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Ovarian Cancer Genomic Analysis Reveals Seven Disease-Stratifying Clusters

NEW YORK (GenomeWeb) – Genomic analysis appears to provide new information for classifying ovarian cancer, beyond what is available from traditional ovarian cancer histotypes, a new study suggests.

An international team led by investigators at the BC Cancer Agency and the University of British Columbia tracked point mutations and structural variants in more than 100 ovarian cancers, representing four established subtypes of the disease. From these alterations, the investigators identified seven tumor clusters — molecular subtypes that spanned histotype-based subtypes in some cases. The findings were published online in Nature Genetics today.

"Our results show that properties of the somatic genome on both the structural and point mutation scales are powerful, discriminant biomarkers between and within histotypes for subgroup discovery in ovarian cancer," corresponding authors Sohrab Shah and David Huntsman and their co-authors wrote.

For their analysis, the researchers considered 133 ovarian cancer cases, through genome sequencing on matched tumor and normal samples from 59 individuals with high-grade serous ovarian cancer, 35 individuals with clear cell ovarian cancer, 29 endometrioid cases, and 10 cases of adult granulosa cell ovarian cancer.

In addition to verifying potential structural variants by amplicon sequencing, the team profiled BRCA1/2 germline mutations, methylation status at the BRCA1 promoter, and microsatellite instability patterns in the tumors. Clinical outcome data was incorporated into the analyses when available.

Using a combination of 20 genomic features gleaned from point mutation, copy number, small insertion and deletion, and structural variant patterns in these data, the investigators clustered the cases into seven main subgroups. At least one of the subgroups — a form of high-grade serous ovarian cancer marked by foldback inversions — seemed to provide clues to ovarian cancer outcomes.

The foldback inversions turned up in more than 40 percent of high-grade serous ovarian tumors, the researchers reported, and tended to coincide with poorer progression-free survival and overall survival after platinum chemotherapy, particularly when tumors had high levels of such inversions. The remaining high-grade serous ovarian tumors tended to show signs of homologous recombination deficiency and typically had better outcomes, on average.

Those results were supported by the team's subsequent analysis of data for nearly 600 ovarian cancer cases from the International Cancer Genome Consortium and the Cancer Genome Atlas.

The researchers also identified subsets of clear cell carcinoma ovarian cancers marked by age-related mutations and forms of that disease with or without deamination at APOBEC. In endometrioid ovarian cancer, meanwhile, they saw microsatellite instability and a related mutational signature in a substantial subset of cases.

Overall, the study's authors noted that their results "present a novel stratification of ovarian cancer diseases, dividing the classical histotypes and identifying new biological strata that may inform contemporary and future therapeutic opportunities."