🔗

Mappings

MONDO

MONDO:0000548 ovarian clear cell cancer

Primary MONDO disease identifier for the mechanism-level OCCC entry.

MONDO:0006045 ovarian clear cell adenocarcinoma Not Yet Curated

The curated disease unit is the OCCC mechanism graph as a whole; MONDO:0006045 is a tighter adenocarcinoma morphology neighbor represented directly in histopathology with NCIT:C40078 rather than as a separate dismech disease page.

⚙

Pathophysiology

8

Endometriosis-Associated Precursor Lesion

OCCC frequently develops in endometriotic cysts, and the transition field is marked by molecularly altered endometriotic epithelium contiguous with carcinoma. This precursor context supports modeling OCCC as an endometriosis-associated ovarian epithelial malignancy rather than as a de novo ovarian surface tumor.

glandular endometrial unciliated epithelial cell link

ovary link

Show evidence (1 reference)

PMID:22976498 SUPPORT Human Clinical

"All of the 31 informative cases showed loss of ARID1A immunoreactivity in the carcinoma and in the endometriotic cyst epithelium in direct continuity with the carcinoma but not in the cyst epithelium that was not adjacent to the tumor."

Human pathology data place the molecularly altered precursor field inside endometriotic cyst epithelium contiguous with OCCC.

ARID1A Tumor Suppressor Loss

ARID1A loss is a recurrent early driver event in OCCC and disrupts SWI/SNF-mediated chromatin remodeling in precursor and invasive tumor cells. This event is common in human tumors and is already detectable in endometriotic cyst epithelium adjacent to carcinoma, supporting a foundational role in tumor initiation.

epithelial cell link

chromatin remodeling link ⚠ ABNORMAL

Show evidence (2 references)

PMID:22976498 SUPPORT Human Clinical

"Loss of ARID1A function as shown by loss of expression, presumably due to mutations, is an early molecular event in the development of most ovarian clear cell and endometrioid carcinomas arising in endometriomas."

Supports ARID1A loss as an initiating human disease event in endometriosis-related OCCC development.

PMID:39543535 SUPPORT Human Clinical

"On analyzing 102 OCCC samples, ARID1A (67%) and PIK3CA (49%) emerged as the most frequently mutated driver genes."

Confirms ARID1A as the dominant recurrent human driver mutation in OCCC.

PI3K Pathway Activation

PI3K pathway activation, most often through PIK3CA mutation, cooperates with ARID1A loss to enable tumor formation and growth. In OCCC models, PI3K activation is not merely correlative but required for the ARID1A-deficient state to progress to invasive carcinoma.

epithelial cell link

phosphatidylinositol 3-kinase/protein kinase B signal transduction link ↑ INCREASED

Show evidence (2 references)

PMID:25625625 SUPPORT Model Organism

"We find that ARID1A inactivation is not sufficient for tumour formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA."

Mouse modeling demonstrates that PI3K activation is functionally required to cooperate with ARID1A loss in OCCC tumorigenesis.

PMID:39543535 SUPPORT Human Clinical

"Reconstruction of clonal evolution revealed that early genetic events likely driving tumorigenesis included mutations in the ARID1A, PIK3CA, TERT, KRAS, and TP53 genes."

Human clonal reconstruction supports PIK3CA mutation as an early genetic event in OCCC evolution.

IL-6 Inflammatory Signaling

ARID1A and PIK3CA cooperation converges on sustained IL-6 signaling, linking chromatin remodeling defects and PI3K pathway activation to a pro-tumorigenic inflammatory state. In human disease, elevated IL-6 is strongest in advanced OCCC and is associated with thrombotic risk and worse progression outcomes.

interleukin-6-mediated signaling pathway link ↑ INCREASED

Show evidence (2 references)

PMID:25625625 SUPPORT Model Organism

"Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signalling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumour growth through sustained IL-6 overproduction."

Functional modeling shows IL-6 is a mechanistic convergence point downstream of ARID1A loss and PI3K activation.

PMID:26238017 SUPPORT Human Clinical

"Patients with advanced OCCC had the highest 2-year cumulative VTE rates (advanced OCCC 43.1%, advanced SOC 16.2%, early-stage OCCC 11.9% and early-stage SOC 6.4%, P<0.0001) and the highest median levels of IL-6 (advanced OCCC 17.8 pg/mL, advanced SOC 9.0 pg/mL, early-stage OCCC 4.2 pg/mL and..."

Clinical data connect elevated IL-6 with the advanced, high-thrombosis OCCC phenotype.

HNF1B-Driven Glycolytic Reprogramming

HNF1B is a lineage-defining OCCC regulator that rewires tumor metabolism toward aerobic glycolysis. This supports cell survival under hypoxic and treatment stress and helps explain why OCCC maintains a distinct metabolic phenotype compared with other ovarian cancer histologies.

epithelial cell link

glycolytic process link ↑ INCREASED

Show evidence (1 reference)

PMID:26318292 SUPPORT In Vitro

"HNF1β drastically alters intracellular metabolism, especially in direction to enhance aerobic glycolysis, so called the "Warburg effect"."

Cell-line metabolomic data support HNF1B-driven glycolytic rewiring as a core OCCC mechanism.

Glutathione-Dependent Oxidative Stress Buffering

OCCC cells use HNF1B-linked antioxidant metabolism to buffer oxidative stress through increased glutathione availability and reduced ROS activity. This stress-adapted state supports survival in the endometriotic cyst microenvironment and contributes to intrinsic platinum resistance.

glutathione metabolic process link ↑ INCREASED response to oxidative stress link ⚠ ABNORMAL

Show evidence (1 reference)

PMID:26318292 SUPPORT In Vitro

"Augmented cell survival was based on the reduced ROS activity derived from metabolic alteration such as shift from oxidative phosphorylation to glycolysis and increased intracellular anti-oxidant, glutathione (GSH)."

Supports glutathione-linked oxidative stress buffering as a survival mechanism in HNF1B-positive OCCC.

Intrinsic Carboplatin Resistance

Unlike high-grade serous ovarian carcinoma, OCCC is often intrinsically resistant to platinum therapy. HNF1B-driven glutathione synthesis and related detoxification programs directly contribute to carboplatin resistance and are consistent with the poor outcomes seen in advanced-stage disease.

Show evidence (3 references)

PMID:26520442 SUPPORT In Vitro

"ovarian clear cell carcinoma (OCCC) is intrinsically resistant."

Establishes that intrinsic platinum resistance is a defining feature of OCCC rather than solely an acquired treatment phenotype.

PMID:26520442 SUPPORT In Vitro

"ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin."

Directly links glutathione metabolism to carboplatin resistance in OCCC cells.

PMID:26404183 SUPPORT Human Clinical

"Women with advanced OCCC have poor survival and are often chemotherapy resistant/refractory."

Human outcomes data show that the resistant phenotype is clinically important in advanced OCCC.

OCCC-Associated Hypercoagulability

OCCC carries a disproportionate risk of venous thromboembolism, especially in advanced-stage disease. This hypercoagulable phenotype tracks with IL-6 elevation and is associated with worse recurrence-free and overall survival, making thrombosis part of the disease biology rather than a purely incidental complication.

blood coagulation link ↑ INCREASED

Show evidence (3 references)

PMID:24041880 SUPPORT Human Clinical

"Among 74 patients with OCCC, VTE was diagnosed in 11 (15%) during primary treatment and 7 (9%) at time of cancer recurrence."

Supports the clinically important thrombotic phenotype in OCCC.

PMID:24041880 SUPPORT Human Clinical

"This increased risk is not attributable to VTE-related mortality and raises the possibility that a paracrine circuit involving thrombosis might contribute to a more aggressive tumor biology."

Suggests thrombosis is biologically linked to aggressive OCCC rather than being only a treatment complication.

PMID:37104696 SUPPORT Human Clinical

"The pooled prevalence of VTE among OCCC patients was 21.32% (95%CI=(17.38-25.87))."

Meta-analysis supports VTE as a frequent clinical phenotype in OCCC.

✶

Histopathology

1

Ovarian Clear Cell Adenocarcinoma Morphology VERY_FREQUENT

OCCC shows clear-cell adenocarcinoma morphology with papillary, tubulocystic, and solid architectural patterns, and with clear, hobnail, eosinophilic, and flattened cell types.

Show evidence (1 reference)

PMID:2469661 SUPPORT Human Clinical

"Microscopically, three architectural patterns (papillary, tubulocystic, and solid) and four cell types (clear, hobnail, eosinophilic, and flattened) were seen."

Classic clinicopathologic series defining the characteristic morphology of OCCC.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

2

Blood 1

Venous Thromboembolism OCCASIONAL Thromboembolism (HP:0001907)

Show evidence (1 reference)

PMID:37104696 SUPPORT Human Clinical

"VTE was more common in patients with advanced stages (37.79%) compared to those with early stages of the disease (16.54%)."

Supports venous thromboembolism as an OCCC phenotype with stage-dependent frequency.

Genitourinary 1

Ovarian Carcinoma VERY_FREQUENT Ovarian carcinoma (HP:0025318)

🧬

Genetic Associations

2

ARID1A (Recurrent tumor suppressor mutation with frequent biallelic loss)

Show evidence (1 reference)

PMID:39543535 SUPPORT Human Clinical

"On analyzing 102 OCCC samples, ARID1A (67%) and PIK3CA (49%) emerged as the most frequently mutated driver genes."

Large human exome study identifies ARID1A as the most frequent recurrent driver in OCCC.

PIK3CA (Recurrent activating driver mutation)

Show evidence (1 reference)

PMID:39543535 SUPPORT Human Clinical

"On analyzing 102 OCCC samples, ARID1A (67%) and PIK3CA (49%) emerged as the most frequently mutated driver genes."

Large human exome study identifies PIK3CA as the second dominant recurrent driver in OCCC.

💊

Treatments

1

First-Line Platinum-Taxane Chemotherapy

Action: chemotherapy MAXO:0000647

Carboplatin plus paclitaxel remains the standard first-line chemotherapy backbone for OCCC, even though advanced-stage disease often shows relative platinum resistance and the regimen remains imperfect for this histology.

Show evidence (2 references)

PMID:20169667 SUPPORT Human Clinical

"Paclitaxel plus carboplatin (TC) is generally considered to be the "gold standard" regimen for treatment of epithelial ovarian carcinomas."

Supports the carboplatin/paclitaxel doublet as the conventional first-line regimen applied to OCCC.

PMID:20169667 SUPPORT Human Clinical

"Progression-free survival (PFS) showed no significant difference between the 2 treatment groups."

Trial data show that standard first-line chemotherapy remains suboptimal and has not clearly outperformed irinotecan/cisplatin in this histology.

📚

Literature Summaries

1

Clear Cell Ovarian Carcinoma Deep Research Notes ▸

Clear Cell Ovarian Carcinoma Deep Research Notes

Modeling choices applied from issue #1198

The dismech page is the mechanism-graph unit for OCCC, not a page for every ontology subclass.
The disease anchor is MONDO-first: MONDO:0000548 (ovarian clear cell cancer).
I treated MONDO:0006045 (ovarian clear cell adenocarcinoma) as a close ontology neighbor rather than creating a second disorder page.
I used NCIT where it materially improves oncology specificity:
NCIT:C40078 for the adenocarcinoma morphology
I evaluated NCIT regimen terms for first-line therapy, but the repo's current RegimenTerm validator closure rejects both NCIT:C63402 (Carboplatin/Paclitaxel Regimen) and NCIT:C63522 (Regimen Used to Treat Malignant Ovarian Neoplasm), so the validated YAML retains the MAXO chemotherapy action and records the NCIT regimen detail in research notes.
I did not create separate disease files for advanced, recurrent, metastatic, or histology-adjacent NCIT subclasses because they do not represent a distinct causal program for this slice.

Disease identity and ontology grounding

MONDO disease anchor: MONDO:0000548 ovarian clear cell cancer
Close MONDO neighbor: MONDO:0006045 ovarian clear cell adenocarcinoma
NCIT morphology: NCIT:C40078 Ovarian Clear Cell Adenocarcinoma
NCIT regimen candidates evaluated: NCIT:C63402 Carboplatin/Paclitaxel Regimen, NCIT:C63522 Regimen Used to Treat Malignant Ovarian Neoplasm

Mechanistic synthesis used in the YAML curation

1. Endometriosis-associated precursor context

PMID:22976498
Evidence source: HUMAN_CLINICAL
Quote:

All of the 31 informative cases showed loss of ARID1A immunoreactivity in the carcinoma and in the endometriotic cyst epithelium in direct continuity with the carcinoma but not in the cyst epithelium that was not adjacent to the tumor.
Curation implication: OCCC is modeled as an endometriosis-associated epithelial ovarian malignancy with a precursor field in contiguous endometriotic cyst epithelium.

2. Early ARID1A loss and chromatin remodeling failure

PMID:22976498
Evidence source: HUMAN_CLINICAL
Quote:

Loss of ARID1A function as shown by loss of expression, presumably due to mutations, is an early molecular event in the development of most ovarian clear cell and endometrioid carcinomas arising in endometriomas.
PMID:39543535
Evidence source: HUMAN_CLINICAL
Quote:

On analyzing 102 OCCC samples, ARID1A (67%) and PIK3CA (49%) emerged as the most frequently mutated driver genes.
Curation implication: ARID1A loss is represented as an atomic pathophysiology node linked to abnormal chromatin remodeling rather than bundled into a generic "epigenetic dysregulation" block.

3. PI3K pathway activation cooperates with ARID1A loss

PMID:25625625
Evidence source: MODEL_ORGANISM
Quote:

We find that ARID1A inactivation is not sufficient for tumour formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA.
PMID:39543535
Evidence source: HUMAN_CLINICAL
Quote:

Reconstruction of clonal evolution revealed that early genetic events likely driving tumorigenesis included mutations in the ARID1A, PIK3CA, TERT, KRAS, and TP53 genes.
Curation implication: PI3K activation is a separate node downstream of ARID1A loss, grounded to GO:0043491.

4. IL-6 inflammatory signaling is a mechanistic convergence point

PMID:25625625
Evidence source: MODEL_ORGANISM
Quote:

Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signalling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumour growth through sustained IL-6 overproduction.
PMID:26238017
Evidence source: HUMAN_CLINICAL
Quote:

Patients with advanced OCCC had the highest 2-year cumulative VTE rates ... and the highest median levels of IL-6.
Curation implication: I split IL-6 signaling into its own atomic node and linked it downstream to the thrombosis biology rather than hiding it inside a broader "inflammation" label.

5. HNF1B-driven glycolytic and antioxidant rewiring

PMID:26318292
Evidence source: IN_VITRO
Quote:

HNF1β drastically alters intracellular metabolism, especially in direction to enhance aerobic glycolysis, so called the "Warburg effect".
PMID:26318292
Evidence source: IN_VITRO
Quote:

Augmented cell survival was based on the reduced ROS activity derived from metabolic alteration such as shift from oxidative phosphorylation to glycolysis and increased intracellular anti-oxidant, glutathione (GSH).
Curation implication: I separated glycolytic rewiring from glutathione/oxidative-stress buffering so the graph keeps the metabolic nodes atomic.

6. Intrinsic carboplatin resistance

PMID:26520442
Evidence source: IN_VITRO
Quote:

ovarian clear cell carcinoma (OCCC) is intrinsically resistant.
PMID:26520442
Evidence source: IN_VITRO
Quote:

ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin.
PMID:26404183
Evidence source: HUMAN_CLINICAL
Quote:

Women with advanced OCCC have poor survival and are often chemotherapy resistant/refractory.
Curation implication: Chemoresistance is represented as its own disease mechanism node and connected to glutathione metabolism rather than treated only as a treatment failure note.

7. OCCC-associated hypercoagulability

PMID:24041880
Evidence source: HUMAN_CLINICAL
Quote:

Among 74 patients with OCCC, VTE was diagnosed in 11 (15%) during primary treatment and 7 (9%) at time of cancer recurrence.
PMID:24041880
Evidence source: HUMAN_CLINICAL
Quote:

This increased risk is not attributable to VTE-related mortality and raises the possibility that a paracrine circuit involving thrombosis might contribute to a more aggressive tumor biology.
PMID:37104696
Evidence source: HUMAN_CLINICAL
Quote:

The pooled prevalence of VTE among OCCC patients was 21.32% (95%CI=(17.38-25.87)).
Curation implication: Thrombosis is modeled as part of disease biology with an atomic coagulation node and an HPO phenotype, not as unrelated supportive-care noise.

Histopathology and phenotype evidence

Histopathology

PMID:2469661
Evidence source: HUMAN_CLINICAL
Quote:

Microscopically, three architectural patterns (papillary, tubulocystic, and solid) and four cell types (clear, hobnail, eosinophilic, and flattened) were seen.
Use in curation: Grounds the NCIT morphology node NCIT:C40078.

Stage distribution and clinical phenotype

PMID:26404183
Evidence source: HUMAN_CLINICAL
Quote:

OCCC often presents in early stage.
Use in curation: Supports the disease summary and the choice to treat stage as a flat clinical axis rather than a separate disease page.

Treatment evidence incorporated

PMID:20169667
Evidence source: HUMAN_CLINICAL
Quote:

Paclitaxel plus carboplatin (TC) is generally considered to be the "gold standard" regimen for treatment of epithelial ovarian carcinomas.
PMID:20169667
Evidence source: HUMAN_CLINICAL
Quote:

Progression-free survival (PFS) showed no significant difference between the 2 treatment groups.
Curation implication: The YAML uses the validated MAXO chemotherapy action, while the research note records the blocked NCIT regimen candidates and still captures that standard carboplatin/paclitaxel-based therapy remains an imperfect solution for OCCC.

Additional high-value human genomic evidence retained in notes

PMID:28611940
Evidence source: HUMAN_CLINICAL
Quote:

Gene expression analyses revealed a distinct OCCC profile compared to other histological subtypes.
PMID:28611940
Evidence source: HUMAN_CLINICAL
Quote:

Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors.
Use in curation: These findings informed the summary and reinforced the choice to keep chromatin-remodeling defects central to the mechanism graph.

{ }

Source YAML

click to show

name: Clear Cell Ovarian Carcinoma
creation_date: "2026-04-12T23:00:00Z"
updated_date: "2026-04-13T08:43:17Z"
description: >-
  Clear cell ovarian carcinoma (OCCC) is a distinct epithelial ovarian cancer subtype
  that commonly arises in endometriosis-associated ovarian cysts and is often diagnosed
  at stage I, but advanced-stage disease has poor outcomes and marked platinum
  resistance. Recurrent disease biology is centered on early ARID1A loss in precursor
  epithelium, cooperative PI3K pathway activation through PIK3CA, IL-6-driven
  inflammatory signaling, HNF1B-mediated glycolytic and glutathione-based stress
  adaptation, and a high burden of cancer-associated thrombosis. Following the cancer
  curation guidance from issue 1198, this entry models the mechanism-level OCCC
  disease unit rather than proliferating separate disorder pages for stage or other
  ontology subclasses; MONDO anchors the disease identity, while NCIT is used for the
  oncology-specific adenocarcinoma morphology and regimen detail is captured in
  notes/research while the validated treatment action remains MAXO chemotherapy.
categories:
- Gynecologic Cancer
- Ovarian Cancer
- Solid Tumor
disease_term:
  preferred_term: clear cell ovarian carcinoma
  term:
    id: MONDO:0000548
    label: ovarian clear cell cancer
parents:
- ovarian carcinoma
pathophysiology:
- name: Endometriosis-Associated Precursor Lesion
  description: >-
    OCCC frequently develops in endometriotic cysts, and the transition field is marked
    by molecularly altered endometriotic epithelium contiguous with carcinoma. This
    precursor context supports modeling OCCC as an endometriosis-associated ovarian
    epithelial malignancy rather than as a de novo ovarian surface tumor.
  cell_types:
  - preferred_term: glandular endometrial unciliated epithelial cell
    term:
      id: CL:0002656
      label: glandular endometrial unciliated epithelial cell
  locations:
  - preferred_term: ovary
    term:
      id: UBERON:0000992
      label: ovary
  downstream:
  - target: ARID1A Tumor Suppressor Loss
    description: The precursor field in endometriotic cyst epithelium harbors the early molecular alterations that seed invasive OCCC.
  evidence:
  - reference: PMID:22976498
    reference_title: Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of the 31 informative cases showed loss of ARID1A immunoreactivity in the
      carcinoma and in the endometriotic cyst epithelium in direct continuity with the
      carcinoma but not in the cyst epithelium that was not adjacent to the tumor.
    explanation: >-
      Human pathology data place the molecularly altered precursor field inside
      endometriotic cyst epithelium contiguous with OCCC.
- name: ARID1A Tumor Suppressor Loss
  description: >-
    ARID1A loss is a recurrent early driver event in OCCC and disrupts SWI/SNF-mediated
    chromatin remodeling in precursor and invasive tumor cells. This event is common in
    human tumors and is already detectable in endometriotic cyst epithelium adjacent to
    carcinoma, supporting a foundational role in tumor initiation.
  cell_types:
  - preferred_term: epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  biological_processes:
  - preferred_term: chromatin remodeling
    modifier: ABNORMAL
    term:
      id: GO:0006338
      label: chromatin remodeling
  downstream:
  - target: PI3K Pathway Activation
    description: ARID1A-deficient tumors frequently acquire or co-select PI3K pathway activation to complete the oncogenic program.
  evidence:
  - reference: PMID:22976498
    reference_title: Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss of ARID1A function as shown by loss of expression, presumably due to
      mutations, is an early molecular event in the development of most ovarian clear
      cell and endometrioid carcinomas arising in endometriomas.
    explanation: >-
      Supports ARID1A loss as an initiating human disease event in endometriosis-related
      OCCC development.
  - reference: PMID:39543535
    reference_title: Molecular profiling reveals novel therapeutic targets and clonal evolution in ovarian clear cell carcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On analyzing 102 OCCC samples, ARID1A (67%) and PIK3CA (49%) emerged as the most
      frequently mutated driver genes.
    explanation: >-
      Confirms ARID1A as the dominant recurrent human driver mutation in OCCC.
- name: PI3K Pathway Activation
  description: >-
    PI3K pathway activation, most often through PIK3CA mutation, cooperates with ARID1A
    loss to enable tumor formation and growth. In OCCC models, PI3K activation is not
    merely correlative but required for the ARID1A-deficient state to progress to
    invasive carcinoma.
  cell_types:
  - preferred_term: epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  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: IL-6 Inflammatory Signaling
    description: Cooperative ARID1A and PI3K pathway activation sustains a pro-tumorigenic inflammatory cytokine program.
  evidence:
  - reference: PMID:25625625
    reference_title: Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We find that ARID1A inactivation is not sufficient for tumour formation, but
      requires concurrent activation of the phosphoinositide 3-kinase catalytic
      subunit, PIK3CA.
    explanation: >-
      Mouse modeling demonstrates that PI3K activation is functionally required to
      cooperate with ARID1A loss in OCCC tumorigenesis.
  - reference: PMID:39543535
    reference_title: Molecular profiling reveals novel therapeutic targets and clonal evolution in ovarian clear cell carcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reconstruction of clonal evolution revealed that early genetic events likely
      driving tumorigenesis included mutations in the ARID1A, PIK3CA, TERT, KRAS, and
      TP53 genes.
    explanation: >-
      Human clonal reconstruction supports PIK3CA mutation as an early genetic event in
      OCCC evolution.
- name: IL-6 Inflammatory Signaling
  description: >-
    ARID1A and PIK3CA cooperation converges on sustained IL-6 signaling, linking
    chromatin remodeling defects and PI3K pathway activation to a pro-tumorigenic
    inflammatory state. In human disease, elevated IL-6 is strongest in advanced OCCC
    and is associated with thrombotic risk and worse progression outcomes.
  biological_processes:
  - preferred_term: interleukin-6-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0070102
      label: interleukin-6-mediated signaling pathway
  downstream:
  - target: OCCC-Associated Hypercoagulability
    description: Elevated IL-6 is clinically linked to thrombosis in advanced OCCC.
  evidence:
  - reference: PMID:25625625
    reference_title: Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cross-species gene expression comparisons support a role for IL-6 inflammatory
      cytokine signalling in OCCC pathogenesis. We further show that ARID1A and PIK3CA
      mutations cooperate to promote tumour growth through sustained IL-6 overproduction.
    explanation: >-
      Functional modeling shows IL-6 is a mechanistic convergence point downstream of
      ARID1A loss and PI3K activation.
  - reference: PMID:26238017
    reference_title: Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with advanced OCCC had the highest 2-year cumulative VTE rates
      (advanced OCCC 43.1%, advanced SOC 16.2%, early-stage OCCC 11.9% and
      early-stage SOC 6.4%, P<0.0001) and the highest median levels of IL-6
      (advanced OCCC 17.8 pg/mL, advanced SOC 9.0 pg/mL, early-stage OCCC 4.2
      pg/mL and early-stage SOC 5.0 pg/mL, P=0.006).
    explanation: >-
      Clinical data connect elevated IL-6 with the advanced, high-thrombosis OCCC
      phenotype.
- name: HNF1B-Driven Glycolytic Reprogramming
  description: >-
    HNF1B is a lineage-defining OCCC regulator that rewires tumor metabolism toward
    aerobic glycolysis. This supports cell survival under hypoxic and treatment stress
    and helps explain why OCCC maintains a distinct metabolic phenotype compared with
    other ovarian cancer histologies.
  cell_types:
  - preferred_term: epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  biological_processes:
  - preferred_term: glycolytic process
    modifier: INCREASED
    term:
      id: GO:0006096
      label: glycolytic process
  downstream:
  - target: Glutathione-Dependent Oxidative Stress Buffering
    description: Glycolytic rewiring supports antioxidant programs that lower ROS and sustain tumor survival.
  evidence:
  - reference: PMID:26318292
    reference_title: Metabolic alterations caused by HNF1β expression in ovarian clear cell carcinoma contribute to cell survival.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      HNF1β drastically alters intracellular metabolism, especially in direction to
      enhance aerobic glycolysis, so called the "Warburg effect".
    explanation: >-
      Cell-line metabolomic data support HNF1B-driven glycolytic rewiring as a core OCCC
      mechanism.
- name: Glutathione-Dependent Oxidative Stress Buffering
  description: >-
    OCCC cells use HNF1B-linked antioxidant metabolism to buffer oxidative stress through
    increased glutathione availability and reduced ROS activity. This stress-adapted
    state supports survival in the endometriotic cyst microenvironment and contributes to
    intrinsic platinum resistance.
  biological_processes:
  - preferred_term: glutathione metabolic process
    modifier: INCREASED
    term:
      id: GO:0006749
      label: glutathione metabolic process
  - preferred_term: response to oxidative stress
    modifier: ABNORMAL
    term:
      id: GO:0006979
      label: response to oxidative stress
  downstream:
  - target: Intrinsic Carboplatin Resistance
    description: Glutathione-mediated detoxification and ROS buffering blunt carboplatin cytotoxicity in OCCC cells.
  evidence:
  - reference: PMID:26318292
    reference_title: Metabolic alterations caused by HNF1β expression in ovarian clear cell carcinoma contribute to cell survival.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Augmented cell survival was based on the reduced ROS activity derived from
      metabolic alteration such as shift from oxidative phosphorylation to glycolysis and
      increased intracellular anti-oxidant, glutathione (GSH).
    explanation: >-
      Supports glutathione-linked oxidative stress buffering as a survival mechanism in
      HNF1B-positive OCCC.
- name: Intrinsic Carboplatin Resistance
  description: >-
    Unlike high-grade serous ovarian carcinoma, OCCC is often intrinsically resistant to
    platinum therapy. HNF1B-driven glutathione synthesis and related detoxification
    programs directly contribute to carboplatin resistance and are consistent with the
    poor outcomes seen in advanced-stage disease.
  evidence:
  - reference: PMID:26520442
    reference_title: HNF1β drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ovarian clear cell carcinoma (OCCC) is intrinsically resistant.
    explanation: >-
      Establishes that intrinsic platinum resistance is a defining feature of OCCC rather
      than solely an acquired treatment phenotype.
  - reference: PMID:26520442
    reference_title: HNF1β drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH
      production by BSO sensitizes ES2 to carboplatin.
    explanation: >-
      Directly links glutathione metabolism to carboplatin resistance in OCCC cells.
  - reference: PMID:26404183
    reference_title: "Ovarian clear cell carcinoma, outcomes by stage: the MSK experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Women with advanced OCCC have poor survival and are often chemotherapy
      resistant/refractory.
    explanation: >-
      Human outcomes data show that the resistant phenotype is clinically important in
      advanced OCCC.
- name: OCCC-Associated Hypercoagulability
  description: >-
    OCCC carries a disproportionate risk of venous thromboembolism, especially in
    advanced-stage disease. This hypercoagulable phenotype tracks with IL-6 elevation and
    is associated with worse recurrence-free and overall survival, making thrombosis part
    of the disease biology rather than a purely incidental complication.
  biological_processes:
  - preferred_term: blood coagulation
    modifier: INCREASED
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:24041880
    reference_title: Venous thromboembolism during primary treatment of ovarian clear cell carcinoma is associated with decreased survival.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 74 patients with OCCC, VTE was diagnosed in 11 (15%) during primary
      treatment and 7 (9%) at time of cancer recurrence.
    explanation: >-
      Supports the clinically important thrombotic phenotype in OCCC.
  - reference: PMID:24041880
    reference_title: Venous thromboembolism during primary treatment of ovarian clear cell carcinoma is associated with decreased survival.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This increased risk is not attributable to VTE-related mortality and raises the
      possibility that a paracrine circuit involving thrombosis might contribute to a
      more aggressive tumor biology.
    explanation: >-
      Suggests thrombosis is biologically linked to aggressive OCCC rather than being
      only a treatment complication.
  - reference: PMID:37104696
    reference_title: "Clear cell carcinoma of the ovary and venous thromboembolism: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled prevalence of VTE among OCCC patients was 21.32% (95%CI=(17.38-25.87)).
    explanation: >-
      Meta-analysis supports VTE as a frequent clinical phenotype in OCCC.
histopathology:
- name: Ovarian Clear Cell Adenocarcinoma Morphology
  finding_term:
    preferred_term: Ovarian Clear Cell Adenocarcinoma
    term:
      id: NCIT:C40078
      label: Ovarian Clear Cell Adenocarcinoma
  frequency: VERY_FREQUENT
  description: >-
    OCCC shows clear-cell adenocarcinoma morphology with papillary, tubulocystic, and
    solid architectural patterns, and with clear, hobnail, eosinophilic, and flattened
    cell types.
  evidence:
  - reference: PMID:2469661
    reference_title: Ovarian clear cell carcinoma. A clinicopathologic analysis of 44 cases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microscopically, three architectural patterns (papillary, tubulocystic, and solid)
      and four cell types (clear, hobnail, eosinophilic, and flattened) were seen.
    explanation: >-
      Classic clinicopathologic series defining the characteristic morphology of OCCC.
phenotypes:
- category: Neoplastic
  name: Ovarian Carcinoma
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    The disease presents as a malignant epithelial ovarian carcinoma and is usually
    classified within epithelial ovarian cancer histology workups.
  phenotype_term:
    preferred_term: Ovarian carcinoma
    term:
      id: HP:0025318
      label: Ovarian carcinoma
- category: Hematologic
  name: Venous Thromboembolism
  frequency: OCCASIONAL
  description: >-
    Venous thromboembolism is common enough in OCCC to represent part of the disease
    phenotype, especially in advanced-stage disease.
  phenotype_term:
    preferred_term: venous thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  evidence:
  - reference: PMID:37104696
    reference_title: "Clear cell carcinoma of the ovary and venous thromboembolism: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VTE was more common in patients with advanced stages (37.79%) compared to those
      with early stages of the disease (16.54%).
    explanation: >-
      Supports venous thromboembolism as an OCCC phenotype with stage-dependent
      frequency.
genetic:
- name: ARID1A
  association: Recurrent tumor suppressor mutation with frequent biallelic loss
  gene_term:
    preferred_term: ARID1A
    term:
      id: hgnc:11110
      label: ARID1A
  evidence:
  - reference: PMID:39543535
    reference_title: Molecular profiling reveals novel therapeutic targets and clonal evolution in ovarian clear cell carcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On analyzing 102 OCCC samples, ARID1A (67%) and PIK3CA (49%) emerged as the most
      frequently mutated driver genes.
    explanation: >-
      Large human exome study identifies ARID1A as the most frequent recurrent driver in
      OCCC.
  notes: >-
    ARID1A loss is both a recurrent human driver alteration and an early event in the
    endometriosis-associated precursor field.
- name: PIK3CA
  association: Recurrent activating driver mutation
  gene_term:
    preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  evidence:
  - reference: PMID:39543535
    reference_title: Molecular profiling reveals novel therapeutic targets and clonal evolution in ovarian clear cell carcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On analyzing 102 OCCC samples, ARID1A (67%) and PIK3CA (49%) emerged as the most
      frequently mutated driver genes.
    explanation: >-
      Large human exome study identifies PIK3CA as the second dominant recurrent driver
      in OCCC.
  notes: >-
    PIK3CA activation functionally cooperates with ARID1A loss and helps define the core
    OCCC oncogenic program.
treatments:
- name: First-Line Platinum-Taxane Chemotherapy
  description: >-
    Carboplatin plus paclitaxel remains the standard first-line chemotherapy backbone for
    OCCC, even though advanced-stage disease often shows relative platinum resistance and
    the regimen remains imperfect for this histology.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
  evidence:
  - reference: PMID:20169667
    reference_title: "Randomized phase II trial of paclitaxel plus carboplatin therapy versus irinotecan plus cisplatin therapy as first-line chemotherapy for clear cell adenocarcinoma of the ovary: a JGOG study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paclitaxel plus carboplatin (TC) is generally considered to be the "gold standard"
      regimen for treatment of epithelial ovarian carcinomas.
    explanation: >-
      Supports the carboplatin/paclitaxel doublet as the conventional first-line regimen
      applied to OCCC.
  - reference: PMID:20169667
    reference_title: "Randomized phase II trial of paclitaxel plus carboplatin therapy versus irinotecan plus cisplatin therapy as first-line chemotherapy for clear cell adenocarcinoma of the ovary: a JGOG study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progression-free survival (PFS) showed no significant difference between the 2
      treatment groups.
    explanation: >-
      Trial data show that standard first-line chemotherapy remains suboptimal and has
      not clearly outperformed irinotecan/cisplatin in this histology.
  notes: >-
    The actual backbone captured by the evidence is carboplatin plus paclitaxel. The
    relevant NCIT regimen terms NCIT:C63402 (Carboplatin/Paclitaxel Regimen) and
    NCIT:C63522 (Regimen Used to Treat Malignant Ovarian Neoplasm) were evaluated during
    curation but are currently rejected by the repo's RegimenTerm validator closure, so
    the validated YAML binding uses the MAXO chemotherapy action alone.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000548
      label: ovarian clear cell cancer
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for the mechanism-level OCCC entry.
  - term:
      id: MONDO:0006045
      label: ovarian clear cell adenocarcinoma
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      The curated disease unit is the OCCC mechanism graph as a whole; MONDO:0006045 is
      a tighter adenocarcinoma morphology neighbor represented directly in histopathology
      with NCIT:C40078 rather than as a separate dismech disease page.
datasets: []