The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma

Abstract

Purpose: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. Experimental Design: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. Results: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. Conclusions: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness.

A Randomised, Multi-centre Phase II Trial of Weekly Paclitaxel and Vistusertib in Platinum-Resistant Ovarian High-Grade Serous Carcinoma: OCTOPUS Arm 1

“…CN signature 4, marked by high segment copy number, was significantly associated with whole genome duplication and mutations in the PI3K/AKT pathway (37). Our recent comparison of early-and late-stage HGSC genomes confirmed the link between CN signature 4 and high ploidy, as well as its association with poor prognosis (38). Here, we showed that high CN signature 4 exposure was again negatively prognostic in the control arm but was associated with an improvement in PFS in the experimental arm, although this did not reach statistical significance.…”

Double Trouble: Whole-Genome Doubling Distinguishes Early from Late Ovarian Cancer

“…Cheng and colleagues ( 1 ) reported similar age-at-diagnosis comparing early- and late-stage HGSC as evidence to support their distinct developmental origins. While this observation is intriguing, it would be of interest to further investigate whether early-stage disease was related to the patient's primary differential diagnosis or was discovered incidentally.…”

“…In this issue of Clinical Cancer Research , Cheng and colleagues ( 1 ) describe results from a retrospective, hypothesis-generating study that explores the evolutionary origins of high-grade serous ovarian cancer (HGSC) by comparing genomic differences of early-stage (stage IA–IIA; n = 46) to late-stage HGSCs (stage IIIC–IV; n = 52). As significant prognostic disparity exists between early- and late-stage HGSC, it is unclear whether early-stage disease represents a molecularly distinct subtype that lacks peritoneal dissemination potential or if it reflects a premetastatic precursor state of late-stage HGSC.…”

“… A, Summary of the proposed origins of early- and late-stage HGSC by Cheng and colleagues ( 1 ). B, Prospective HGSC screening by applying ctDNA-based biomarkers to detect early-stage disease and facilitate longitudinal collection of precursor, blood, and HGSC biospecimens to enable ongoing HGSC research.…”

“…In HGSCs, single-gene biomarkers have been explored, however none has demonstrated the ability to discern early- from late-stage disease. Here, Cheng and colleagues ( 1 ) present CN signature exposures and WGD as additional genome-wide prognostic indicators of HGSC.…”