Anaplastic Thyroid Carcinoma

MONDO:0006468 Pathograph 8 thyroid carcinoma

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.

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2
Mappings
0
Definitions
0
Inheritance
7
Pathophysiology
2
Histopathology
6
Phenotypes
8
Pathograph
4
Genes
3
Treatments
0
Subtypes
0
Differentials
0
Datasets
1
Trials
0
Models
1
Deep Research
🏷

Classifications

Harrison's Chapter
cancer solid tumor
ICD-O Morphology
Carcinoma
🔗

Mappings

MONDO
MONDO:0006468 thyroid gland undifferentiated (anaplastic) carcinoma
skos:exactMatch MONDO
MONDO provides an exact disease term for anaplastic thyroid carcinoma.
NCIT
NCIT:C3878 Thyroid Gland Anaplastic Carcinoma
skos:exactMatch NCIT
NCIT provides an exact neoplasm term for anaplastic thyroid carcinoma; cross-referenced from MONDO:0006468.
NCIT
NCIT:C3878 Thyroid Gland Anaplastic Carcinoma
skos:exactMatch NCIT
NCIT provides an exact neoplasm term for anaplastic thyroid carcinoma; cross-referenced from MONDO:0006468.
⚙

Pathophysiology

7
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 link
MAPK cascade link ↑ INCREASED
thyroid gland link
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 link ↓ 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 link ↑ 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 link ↑ 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.
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 link ↓ DECREASED
Downstream
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.
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 link ↑ INCREASED
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 link tumor-associated macrophage link
Negative Regulation of T Cell Mediated Immunity link ↑ 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

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Anaplastic Thyroid Carcinoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

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.
💊

Treatments

3
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 ↗ trametinib ↗
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.
🔬

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

1
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 ↗
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.
{ }

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
  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
  - target: TERT Reactivation and Telomere Maintenance
    description: TERT promoter mutation supports immortalization during tumor progression
  - target: PI3K-AKT Survival Signaling
    description: PI3K pathway activation adds a parallel survival and growth program
  - target: Dedifferentiation and Loss of Thyroid Identity
    description: MAPK-driven tumor evolution culminates in loss of differentiated thyroid functions
  - 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
- 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
- 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
- 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
- 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: Matrix Metalloproteinase Dysregulation and Invasion
    description: Dedifferentiated tumors acquire a more 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
- 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.
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
    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.
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
  harrisons_chapter:
  - classification_value: cancer
  - classification_value: solid tumor
📚

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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