Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

Abstract

We studied the whole-genome point mutation and structural variation patterns of 133 tumors (59 high-grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell (GCT)) as a substrate for class discovery in ovarian cancer. Ab initio clustering of integrated point mutation and structural variation signatures identified seven subgroups both between and within histotypes. Prevalence of foldback inversions identified a prognostically significant HGSC group associated with inferior survival. This finding was recapitulated in two independent cohorts (n = 576 cases), transcending BRCA1 and BRCA2 mutation and gene expression features of HGSC. CCOC cancers grouped according to APOBEC deamination (26%) and age-related mutational signatures (40%). ENOCs were divided by cases with microsatellite instability (28%), with a distinct mismatch-repair mutation signature. Taken together, our work establishes the potency of the somatic genome, reflective of diverse DNA repair deficiencies, to stratify ovarian cancers into distinct biological strata within the major histotypes.

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

“…A recent study in localized prostate cancer demonstrated clusters of genomic rearrangements each occurring in 5–6% of samples (Fraser et al, 2017). In addition, previous studies have demonstrated that SVs may define subtypes of ovarian, pancreatic, and breast cancers (Nik-Zainal et al, 2016; Patch et al, 2015; Waddell et al, 2015; Wang et al, 2017). Of note, the majority of SVs involve intergenic or intronic noncoding regions of the genome and are not captured by exome sequencing or transcriptome analysis.…”

Distinct molecular pathways in ovarian endometrioid adenocarcinoma with concurrent endometriosis

“…Thus, there is a clinical need to understand the key molecular drivers of cancer subsets such as those arising from endometriosis, which may drive treatment recommendations. Currently, whole genome sequencing analysis of ovarian cancer samples allows stratification into histotypes, including subclassification of OEA into tissues that are microsatellite stable and those with microsatellite instability . While large amounts of genomic data have been generated based on histotype, there is limited information regarding the molecular contribution of the endometriotic tumor microenvironment on OEA.…”

The role of MicroRNA molecules and MicroRNA-regulating machinery in the pathogenesis and progression of epithelial ovarian cancer

“…Thus, use of single nucleotide polymorphisms in microRNA machinery genes, mature microRNA molecules, or microRNA binding sites in genes to determine the risk of EOC diagnosis has been not been replicated clinically. Larger studies and grouping samples according to newly published genetic changes (4) instead of histotype or grade may allow for results that are more replicable.…”

“…The molecular landscape of each histotype of EOC is distinct (3, 4). However, all patients are treated similarly with standard of care debulking surgery and chemotherapy regimens, with dismal “cure” rates of 20% (1).…”

“…Each histotype is thought to arise from distinct precursor lesions of the female reproductive tract (2). Molecularly, the landscape of each individual EOC histotype is distinct at the gene expression and genomic DNA level, allowing novel means to classify tumors beyond traditional histology (3, 4). …”