Background 
Ovarian carcinomas consist of at least five distinct diseases: high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous. Biomarker and molecular characterization may represent a more biologically relevant basis for grouping and treating this family of tumors, rather than site of origin. Molecular characteristics have become the new standard for clinical pathology, however development of tailored type-specific therapies is hampered by a failure of basic research to recognize that model systems used to study these diseases must also be stratified. Unrelated model systems do offer value for study of biochemical processes but specific cellular context needs to be applied to assess relevant therapeutic strategies.


Methods 
We have focused on the identification of clear cell carcinoma cell line models. A panel of 32 “ovarian cancer” cell lines has been classified into histotypes using a combination of mutation profiles, IHC mutation-surrogates, and a validated immunohistochemical model. All cell lines were identity verified using STR analysis.


Results 
Many described ovarian clear cell lines have characteristic mutations (including ARID1A and PIK3CA) and an overall molecular/immuno-profile typical of primary tumors. Mutations in TP53 were present in the majority of high-grade serous cell lines. Advanced genomic analysis of bona-fide clear cell carcinoma cell lines also support copy number changes in typical biomarkers such at MET and HNF1B and a lack of any recurrent expressed re-arrangements.

Conclusions: As with primary ovarian tumors, mutation status of cancer genes like ARID1A and TP53 and a general immuno-profile serve well for establishing histotype of ovarian cancer cell We describe specific biomarkers and molecular features to re-classify generic “ovarian carcinoma” cell lines into type specific categories. Our data supports the use of prototype clear cell lines, such as TOV21G and JHOC-5, and questions the use of SKOV3 and A2780 as models of high-grade serous carcinoma.

/pdf/type-specific-cell-line-models-for-type-specific-ovarian-4d8tbi25hy.pdf

Type-Specific Cell Line Models for Type-Specific Ovarian Cancer Research

https://www.gynecologiconcology-online.net/article/S0090-8258(11)00017-5/pdf

Clear cell carcinoma of the ovary: a report from the first Ovarian Clear Cell Symposium, June 24th, 2010.

https://www.gynecologiconcology-online.net/article/S0090-8258(12)00276-4/pdf

Clear cell carcinoma of the ovary: A review of the literature

Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2-amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p < 0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non-amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.

/pdf/molecular-characterization-of-mucinous-ovarian-tumours-42nfs8wak9.pdf

Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma.

https://www.gynecologiconcology-online.net/article/S0090-8258(09)00728-8/pdf

Tumor type and substage predict survival in stage I and II ovarian carcinoma: Insights and implications

Tumor grade has been the most accepted prognostic indicator of disease-specific survival among women with stage I and II ovarian carcinomas. Many investigators have included stage IB, grade 1 at diagnosis as low-risk disease and have suggested that women in this category should not receive adjuvant therapy. However, grading assignment appears to be unreliable because of problems with reproducibility and lack of consideration of biological differences between the different tumor types. Some investigators believe that classification based on tumor typing using new histopathological criteria was more reproducible than grade assignment and would more accurately reflect biological differences.
This population-based cohort study evaluated the effectiveness of updated tumor type to predict outcome for patients with low-stage ovarian carcinoma at low risk of death. Between 1984 and 2003, 1326 women with a diagnosis of stage I–II ovarian carcinoma were referred to the British Columbia Cancer Agency. Of these, 652 (49%) were available for full slide review. Type and grade were assessed using contemporary histopathological criteria. Tumor types investigated accounting for 98% of ovarian carcinomas included high-grade serous, endometrioid, clear cell, mucinous, and low-grade serous. Of the 630 cases confirmed as ovarian carcinomas, 25 were rare types and were excluded, leaving 605 cases available for the final analysis. Outcomes among different subtypes were assessed using univariate models and recursive partitioning analysis. An excellent outcome (low risk of death) was defined as a disease-specific survival at 10 years (DSS10y) ≥95%.
There was an excellent outcome in 77 cases with ovarian carcinomas of endometrioid and mucinous type, stage IA or IB. The outcome for high-grade serous carcinomas was poor (DSS10y = 57%); no subset could be identified with an excellent outcome. Although no subsets of clear cell carcinomas had an excellent outcome, a small group of patients with stage IA or IB tumors had a more favorable outcome (DSS10y = 87%) compared to those with stage IC–II (DSS10y = 66%).
These findings indicate that tumor type is superior to grade in identifying the risk of death from ovarian carcinoma among women with stage I/II disease. Classification of all stage IA or IB endometrioid and mucinous ovarian carcinomas at time of presentation as low-risk would allow the proportion of patients for which adjuvant treatment could be avoided to be increased from 6.5% to 12.2%.

Kenneth D. Swenerton

Papers

Tumor type and substage predict survival in stage I and II ovarian carcinoma: Insights and implications

Tumor Type and Substage Predict Survival in Stage I and Ii Ovarian Carcinoma: Insights and Implications