern in ATC.
biochemical:
- name: Comprehensive genomic profiling
  notes: >-
    Broad molecular testing is essential in unresectable or metastatic ATC to
    identify BRAF V600E and rarer actionable fusions or biomarkers that may
    expand systemic treatment options.
  evidence:
  - reference: PMID:38044137
    reference_title: >-
      The frequency of mutations in advanced thyroid cancer in Japan: a
      single-center study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, 58.8% of ATC, 93.8% of PTC, and 42.9% of PDTC had genetic
      alterations linked to therapeutic agents. Active gene panel testing is
      required to increase treatment options.
    explanation: >-
      Supports routine genomic profiling in advanced ATC because actionable
      alterations are common enough to change treatment selection.
- name: Radioiodine avidity
  notes: >-
    ATC is typically radioiodine refractory because dedifferentiation impairs
    thyroid-specific iodide handling rather than preserving differentiated
    thyroid-cell function.
  evidence:
  - reference: PMID:41462994
    reference_title: >-
      Dedifferentiation and Redifferentiation of Follicular-Cell-Derived
      Thyroid Carcinoma: Mechanisms and Therapeutic Implications.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These alterations promote the loss of thyroid-specific functions,
      including iodide metabolism, and correlate with poor clinical
      outcomes.
    explanation: >-
      Supports loss of iodide handling (i.e. loss of radioiodine avidity)
      as a functional consequence of ATC dedifferentiation.
genetic:
- name: BRAF
  association: Somatic activating mutation
  notes: >-
    BRAF V600E is a common initiating or retained driver in ATC and creates a
    directly targetable MAPK dependency.
  evidence:
  - reference: PMID:38044137
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    reference_title: >-
      The frequency of mutations in advanced thyroid cancer in Japan: a
      single-center study.
    snippet: Of ATC cases, 52.9% had BRAF mutations, and 5.9% had RET fusion.
    explanation: >-
      Supports frequent BRAF alteration in advanced ATC and its therapeutic
      relevance.
- name: TP53
  association: Somatic loss-of-function alteration
  notes: >-
    TP53 disruption is a hallmark late progression event associated with
    dedifferentiation and aggressive biology in ATC.
  evidence:
  - reference: PMID:38044137
    reference_title: >-
      The frequency of mutations in advanced thyroid cancer in Japan: a
      single-center study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ATC cases had a significantly higher prevalence of TP53 alterations than
      the other cases (82.3% vs. 11.8%)
    explanation: >-
      Supports TP53 alteration as a characteristic high-frequency event in ATC.
- name: TERT
  association: Somatic promoter mutation
  notes: >-
    TERT promoter mutations are common late events that cooperate with driver
    mutations to sustain immortalization and progression.
  evidence:
  - reference: PMID:38044137
    reference_title: >-
      The frequency of mutations in advanced thyroid cancer in Japan: a
      single-center study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whereas the frequencies of TERT promoter mutations were 88.2% in ATC cases and
      64.7% in the other cases, albeit without a significant difference.
    explanation: >-
      Supports the high prevalence of TERT promoter mutations in ATC.
- name: RET
  association: Rare somatic gene fusion
  notes: >-
    RET fusions are uncommon in ATC but can identify a therapeutically relevant
    molecular subset when present.
  evidence:
  - reference: PMID:38044137
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    reference_title: >-
      The frequency of mutations in advanced thyroid cancer in Japan: a
      single-center study.
    snippet: Of ATC cases, 52.9% had BRAF mutations, and 5.9% had RET fusion.
    explanation: >-
      Supports RET fusion as an uncommon but actionable genomic alteration in ATC.
treatments:
- name: Surgery and Airway Stabilization
  description: >-
    Selected localized tumors may undergo aggressive resection, but airway
    preservation or tracheostomy is often the more urgent intervention because
    many patients present with compressive neck disease.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:38179406
    reference_title: Update on current diagnosis and management of anaplastic thyroid carcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recent management policy is based on surgery, even debulking,
      chemotherapy (cisplatin or doxorubicin), radiotherapy (adjuvant or
      definitive), targeted biological agents and immunotherapy.
    explanation: >-
      Supports surgery (including debulking resection) as a core component
      of current ATC management alongside radiotherapy and systemic therapy.
- name: External Beam Radiation Therapy
  description: >-
    External beam radiation is used for locoregional control, palliation of
    compressive symptoms, and as part of multimodality treatment when feasible.
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: MAXO:0000014
      label: radiation therapy
  evidence:
  - reference: PMID:38179406
    reference_title: Update on current diagnosis and management of anaplastic thyroid carcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recent management policy is based on surgery, even debulking,
      chemotherapy (cisplatin or doxorubicin), radiotherapy (adjuvant or
      definitive), targeted biological agents and immunotherapy.
    explanation: >-
      Directly supports adjuvant or definitive radiotherapy as a component
      of current ATC management strategy.
- name: Dabrafenib Plus Trametinib
  description: >-
    Combined BRAF and MEK inhibition provides substantial clinical benefit in
    BRAF V600E-mutant ATC and is a core systemic option for molecularly selected
    patients.
  evidence:
  - reference: PMID:35026411
    reference_title: >-
      Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic
      thyroid cancer: updated analysis from the phase II ROAR basket study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to
      72.1%), including three complete responses; the 12-month DOR rate was
      50%.
    explanation: >-
      The updated ROAR ATC cohort showed meaningful response and durability with
      dabrafenib plus trametinib in BRAF V600E-mutant disease.
  - reference: PMID:35026411
    reference_title: >-
      Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic
      thyroid cancer: updated analysis from the phase II ROAR basket study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These updated results confirm the substantial clinical benefit and
      manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant
      ATC.
    explanation: >-
      Directly supports dabrafenib plus trametinib as a clinically useful
      targeted treatment in ATC.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: dabrafenib
      term:
        id: CHEBI:75045
        label: dabrafenib
    - preferred_term: trametinib
      term:
        id: CHEBI:75998
        label: trametinib
  target_mechanisms:
  - target: MAPK-Activating Truncal Driver Alteration
    treatment_effect: INHIBITS
    description: >-
      Combined BRAF and MEK inhibition suppresses the MAPK-dependent oncogenic
      program that persists in BRAF V600E-mutant ATC.
    evidence:
    - reference: PMID:40396891
      reference_title: >-
        NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO
        TREATMENTS: Molecular insights into the origin, biology, and treatment
        of anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Indeed, genotype-guided targeting of the MAPK pathway is now the
        standard of care for subgroups of ATC patients
      explanation: >-
        Review supports genotype-guided MAPK inhibition as standard treatment
        strategy for molecularly defined ATC subsets.
- name: Lenvatinib Plus Pembrolizumab
  description: >-
    Combination of the multikinase inhibitor lenvatinib with the anti-PD-1
    immune checkpoint inhibitor pembrolizumab is an emerging systemic option for
    anaplastic and poorly differentiated thyroid carcinoma. It exploits the high
    tumor mutational burden and elevated PD-L1 expression characteristic of these
    dedifferentiated tumors, with the most durable responses seen in tumors with
    increased TMB or a high PD-L1 tumor proportion score.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: lenvatinib
      term:
        id: CHEBI:85994
        label: lenvatinib
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
  evidence:
  - reference: PMID:33509020
    reference_title: >-
      Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment
      Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These tumor properties implicate responsiveness to antiangiogenic and
      antiproliferative multikinase inhibitors such as lenvatinib, and immune
      checkpoint inhibitors such as pembrolizumab.
    explanation: >-
      The biological rationale links ATC's high tumor mutational burden and
      elevated PD-L1 to responsiveness to combined lenvatinib and pembrolizumab.
  - reference: PMID:33509020
    reference_title: >-
      Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment
      Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results implicate that the combination of lenvatinib and pembrolizumab
      might be safe and effective in patients with ATC/PDTC and can result in
      complete and long-term remissions.
    explanation: >-
      The retrospective ATC/PDTC series reported complete and durable remissions,
      supporting the combination as an effective systemic treatment option.
  target_mechanisms:
  - target: Adaptive Immune Resistance and Immunosuppressive Microenvironment
    treatment_effect: INHIBITS
    description: >-
      Pembrolizumab blocks PD-1/PD-L1 engagement, reversing the adaptive immune
      resistance program that shields PD-L1-high ATC cells from cytotoxic T cell
      killing, while lenvatinib provides concurrent antiangiogenic pressure.
    evidence:
    - reference: PMID:35347921
      reference_title: >-
        Advances in targeted therapy for anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The immune checkpoint inhibitor pembrolizumab can be applied to treat
        thyroid cancer with high tumor mutational load and may be considered as
        the preferred modality for the treatment of ATC patients with high
        programmed death ligand-1 expression.
      explanation: >-
        Review supports pembrolizumab targeting the PD-L1-driven immune
        resistance program, with greatest benefit in PD-L1-high ATC.
clinical_trials:
- name: NCT02034110
  phase: PHASE_II
  status: COMPLETED
  description: >-
    ROAR basket study of dabrafenib plus trametinib in BRAF V600E-mutant rare
    cancers, including the anaplastic thyroid carcinoma cohort whose updated
    analysis (PMID:35026411) anchors the targeted-therapy treatment block in
    this entry.
  target_phenotypes:
  - preferred_term: thyroid carcinoma
    term:
      id: HP:0002890
      label: Thyroid carcinoma
  evidence:
  - reference: clinicaltrials:NCT02034110
    reference_title: >-
      A Phase II, Open-label, Study in Subjects With BRAF V600E-Mutated Rare
      Cancers With Several Histologies to Investigate the Clinical Efficacy and
      Safety of the Combination Therapy of Dabrafenib and Trametinib
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This was a Phase II, open-label, non-randomized, multi-center study of
      oral dabrafenib in combination with oral trametinib in subjects with rare
      cancers harboring the BRAF V600E mutation including anaplastic thyroid
      cancer (ATC)
    explanation: >-
      Directly establishes the ROAR study design and the inclusion of an
      anaplastic thyroid carcinoma cohort treated with combined BRAF/MEK
      inhibition, the trial whose ATC cohort underpins the current
      genotype-guided systemic therapy standard.
- name: NCT04171622
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Phase II trial of the multikinase inhibitor lenvatinib combined with the
    anti-PD-1 antibody pembrolizumab in stage IVB locally advanced/unresectable
    or stage IVC metastatic anaplastic thyroid cancer. It prospectively tests
    the lenvatinib-plus-pembrolizumab combination that is curated as a treatment
    in this entry, exploiting ATC's high tumor mutational burden and PD-L1
    expression.
  target_phenotypes:
  - preferred_term: thyroid carcinoma
    term:
      id: HP:0002890
      label: Thyroid carcinoma
  evidence:
  - reference: clinicaltrials:NCT04171622
    reference_title: >-
      Lenvatinib in Combination With Pembrolizumab for Stage IVB Locally
      Advanced and Unresectable or Stage IVC Metastatic Anaplastic Thyroid
      Cancer
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This phase II trial studies how well lenvatinib and pembrolizumab work in
      treating patients with anaplastic thyroid cancer that is stage IVB and has
      spread to nearby tissue or lymph nodes (locally advanced) and cannot be
      removed by surgery (unresectable), or stage IVC that has spread to other
      places in the body (metastatic).
    explanation: >-
      Registers a prospective phase II evaluation of the lenvatinib plus
      pembrolizumab combination in advanced/metastatic ATC, complementing the
      Lenvatinib Plus Pembrolizumab treatment block whose supporting evidence is
      currently a retrospective series.
disease_term:
  preferred_term: anaplastic thyroid carcinoma
  term:
    id: MONDO:0006468
    label: thyroid gland undifferentiated (anaplastic) carcinoma
notes: >-
  ATC is usually diagnosed at an advanced stage and behaves very differently
  from differentiated thyroid cancer because it is rapidly invasive,
  radioiodine refractory, and often lethal without prompt local and systemic
  management. Molecular profiling should be obtained early in unresectable or
  metastatic disease to identify BRAF V600E and other actionable alterations.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0006468
      label: thyroid gland undifferentiated (anaplastic) carcinoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO provides an exact disease term for anaplastic thyroid carcinoma.
  ncit_mappings:
  - term:
      id: NCIT:C3878
      label: Thyroid Gland Anaplastic Carcinoma
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: NCIT provides an exact neoplasm term for anaplastic thyroid carcinoma; cross-referenced from MONDO:0006468.
classifications:
  icdo_morphology:
    classification_value: Carcinoma
    evidence:
    - reference: PMID:25214840
      reference_title: >-
        Update on anaplastic thyroid carcinoma: morphological, molecular, and
        genetic features of the most aggressive thyroid cancer.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Anaplastic thyroid carcinoma (ATC) is the most aggressive form of
        thyroid cancer.
      explanation: >-
        ATC is an undifferentiated carcinoma arising from thyroid follicular
        epithelium, placing it in the carcinoma ICD-O morphology category.
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:22783225
      reference_title: Anaplastic thyroid carcinoma.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Anaplastic Thyroid Carcinoma (ATC) is estimated to comprise 1-2% of
        thyroid malignancies and it accounts for 14-39% of thyroid cancer
        deaths.
      explanation: >-
        ATC is a lethal thyroid malignancy, placing it within the oncology and
        hematology chapter of Harrison's Principles of Internal Medicine.

📚

References & Deep Research

Deep Research

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Anaplastic Thyroid Carcinoma. Core disease mechanisms, molecular and cellu...

Asta Scientific Corpus Retrieval 17 citations 2026-04-11T22:12:46.857072

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Anaplastic Thyroid Carcinoma. Core disease mechanisms, molecular and cellu...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 17
Snippets retrieved: 20

Relevant Papers

[1] Insights in biomarkers complexity and routine clinical practice for the diagnosis of thyroid nodules and cancer

Authors: M. G. de Matos, Mafalda Pinto, A. Gonçalves, Sule Canberk, M. J. Bugalho et al.
Year: 2025
Venue: PeerJ
URL: https://www.semanticscholar.org/paper/655de68f1a7e8137dcba8a2046f14dee4f07594d
DOI: 10.7717/peerj.18801
PMID: 39850836
PMCID: 11756370
Citations: 4
Summary: The knowledge of genetic and molecular biomarkers has achieved a high level of complexity, and the difficulties related to its applicability determine that their implementation in clinical practice is not yet a reality.
Evidence snippets:
Snippet 1 (score: 0.613) > Knowledge of molecular mechanisms implicated in thyroid carcinogenesis has been attained in recent years. Thyroid neoplasm result from alterations in gene expression patterns, which occur due to a gradual accumulation of genetic and epigenetic events. These changes are associated with specific tumor phenotypes and are implicated in disease etiology. Molecular alterations induce the activation of different signaling pathways, such as the mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K/AKT/mTOR), which are involved in and promote carcinogenesis (Hsiao & Nikiforov, 2014). In a few years, the knowledge of molecular mechanisms implicated in thyroid carcinogenesis changed from understanding signaling pathways and identification of a few genes mutations to the knowledge of the main genes implicated in thyroid carcinogenesis, reviewed by De Leo et al. (2024). Genetic changes in thyroid neoplasms were divided in early/driver molecular alterations and late/progression events. Late/ progression events may be associated with early/driver molecular alterations and represent the evolution from well-differentiated to high-grade and undifferentiated carcinoma, being (Pozdeyev et al., 2018). Most frequent gene mutations present in follicular-cell derived thyroid tumors are BRAF, RAS, and TERTp mutations, associate with clinically relevant clinicopathologic features, as shown in Table 3.

[2] Molecular Pathology of Poorly Differentiated and Anaplastic Thyroid Cancer: What Do Pathologists Need to Know?

Authors: M. Volante, Alfred K. Lam, M. Papotti, G. Tallini
Year: 2021
Venue: Endocrine Pathology
URL: https://www.semanticscholar.org/paper/813bc7af19d86eddb462f29d8f38ab51c3ec47e6
DOI: 10.1007/s12022-021-09665-2
PMID: 33543394
PMCID: 7960587
Citations: 73
Influential citations: 6
Summary: The combination of genomic and epigenetic data shows that several molecular alterations affect druggable cellular pathways in poorly differentiated and anaplastic thyroid carcinomas, although the clinical impact of molecular typing of these tumors in terms of predictive biomarker testing is still under exploration.
Evidence snippets:
Snippet 1 (score: 0.580) > The molecular characterization of poorly and anaplastic thyroid carcinomas has been greatly improved in the last years following the advent of high throughput technologies. However, with special reference to genomic data, the prevalence of reported alterations is partly affected by classification criteria. The impact of molecular pathology in these tumors is multifaceted and bears diagnostic, prognostic, and predictive implications although its use in the clinical practice is not completely assessed. Genomic profiling data claim that genetic alterations in poorly differentiated and anaplastic thyroid carcinomas include “Early” and “Late” molecular events, which are consistent with a multi-step model of progression. “Early” driver events are mostly RAS and BRAF mutations, whereas “Late” changes include above all TP53 and TERT promoter mutations, as well as dysregulation of gene involved in the cell cycle, chromatin remodeling, histone modifications, and DNA mismatch repair. Gene fusions are rare but represent relevant therapeutic targets. Epigenetic modifications are also playing a relevant role in poorly differentiated and anaplastic thyroid carcinomas, with altered regulation of either genes by methylation/deacetylation or non-coding RNAs. The biological effects of epigenetic modifications are not fully elucidated but interfere with a wide spectrum of cellular functions. From a clinical standpoint, the combination of genomic and epigenetic data shows that several molecular alterations affect druggable cellular pathways in poorly differentiated and anaplastic thyroid carcinomas, although the clinical impact of molecular typing of these tumors in terms of predictive biomarker testing is still under exploration.
Snippet 2 (score: 0.560) > The genomic map of poorly differentiated and anaplastic thyroid carcinomas is not fully explaining the pathogenesis of these tumor types, their biological and clinical properties, or their pathways of progression. Although the prevalence of specific gene alterations increases proportionally to the loss of differentiation and aggressiveness, most gene alterations are shared by well differentiated and poorly differentiated/ anaplastic carcinomas; thus, they probably represent initiating events in the oncogenic process. In this context, epigenetic regulatory mechanisms possibly represent major complementary players in the progression to both poorly differentiated and anaplastic thyroid carcinoma (Fig. 2). The impact of epigenetic mechanisms is also claimed by the few data on gene expression signatures available. In fact, well-differentiated thyroid carcinomas mostly display gene expression features consistent with two major signatures, BRAF-and RAS-like. However, in aggressive carcinomasin particular anaplastic carcinoma-transcriptomic profiles seem to be distinctive of the tumor types per se, irrespective of the genotype [24]. Moreover, genomic data and transcriptomic profiling show that epigenetic mechanisms are involved in aggressive types of thyroid cancer. In fact, histone methyltransferase genes (KMT2A, KMT2C, KMT2D, and SETD2) are increasingly impaired in poorly differentiated and anaplastic thyroid carcinomas [15]. Nevertheless, the increased expression of histone methyltransferase genes that is associated with the pattern of dedifferentiation observed in poorly differentiated and anaplastic thyroid carcinomas needs to be further investigated. Similar trends hold true for genes belonging to the SWI/SNF complex, a chromatin remodeling complex which is active in nucleosome-remodeling.

[3] Genome-wide expression analysis suggests a crucial role of dysregulation of matrix metalloproteinases pathway in undifferentiated thyroid carcinoma

Authors: J. Espinal-Enríquez, S. Muñoz-Montero, Ivan Imaz-Rosshandler, Aldo Huerta-Verde, Carmen Mejía et al.
Year: 2015
Venue: BMC Genomics
URL: https://www.semanticscholar.org/paper/aaf44d01ab95964e2cee2acee8339ddf6bd039c7
DOI: 10.1186/s12864-015-1372-0
Summary: The genome-wide analysis of thyroid carcinoma subtypes emphasizes the preponderance of pathway-dysregulation mechanisms over simple gene-malfunction as the main mechanism involved in the development of a cancer phenotype.
Evidence snippets:
Snippet 1 (score: 0.547) > Thyroid cancer (TC) is the most common malignant cancer of the Endocrine System. Histologically, there are three main subtypes of TC: follicular, papillary and anaplastic. Diagnosing a thyroid tumor subtype with a high level of accuracy and confidence is still a difficult task because genetic, molecular and cellular mechanisms underlying the transition from differentiated to undifferentiated thyroid tumors are not well understood. A genome-wide analysis of these three subtypes of thyroid carcinoma was carried out in order to identify significant differences in expression levels as well as enriched pathways for non-shared molecular and cellular features between subtypes. Inhibition of matrix metalloproteinases pathway is a major event involved in thyroid cancer progression and its dysregulation may result crucial for invasiveness, migration and metastasis. This pathway is drastically altered in ATC while in FTC and PTC, the most important pathways are related to DNA-repair activation or cell to cell signaling events. A progression from FTC to PTC and then to ATC was detected and validated on two independent datasets. Moreover, PTX3, COLEC12 and PDGFRA genes were found as possible candidates for biomarkers of ATC while GPR110 could be tested to distinguish PTC over other tumor subtypes. The genome-wide analysis emphasizes the preponderance of pathway-dysregulation mechanisms over simple gene-malfunction as the main mechanism involved in the development of a cancer phenotype.

[4] Association of CYP2D6*4 gene polymorphism with early papillary thyroid carcinoma

Authors: Aynur Dağlar Aday, T. Öztürk, Başak Akadam Teker, F. Aksoy, H. Aydogan et al.
Year: 2021
Venue: Turkish Journal of Biochemistry
URL: https://www.semanticscholar.org/paper/db3c0cf5196ebfc63ae9fafe575afc3ad519f7c0
DOI: 10.1515/tjb-2020-0103
Citations: 2
Summary: The findings indicate that the poor metabolizer CYP2D6*4 genotype may be a risk factor, especially in early PTC development.
Evidence snippets:
Snippet 1 (score: 0.544) > Although thyroid carcinomas constitute only 1% of all malignancies in humans; they are responsible for more than 90% of all endocrine cancers [1]. The majority of thyroid cancers are epithelial tumors that arise from thyroid follicular cells. They are mainly classified into three subtypes: papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC) and anaplastic thyroid carcinoma (ATC). Differently, medullary thyroid carcinoma (MTC) derives from thyroid parafollicular (C) cells [2]. > PTC, the commonest type of endocrine malignancy, is a differentiated cancer and its incidence has risen a lot in recent decades [3]. PTC is classified into three major variants. Those are classic (CVPTC), follicular (FVPTC) and tall cell variants (TCVPTC). The genetic alterations of the signaling proteins in the mitogen-activated protein kinase (MAPK) pathway, including RET, ALK, RAS and BRAF are closely related with PTC [4]. Many additional tests used together with thyroid specimens have focused on biomarkers in this signaling pathway [5]. Although more advanced molecular tests are convenient, BRAF mutation is the most crucial biomarker for the diagnosis of PTC [6]. The molecular mechanisms that participate in PTC tumorigenesis and progression are not fully understood. Thus, elucidation of the underlying molecular mechanisms will be useful for the advancement of new diagnosis and treatment strategies for PTC. > Cytochrome P450s (CYPs) are mostly located in the liver and metabolize xenobiotics to non-toxic or carcinogenic metabolites [7]. CYP2D6 (debrisoquine hydroxylase) is a member of CYP family and the CYP2D6 gene takes place on chromosome 22q13.1 [8]. CYP2D6, takes part in the metabolism of drugs and bioactivation of several procarcinogens and neurotoxins [9].

[5] Genome-wide expression analysis suggests a crucial role of dysregulation of matrix metalloproteinases pathway in undifferentiated thyroid carcinoma

Authors: J. Espinal-Enríquez, S. Muñoz-Montero, Ivan Imaz-Rosshandler, Aldo Huerta-Verde, Carmen Mejía et al.
Year: 2015
Venue: BMC Genomics
URL: https://www.semanticscholar.org/paper/1fb1a61c2fe43d4da715198684f601bccee5a2b6
DOI: 10.1186/s12864-015-1372-0
PMID: 25887408
PMCID: 4377021
Citations: 37
Influential citations: 2
Summary: A progression from FTC to PTC and then to ATC was detected and validated on two independent datasets and the preponderance of pathway-dysregulation mechanisms over simple gene-malfunction as the main mechanism involved in the development of a cancer phenotype was emphasized.
Evidence snippets:
Snippet 1 (score: 0.543) > BackgroundThyroid cancer (TC) is the most common malignant cancer of the Endocrine System. Histologically, there are three main subtypes of TC: follicular, papillary and anaplastic. Diagnosing a thyroid tumor subtype with a high level of accuracy and confidence is still a difficult task because genetic, molecular and cellular mechanisms underlying the transition from differentiated to undifferentiated thyroid tumors are not well understood.A genome-wide analysis of these three subtypes of thyroid carcinoma was carried out in order to identify significant differences in expression levels as well as enriched pathways for non-shared molecular and cellular features between subtypes.ResultsInhibition of matrix metalloproteinases pathway is a major event involved in thyroid cancer progression and its dysregulation may result crucial for invasiveness, migration and metastasis. This pathway is drastically altered in ATC while in FTC and PTC, the most important pathways are related to DNA-repair activation or cell to cell signaling events.ConclusionA progression from FTC to PTC and then to ATC was detected and validated on two independent datasets. Moreover, PTX3, COLEC12 and PDGFRA genes were found as possible candidates for biomarkers of ATC while GPR110 could be tested to distinguish PTC over other tumor subtypes. The genome-wide analysis emphasizes the preponderance of pathway-dysregulation mechanisms over simple gene-malfunction as the main mechanism involved in the development of a cancer phenotype.
Snippet 2 (score: 0.532) > Diagnosing the subtype of thyroid carcinoma with a high level of accuracy and confidence is still a difficult task. A better understanding of the genetic, molecular and cellular mechanisms underlying the transition from differentiated to undifferentiated thyroid tumor, as well as their progression is necessary to develop more specific and non-invasive treatments depending on the subtype of carcinoma. This is the rationale behind the present study. Here, by means of a Systems Biology approach, a genome-wide analysis of 11 anaplastic (ATC), 12 follicular (FTC) and 72 papillary thyroid carcinomas (PTC) samples, as well as 64 normal thyroid samples was carried out to understand the genetic and biochemical differences and similarities among them. Through pathway analysis, deregulation of genes involved in the inhibition of matrix metalloproteinases pathway has been pointed out as crucial for invasiveness, migration and metastasis. > The genetic analysis performed also suggests a progression from FTC to PTC and then to ATC, since a significant change in the expression level of some genes involved in determined pathways can be observed, mainly related to arrest of cell cycle, apoptosis, cell to cell signaling and mitosis. Furthermore, we established a possible crosstalk in cell-death-and-survival events that could be involved in the transition from PTC to ATC. Finally, a series of 4 genes that could be useful to determine the cancer subtype was set up. PTX3, COLEC12 and PDGFRA proved to differentiate anaplastic thyroid carcinomas from other subtype while GPR110 seems suitable to become a biomarker for papillary thyroid carcinomas. This analysis can be applied to other carcinogenic ailments as an alternative tool to discriminate among different tumor subtypes.

[6] Integrative bioinformatic analysis identifies differentially expressed gene targets as potential biomarkers for anaplastic thyroid cancer

Authors: A. S. Treviño-Juarez, J. González‐González, René Rodríguez-Gutiérrez, Adriana Sánchez-García, Camilo Gonzalez-Velazquez
Year: 2025
Venue: Journal of the Egyptian National Cancer Institute
URL: https://www.semanticscholar.org/paper/dd93d0dda16e8f80628b5c9b7db1c23c89790e73
DOI: 10.1186/s43046-025-00282-2
PMID: 40350533
Citations: 2
Summary: An integrative bioinformatic analysis of microarray datasets from the GEO database shed light on key genes and pathways that may contribute to ATC pathogenesis and provide a foundation for identifying potential diagnostic biomarkers and therapeutic targets.
Evidence snippets:
Snippet 1 (score: 0.540) > Anaplastic thyroid carcinoma (ATC) is among the most lethal thyroid malignancies, with poor clinical outcomes and limited treatment strategies. To gain insights into the molecular mechanisms involved in its progression, we performed an integrative bioinformatic analysis. We analyzed five microarray datasets from the GEO database to compare gene expression profiles between ATC samples and normal thyroid tissues. Differentially expressed genes (DEGs) were identified using GEO2R, and overlapping genes across datasets were detected through Venn diagram analysis. Functional enrichment was performed using DAVID and Metascape. A protein–protein interaction (PPI) network was constructed with STRING, and significant gene modules were identified using the MCODE plugin in Cytoscape. Co-expression analysis was further explored with GeneMANIA. We identified 7532 DEGs, of which 3509 were upregulated and 4023 were downregulated. Upregulated genes were mainly involved in cell division and mitotic control, while downregulated genes were related to thyroid hormone production and gland development. Six hub genes stood out for their centrality in the network: TPX2, MAD2L1, CDC20, CDKN3, CENPF, and NEK2. Our findings shed light on key genes and pathways that may contribute to ATC pathogenesis. These results provide a foundation for identifying potential diagnostic biomarkers and therapeutic targets for this aggressive cancer.

[7] Differential expression profiles of immunoregulatory genes in anaplastic thyroid carcinomas with a coexistent papillary carcinoma component

Authors: G. Orlando, F. Napoli, Vanessa Zambelli, F. Maletta, Giulia Capella et al.
Year: 2025
Venue: Virchows Archiv
URL: https://www.semanticscholar.org/paper/6bc9a36d7e5faf3f4f74deaa1e35244f93105e90
DOI: 10.1007/s00428-025-04262-8
PMID: 40965626
PMCID: 12546323
Citations: 2
Summary: ATC displays high levels of expression of immunoregulatory genes as compared to PDTC, and a subset of genes and miRNAs is significantly de-regulated along progression from PTC to ATC, suggesting their potential role as biomarkers and involvement in key functional mechanisms.
Evidence snippets:
Snippet 1 (score: 0.527) > Thyroid carcinoma is the most common endocrine neoplasm, in which thyroid follicular cells transform through a multistep process, resulting in several histological types, from well-differentiated thyroid carcinoma (WDTC) (including papillary (PTC) and follicular thyroid carcinomas (FTC)) to high-grade follicular cell-derived non-anaplastic thyroid carcinoma (including poorly differentiated carcinoma (PDTC) and high-grade differentiated thyroid carcinoma) and to anaplastic thyroid carcinoma (ATC). PDTCs and ATCs are rarer than WDTCs, but clinically more aggressive, with a short median survival time (5 years and 6 months, respectively) [1,2]. In the past 40 years, several studies have recognized a well-differentiated component in a significant number of PDTC and ATC cases, suggesting the existence of evolutionary pathways of progression from well-differentiated to poorly differentiated or undifferentiated forms. In particular, a PTC component represents the most commonly observed histotype in association with ATC [3][4][5][6]. At the molecular level, a progressive increase of tumor mutational burden exists from WDTC to PDTC and ATC [7][8][9]. BRAF V600E and other molecular drivers, such as RAS mutations or RET and NTRK rearrangements, are typically associated with PTCs. The same alterations can be observed in PDTCs and ATCs with similar prevalence rates [8]. Moreover, in highgrade carcinomas, additional mutations occur (including TERT-promoter and TP53 mutations) that have been proposed to play a major role in tumor progression [10,11]. A study by Ragazzi et al. highlighted that coexistent PTC and ATC components are characterized by common early driver (BRAF, PIK3CA, RAS) and late (TERT-promoter) mutations, whereas TP53 mutations occur almost exclusively in the ATC component [12]. These findings suggest that non-genomic mechanisms may concur in tumor progression-related mechanisms in thyroid cancer.

[8] Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice

Authors: E. Tirrò, F. Martorana, Chiara Romano, S. Vitale, G. Motta et al.
Year: 2019
Venue: Genes
URL: https://www.semanticscholar.org/paper/d1ff1d9e8131c2446837add86af2de83c66ef8f6
DOI: 10.3390/genes10090709
PMID: 31540307
PMCID: 6771012
Citations: 87
Influential citations: 6
Summary: The genomic alterations and biological processes intertwined with thyroid cancer development are described, also providing a thorough overview of targeted drugs already tested or under investigation for these tumors.
Evidence snippets:
Snippet 1 (score: 0.521) > As thyroid cancer progresses, the accumulation of molecular alterations disrupting multiple normal cell functions results in RAIR development, due to impaired NIS expression [23][24][25].Indeed, dysregulation of different receptor-tyrosine kinase (RTK)-dependent signaling and proliferation pathways-such as the mitogen-activated protein kinase (MAPK), the phosphoinositide 3 kinase (PI3K), the Wingless/Integrated (WNT), the p53 and p73 pathways-are involved in the multistep tumorigenic process of thyroid cancer [25][26][27] (Figure 1).Alterations of these cascades can be linked to different mechanisms, including genetic and epigenetic modifications in pathway receptors and effectors [28,29].Moreover, distinct, mutually exclusive molecular alterations may be associated with specific disease stages or histotypes [30]. > Figure 1.Genetic events involved in thyroid carcinogenesis.Papillary thyroid carcinomas (PTC), follicular thyroid carcinomas (FTC) and anaplastic thyroid carcinomas (ATC) originate from thyroid follicular cells and are characterized by molecular alterations (mutations, deletions, gene fusions) involving genes and proteins impinging upon different cellular pathways.The transition from PTC/FTC to poorly differentiated (PDTCs) and ATCs is attributed to additional molecular alterations.Medullary thyroid carcinoma (MTC) originates from para-follicular C-cells and is prevalently characterized by RET or RAS mutations. > In order to better classify the molecular alterations detected in thyroid cancer, we will initially discuss RTK-related upstream signaling pathways involved in tumorigenesis and subsequently focus on the effectors of these pathways.Finally, we will describe alterations contributing to thyroid carcinogenesis that involve pivotal cellular functions.In order to better classify the molecular alterations detected in thyroid cancer, we will initially discuss RTK-related upstream signaling pathways involved in tumorigenesis and subsequently focus on the effectors of these pathways.Finally, we will describe alterations contributing to thyroid carcinogenesis that involve pivotal cellular functions.

[9] Mitochondrial Energy Metabolism and Thyroid Cancers

Authors: Junguee Lee, J. Chang, Y. Kang, Shinae Yi, Min Hee Lee et al.
Year: 2015
Venue: Endocrinology and Metabolism
URL: https://www.semanticscholar.org/paper/6bfd3564ef53692deb69392dd200c1fcb1f2dd6c
DOI: 10.3803/EnM.2015.30.2.117
PMID: 26194071
PMCID: 4508255
Citations: 19
Summary: Determining the molecular nature of metabolic remodeling in thyroid cancer may provide new biomarkers and therapeutic targets that may be useful in the management of refractory thyroid cancers.
Evidence snippets:
Snippet 1 (score: 0.519) > Primary thyroid cancers including papillary, follicular, poorly differentiated, and anaplastic carcinomas show substantial differences in biological and clinical behaviors. Even in the same pathological type, there is wide variability in the clinical course of disease progression. The molecular carcinogenesis of thyroid cancer has advanced tremendously in the last decade. However, specific inhibition of oncogenic pathways did not provide a significant survival benefit in advanced progressive thyroid cancer that is resistant to radioactive iodine therapy. Accumulating evidence clearly shows that cellular energy metabolism, which is controlled by oncogenes and other tumor-related factors, is a critical factor determining the clinical phenotypes of cancer. However, the role and nature of energy metabolism in thyroid cancer remain unclear. In this article, we discuss the role of cellular energy metabolism, particularly mitochondrial energy metabolism, in thyroid cancer. Determining the molecular nature of metabolic remodeling in thyroid cancer may provide new biomarkers and therapeutic targets that may be useful in the management of refractory thyroid cancers.
Snippet 2 (score: 0.497) > Energy metabolism in most cancer cells differs markedly from that in normal cells to meet the energy needs during tumor progression. Currently, thyroid cancer originating from follicular epithelial cells is classified based on pathological features. The four major types of primary thyroid cancers-papillary, follicular, poorly differentiated, and anaplastic carcinomasshow substantial differences in biological and clinical behaviors. Even among the same pathological types, there is wide variability in the clinical course of disease progression. It is clear that cellular energy metabolism, which is controlled by oncogenes and other tumor-related factors, is a critical factor in determining the clinical phenotypes of cancer. The molecular carcinogenesis of thyroid cancer has advanced tremendously in the last decade [1][2][3][4][5][6]. However, the role and nature of energy metabolism in thyroid cancer remain unclear. > Mitochondria provide 90% of the cellular energy required for various biological functions through oxidative phosphorylation (OxPhos) in the inner mitochondrial membrane [7]. In addition, mitochondria regulate cellular metabolism, including steroid hormone and porphyrin synthesis, the urea cycle, lipid metabolism, and interconversion of amino acids [8]. They also play central roles in apoptosis, cell proliferation, and cellular > Copyright © 2015 Korean Endocrine Society Ca 2+ homeostasis, which affect numerous other cell signaling pathways [8,9]. Thus, mitochondria play an important role in energy metabolism in the normal thyroid gland as well as in thyroid tumors. The roles of functional and structural alterations in mitochondria in tumorigenesis and tumor progression in the thyroid gland need to be explored. This review article focuses on current knowledge of mitochondrial metabolism and its exploitation by thyroid cancer. We give an overview of metabolic changes, mitochondrial alterations, and the significance of mitochondria in slow-growing and fast-growing thyroid cancers.

[10] A biomarker and molecular mechanism investigation for thyroid cancer

Authors: Keju Xie
Year: 2023
Venue: Central-European Journal of Immunology
URL: https://www.semanticscholar.org/paper/c40af7dda04166c392af29999aa75cbe4d0a7c5b
DOI: 10.5114/ceji.2023.132163
PMID: 37901864
PMCID: 10604643
Citations: 4
Summary: The correlation analysis showed that prognostic genes such as CD44 were positively correlated with immune cells such as M1 macrophages and the lysine degradation pathway and cell cycle pathway might take part in the progression of THCA.
Evidence snippets:
Snippet 1 (score: 0.511) > Thyroid cancer (THCA) is the most common endocrine neoplasm, accounting for approximately 1.7% of all cancer diagnoses [1]. This cancer is classified into several histological types, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC) [2]. Treatments including radioactive iodine and thyroidectomy are classic methods for clinical therapy of THCA and thyroid disease [3,4]. However, in many cases, the benefits of these classic methods are inconclusive due to the poor prognosis and complications [5]. Thus, it is urgently necessary to reveal novel diagnostic strategies for the clinical treatment of THCA. > Differentially expressed genes (DEGs) are a group of genes that exhibit significant changes in expression levels between different conditions, such as normal and diseased tissues. Identifying DEGs in thyroid cancer can provide valuable insights into the molecular mechanisms of its development, progression, and response to therapy [6]. > It has been proved that genes such as LGALS3 and CD44 were differentially expressed between normal and THCA samples, which can be used as novel biomarkers for the diagnosis and gene therapy of THCA [7,8]. Bergström et al. reported that the aberrant activation of epidermal growth factors may lead to overexpression and activation of DEGs such as MET, which further contributed to the development of THCA [9]. A previous study showed that immune cells, including macrophages, promote tumor progression through several mechanisms such as cell growth and interact with various genes including COL1A1 [10,11]. Therefore, a further study of the molecular mechanism during THCA progression is vital for the investigation of novel prognostic markers and treatment strategies. > The Cancer Genome Atlas (TCGA) is a comprehensive resource that provides genomic, transcriptomic, and clinical data for various types of human cancer, including thyroid cancer [12].

[11] Bioinformatics analysis of key genes and latent pathway interactions based on the anaplastic thyroid carcinoma gene expression profile

Authors: Yun Huang, Yiming Tao, Xinying Li, Shi Chang, B. Jiang et al.
Year: 2016
Venue: Oncology Letters
URL: https://www.semanticscholar.org/paper/6ac1fba890a3b0dc857bf0a38842da99dd7b1009
DOI: 10.3892/ol.2016.5447
PMID: 28428828
PMCID: 5396846
Citations: 31
Influential citations: 3
Summary: The data obtained in the present study revealed that the TLR signaling pathway, ECM-receptor interaction and cytokine-cytokine receptor interaction pathway, and the FOS, CXCL10, COL5A1, COL11A1 and CCL28 genes have different roles in the progression of ATC, and these may be used as therapeutic targets for ATC.
Evidence snippets:
Snippet 1 (score: 0.510) > Thyroid cancer is one of the most common types of malignancy of the endocrine system (1). Anaplastic thyroid carcinoma (ATC), one of the four types of thyroid carcinoma, is an uncommon but aggressive malignancy in older adults, with a morbidity rate of 1.0-7.5%, however, it accounts for 14-39% of thyroid carcinoma-associated mortality and the mean survival duration of ATC is usually <6 months from diagnosis (2). Although certain novel treatment methods, including surgery, genetic therapy and differentiation therapy, provide possibilities for the treatment of ATC (3), there is no effective systemic therapy for ATC. Therefore, it is important to examine the molecular mechanisms of ATC and identify several treatment methods for patients with a diagnosis of ATC. > The etiology of ATC remains to be fully elucidated. Previous studies have demonstrated that ionizing radiation, abnormal iodine intake, genetic factors and autoimmune disease are the primary factors contributing to the progression of ATC (4). Passaro et al (5) reported that ionizing radiation enhances the cell death of oncolytic adenovirus dl922-947 in ATC. Increased iodine intake contributes to a lower incidence of ATC (6), and it has been reported that forkhead box o3a enhances the proliferation of ATC cells via regulating the transcription factor, cyclin A1 (7). In addition, several pathways involved in the progression of ATC have been identified, including the Notch1 signaling pathway, phosphoinositide 3-kinase/Akt signaling pathway and the epidermal growth factor receptor/extracellular signal-regulated kinase pathway (8)(9)(10). > With developments in biology, several studies have focussed on to the mechanism of ATC. Consequently, several biomarkers have been identified for its treatment. For example, paired-box gene 8 may be a useful biomarker for ATC (11). In a study by Kim et al (12) L1 cell adhesion molecule was found to be overexpressed in patients with ATC and it may be an important therapeutic target for ATC treatment.

[12] Molecular profiling of thyroid cancer subtypes using large-scale text mining

Authors: Chengkun Wu, J. Schwartz, G. Brabant, G. Nenadic
Year: 2014
Venue: BMC Medical Genomics
URL: https://www.semanticscholar.org/paper/c20f2ddf075d6857b59a4872ff1b4230f02ce91c
DOI: 10.1186/1755-8794-7-S3-S3
PMID: 25521965
PMCID: 4290788
Citations: 14
Influential citations: 1
Summary: A large-scale text mining system is developed to generate a molecular profiling of thyroid cancer subtypes and successfully unveiled important genes and pathways, including some instances that are missing from current manually annotated databases or most recent review articles.
Evidence snippets:
Snippet 1 (score: 0.506) > Thyroid cancer (TC) is the most common endocrine malignancy [1] and its incidence increase has been significant in recent years despite some controversies about the extent [2]. Many possible factors causing thyroid cancer have been reported including exposure to ionising radiation, iodine-deficiency and heredity [3]. Conventional treatment strategies include surgical resection, radiation therapy (especially radioactive iodine therapy), chemotherapy and thyroid hormone therapy [4]. However, the understanding of the underlying molecular mechanisms is still incomplete. > Thyroid tumours are usually classified into multiple subtypes according to their histopathological characteristics, and treatments are selected depending on the subtype and stage of thyroid cancer. The main subtypes include papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), anaplastic thyroid cancer (ATC) and medullary thyroid cancer (MTC) [4]. PTC and FTC are also sometimes collectively referred to as differentiated thyroid cancer (DTC) or well-differentiated thyroid cancer (WDTC), while ATC can also be referred to as undifferentiated thyroid cancer. In addition, a number of rare subtypes have been described. Cellular origins and some of the known molecular mechanisms differ for each subtype [5], which may include subtype-specific alterations in DNA methylation patterns [3] and have led to new therapeutic approaches based on the molecular signature of the tumours. > These "targeted therapeutics" of thyroid cancer are being rapidly developed [6,7]. Several potential drugs are currently in preclinical testing or in clinical use [8,9]. However, lack of systematic studies of underlying molecular mechanisms can lead to a high risk for thyroid cancer patients, who might suffer from unexpected side effects. For instance, RET has been shown to be an oncogene in thyroid cancer but is considered as a potential tumour suppressor gene in colorectal cancer [10]. Consequently, studies focusing on one or a few genes are likely to miss the molecular context that could be vital for a comprehensive understanding of the disease. > For systematic studies, a major challenge is to efficiently utilise the myriad of knowledge and information from unstructured scientific literature.

[13] Effects of Dihydrotanshinone I on Proliferation and Invasiveness of Paclitaxel-Resistant Anaplastic Thyroid Cancer Cells

Authors: L. Allegri, Francesca Capriglione, V. Maggisano, G. Damante, F. Baldan
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/0770cdb4cefc030cef946857477221e0b9ac2bf8
DOI: 10.3390/ijms22158083
PMID: 34360846
PMCID: 8347033
Citations: 8
Summary: The results of the present study are the first to demonstrate the antitumor effects of DHT on ATC cells resistant to Paclitaxel in vitro.
Evidence snippets:
Snippet 1 (score: 0.501) > Thyroid cancer (TC) is the most common endocrine carcinoma, accounting for 1-2% of cancer cases worldwide [1].Most thyroid carcinomas derive from follicular cells and are classified according to their differentiation levels in differentiated thyroid cancer, including papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) and in poorly differentiated thyroid cancer or anaplastic thyroid cancer (ATC) [1].While PTC and FTC, which account for more than 95% of tumors, are mostly responsive to the current treatment based on surgery and following radioiodine therapy, resulting in an overall survival rate of over 90% within 10 years, ATCs are a very rare, but extremely aggressive form of thyroid malignancy.They are mostly diagnosed as stage IV disease [1], often are not resectable, and do not respond to radioactive iodine ablation for their undifferentiated phenotype due to the loss of thyroid-specific gene expression [2].For these reasons and considering its extremely fast-growing and aggressive nature, ATC, although representing less than 2% of all thyroid malignancies, is responsible for 20-50% of thyroid cancer mortality [3]. > The current management of ATC has strongly been conditioned by the advent of the molecular testing of thyroid tumors which permits to target the known genetic mutations [4] with the new molecular drugs, mainly inhibitors of tyrosine kinases [5,6].However, for the tumors resistant to these new drugs and those without known detectable genetic aberrations, the current treatment is still represented by palliative surgery and systemic chemotherapy, the latter consisting in taxane monotherapy or combined with carboplatin or anthracyclines [7].Unfortunately, even the combined drug treatments easily induce drug resistance and, in the absence of further reliable therapy, patients with ATCs are destined to shortly die due to unlimited local growth and distal metastases dissemination [6,7].Comprehension of the mechanisms involved in the development of drug resistance has become therefore urgent for improving the prognosis of this very aggressive malignancy.

[14] In silico Analysis of Publicly Available Transcriptomics Data Identifies Putative Prognostic and Therapeutic Molecular Targets for Papillary Thyroid Carcinoma

Authors: A. Almansoori, P. Bhamidimarri, R. Bendardaf, R. Hamoudi
Year: 2022
Venue: International Journal of General Medicine
URL: https://www.semanticscholar.org/paper/6de2046cc1bb187ea53cf5ceef550ba1a4e2b969
DOI: 10.2147/IJGM.S345336
PMID: 35330879
PMCID: 8939872
Citations: 4
Summary: Background Thyroid cancer is the most common endocrine malignancy. However, the molecular mechanism involved in its pathogenesis is not well characterized. Purpose The objective of this study is to identify key cellular pathways and differentially expressed genes along the thyroid cancer pathogenesis sequence as well as to identify potential prognostic and therapeutic targets. Methods Publicly available transcriptomics data comprising a total of 95 samples consisting of 41 normal, 28 non-aggr...
Evidence snippets:
Snippet 1 (score: 0.499) > Thyroid cancer was ranked as the most common endocrine malignancy. 1 Globally, thyroid cancer incidence has been on the rise over the past three decades. Between 2006 and 2012, the annual incidence rate was 6.5% in women and 5.4 in men. 2,3 In the United States between 2000 and 2009, thyroid cancer incidence rate was the highest among all cancers. 4 The mortality rate of thyroid cancer is considered to be low, whilst the reoccurrence and persistence of the disease is still considered high. 5 Morphologically, thyroid cancers are classified into different cellular subtypes such as papillary, follicular, medullary and anaplastic. Differentiated papillary thyroid carcinoma (PTC) form is the most common type comprising more than 80% of all thyroid cases as shown in Table 1. Genetic mutations have been associated with PTC. 6 Whilst many genomic mutational screening studies were carried out on thyroid cancer in general and PTC in particular, only few have identified mutated genes that are correlated with progression of PTC including TP53 and KRAS/BRAF 7 . However, although such studies suggested that thyroid cancer has high degree of intra-tumoral heterogeneity, 8 the mutations identified did not provide clear insights into the molecular mechanism of thyroid cancer phenotypes and progression. Thus, for better clinical outcomes, there is a compelling need to actively study alterations in cellular pathways linked to the underlying mechanism of thyroid cancer initiation and progression. > Few transcriptomic analyses were carried out on PTC identifying some of the cellular pathways involved in its pathogenesis 9 . However, such studies were generally carried out on small number of patients using standard bioinformatics analysis focusing on list of differentially expressed genes. This provided limited insights into the molecular basis of PTC without clear association to diagnostic, prognostic and therapeutic targets. > In this study, we carried out comprehensive and systematic in silico pathway analysis of PTC using in-house bioinformatics pipeline that has shown good ability to identify the transcriptomic profiles and related differentially expressed genes between different subtypes of the same disease. 10 The aim of this study is to attempt to identify the key transcriptomic signatures that drive non-aggressive and metastatic PTC as well as using such signature to identify putative drug targets

[15] Discovery of New Anti-Cancer Agents against Patient-Derived Sorafenib-Resistant Papillary Thyroid Cancer

Authors: Yu-Jeong Kim, H. Yun, Kyung Hwa Choi, Chan Wung Kim, Jae Ha Lee et al.
Year: 2023
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/90d16effbb857882878c124e2eb9917568f08b4b
DOI: 10.3390/ijms242216413
PMID: 38003602
PMCID: 10671409
Citations: 6
Summary: This study aimed to detect novel thyroid cancer target candidates based on validating and identifying one of many anti-cancer drug-resistant targets in patient-derived sorafenib-resistant papillary thyroid cancer cells, and discovered novel SERCA inhibitors by virtual screening.
Evidence snippets:
Snippet 1 (score: 0.498) > Thyroid cancer (TC) is a well-known disease wherein malignant cancer cells form in the thyroid gland on the base of the neck. It is customarily categorized into four cancer subtypes: papillary (PTC), follicular (FTC), medullary (MTC), and anaplastic (ATC) [1][2][3][4]. The categorization of TC provides a basis for the histological type of thyroid cells. Dedifferentiated thyroid cancer (DeTC) and differentiated thyroid cancer (DTC) arise from follicular cells. Differentiated thyroid cancer is sub-classified into PTC, FTC, and Hürtle cell carcinoma (HCC). In particular, TC is categorized into well-differentiated and un-differentiated classes in relation to clinical disclosure based on conventional classification [5,6]. Well-differentiated thyroid cancer (WDTC) usually indicates a good prognosis that is curable, whereas poorly differentiated thyroid cancer (PDTC) and involved undifferentiated thyroid cancer (UTC) have an infrequent and aggressive prognosis [7,8]. Anti-cancer drug-resistant TC is a PDTC that leads to patient death through recurrence or metastasis [9][10][11]. Clinical behavior based on the molecular and biological mechanisms of anti-cancer drug-sensitive cancer and drug-resistant cancer is distinct [12,13]. Many researchers have focused on making a difference by analyzing the span of mutations between anti-cancer drug-sensitive cancer and drug-resistant cancer [14][15][16][17][18][19][20]. However, the mechanism of the molecular distinctions to fully determine the anti-cancer drug-resistantmediated poor prognosis in patients with PTC is undetermined. Characteristics of these refractory PTC continuously gained anti-cancer drug resistance; therefore, there is a requirement for effective and novel clinical approaches [21][22][23]. Sarco/endoplasmic reticulum calcium ATPase (SERCA) is a key regulator of cytosolic free calcium.

[16] Network-Based Genetic Profiling Reveals Cellular Pathway Differences Between Follicular Thyroid Carcinoma and Follicular Thyroid Adenoma

Authors: Md. Ali Hossain, T. Asa, Md. Mijanur Rahman, S. Uddin, A. Moustafa et al.
Year: 2020
Venue: International Journal of Environmental Research and Public Health
URL: https://www.semanticscholar.org/paper/fa6f4474cdd887107f7db9d5897cc55cda3346da
DOI: 10.3390/ijerph17041373
PMID: 32093341
PMCID: 7068514
Citations: 21
Summary: Network-based integrative analyses of FTC and benign follicular thyroid adenoma lesion transcriptomes are employed to identify key genes and pathways that differ between them, and these differences may reflect malignant progression potential and include useful candidate biomarkers for FTC and identifying factors important for FTC pathogenesis.
Evidence snippets:
Snippet 1 (score: 0.495) > Thyroid cancers are the most common type of endocrine malignancy, although they have a relatively low mortality rate compared to most other common metastatic diseases. The United States had 56,460 new diagnoses of thyroid cancer and 1780 related deaths reported in 2012 [1]. The incidence of thyroid cancers is also rising globally at about 5% per year, although some of this increase may be due to improved detection, and it notably affects those in the 20 to 34 year age range [2]. Thyroid cancers include several major types, such as papillary thyroid carcinomas, medullary thyroid carcinoma, anaplastic thyroid carcinoma, and follicular thyroid carcinomas (FTCs) [3]; FTC is one of the more aggressive types, although it accounts for a minority (14%) of total thyroid cancers [4][5][6]. > The causes and cellular processes underlying FTC and controlling these tumours' behaviours are poorly understood; accordingly, these cancers have few effective treatment options [7]. There is therefore a great need to understand the mechanisms that drive development and progression in FTC to identify new approaches to detection, estimate the risk of progression, and find new therapies. In addition, differential diagnosis of FTC is problematic as it can be difficult to distinguish from follicular thyroid adenoma (FTA), a benign and non-invasive lesion. Accordingly, there is more focus on molecular markers that distinguish FTC and FTA (and other types of thyroid lesions). Thus, Wojtas et al. conducted a gene expression comparison of FTC and FTA lesions which identified potential markers that can distinguish FTC from FTA with a sensitivity and specificity of 78% and 80%, respectively [8]. We aim to also use this dataset to identify pathways with different levels of activity in benign and aggressive thyroid tumours (here, FTA and FTC) that may reflect important molecular mechanisms that underlie their behaviour. > For such pathway studies, our starting point is the differential expression of genes (DEGs) between these lesions.

[17] Network medicine approaches for identification of novel prognostic systems biomarkers and drug candidates for papillary thyroid carcinoma

Authors: Medi Kori, Kubra Temiz, E. Gov
Year: 2023
Venue: Journal of Cellular and Molecular Medicine
URL: https://www.semanticscholar.org/paper/94a4aeba681311c594a691c2cd4845397410a4c9
DOI: 10.1111/jcmm.18002
PMID: 37859510
PMCID: 10746936
Citations: 7
Summary: The need for differential co‐expression analysis to gain a systems‐level understanding of a complex disease is highlighted, and a candidate prognostic systems biomarker and novel drugs for PTC are provided.
Evidence snippets:
Snippet 1 (score: 0.495) > Recent cancer statistics show that thyroid cancer is the most common endocrine cancer encountered by mankind. In 2022, it was estimated that 43,800 patients were diagnosed with thyroid cancer, and thyroid cancer was responsible for 2230 deaths in the United States. 1 Papillary, follicular, medullary, and undifferentiated or anaplastic thyroid carcinomas are the major histologic groups of thyroid tumours. Among the various subgroups of thyroid cancer, papillary thyroid carcinoma (PTC) accounts for the largest proportion of all thyroid carcinomas. Notably, the prevalence of PTC is approximately 85% when all thyroid carcinomas are considered. 2 e aetiology of thyroid cancer is not well understood. Therefore, further studies are needed to uncover the underlying mechanisms of the disease, correct over-diagnosis, and find prognostic and/or drug candidates to reduce the prevalence of PTC. > Logarithmic advances in high-throughput sequencing and screening methods in recent decades have produced a substantial amount of X-ome data at various molecular levels, enabling researchers to perform various bioinformatics approaches for different diseases 3,4 and also for PTC. 5 However, some of these studies take only limited account of the reality of the molecular biochemistry of the organism. To discover specific disease biomarkers or drug targets, it is essential to evaluate the entire physical and functional architecture of the organism, because the development of an abnormal phenotype (i.e. disease) is not the result of a single gene, but rather the result of complex gene interactions. One scientific field, network medicine, allows researchers to uncover these complex interactions between biomolecules of a given phenotype in a holistic view. 6 ne and protein networks provide valuable data for molecular interactions within the organism, and co-expression networks represent significantly co-regulated groups of genes (i.e. modules). Any differentiation in gene correlations between different phenotypes can provide clues to the phenotype and supports the discovery of systems biomarkers. 7 To reveal co-expression relationships among genes in thyroid cancer, weighted gene co-expression network analysis (WGCNA) has been performed in a limited number of studies. 8,9 WGCNA identifies gene modules by hierarchical clustering.

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[1] Insights in biomarkers complexity and routine clinical practice for the diagnosis of thyroid nodules and cancer

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[7] Differential expression profiles of immunoregulatory genes in anaplastic thyroid carcinomas with a coexistent papillary carcinoma component

[8] Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice

[9] Mitochondrial Energy Metabolism and Thyroid Cancers

[10] A biomarker and molecular mechanism investigation for thyroid cancer

[11] Bioinformatics analysis of key genes and latent pathway interactions based on the anaplastic thyroid carcinoma gene expression profile

[12] Molecular profiling of thyroid cancer subtypes using large-scale text mining

[13] Effects of Dihydrotanshinone I on Proliferation and Invasiveness of Paclitaxel-Resistant Anaplastic Thyroid Cancer Cells

[14] In silico Analysis of Publicly Available Transcriptomics Data Identifies Putative Prognostic and Therapeutic Molecular Targets for Papillary Thyroid Carcinoma

[15] Discovery of New Anti-Cancer Agents against Patient-Derived Sorafenib-Resistant Papillary Thyroid Cancer

[16] Network-Based Genetic Profiling Reveals Cellular Pathway Differences Between Follicular Thyroid Carcinoma and Follicular Thyroid Adenoma

[17] Network medicine approaches for identification of novel prognostic systems biomarkers and drug candidates for papillary thyroid carcinoma

Notes