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- Title
Genomic Sub-Classification of Ovarian Clear Cell Carcinoma Revealed by Distinct Mutational Signatures.
- Authors
Oliveira, Douglas V. N. P.; Schnack, Tine H.; Poulsen, Tim S.; Christiansen, Anne P.; Høgdall, Claus K.; Høgdall, Estrid V.
- Abstract
Simple Summary: It is well-known that ovarian clear cell carcinoma presents unique molecular traits in comparison to other ovarian cancer subtypes, partially reflecting on chemotherapy resistance. Here, by investigating a panel of cancer-associated genes in a Danish population, our data showed that patients were further stratified into four different molecular subgroups: "PIK3CA", "ARID1A", "PIK3CA-ARID1A" and "Undetermined", in regard to the presence of mutation on these genes. Somatic signature investigation further revealed that those subgroups share common features, such as ageing and defective MMR, whilst also bearing unique signatures. These findings suggest that different groups possess specific molecular backgrounds, indicating that such individuals could better benefit from more individualized therapy regimens. Ovarian clear cell carcinoma (OCCC) is characterized by dismal prognosis, partially due to its low sensitivity to standard chemotherapy regimen. It is also well-known for presenting unique molecular features in comparison to other epithelial ovarian cancer subtypes. Here, we aim to identify potential subgroups of patients in order to (1) determine their molecular features and (2) characterize their mutational signature. Furthermore, we sought to perform the investigation based on a potentially clinically relevant setting. To that end, we assessed the mutational profile and genomic instability of 55 patients extracted from the Gynecologic Cancer Database (DGCD) by using a panel comprised of 409 cancer-associated genes and a microsatellite assay, respectively; both are currently used in our routine environment. In accordance with previous findings, ARID1A and PIK3CA were the most prevalent mutations, present in 49.1% and 41.8%, respectively. From those, the co-occurrence of ARID1A and PIK3CA mutations was observed in 36.1% of subjects, indicating that this association might be a common feature of OCCC. The microsatellite instability frequency was low across samples. An unbiased assessment of signatures identified the presence of three subgroups, where "PIK3CA" and "Double hit" (with ARID1A and PIK3CA double mutation) subgroups exhibited unique signatures, whilst "ARID1A" and "Undetermined" (no mutations on ARID1A nor PIK3CA) subgroups showed similar profiles. Those differences were further indicated by COSMIC signatures. Taken together, the current findings suggest that OCCC presents distinct mutational landscapes within its group, which may indicate different therapeutic approaches according to its subgroup. Although encouraging, it is noteworthy that the current results are limited by sample size, and further investigation on a larger group would be crucial to better elucidate them.
- Subjects
DNA analysis; ADENOCARCINOMA; DATABASES; OVARIAN tumors; GENETIC mutation; CLASSIFICATION; PATIENTS; GENE expression profiling; GENES; GENETIC techniques; BIOLOGICAL assay; DEGENERATION (Pathology)
- Publication
Cancers, 2021, Vol 13, Issue 20, p5242
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers13205242