The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma.
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Authors
Ennis, Darren P
Sokota, Chishimba
Giannone, Gaia
Goranova, Theodora
Piskorz, Anna
BriTROC-1 Investigators
Kaur, Baljeet
Singh, Naveena
Tookman, Laura A
Krell, Jonathan
McDermott, Jacqueline
Publication Date
2022-07-01Journal Title
Clin Cancer Res
ISSN
1078-0432
Publisher
American Association for Cancer Research (AACR)
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Cheng, Z., Mirza, H., Ennis, D. P., Smith, P., Morrill Gavarró, L., Sokota, C., Giannone, G., et al. (2022). The Genomic Landscape of Early-Stage Ovarian High-Grade Serous Carcinoma.. Clin Cancer Res https://doi.org/10.1158/1078-0432.CCR-21-1643
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. See related commentary by Yang et al., p. 2730.
Sponsorship
Cancer Research UK (CB4320)
Cancer Research UK (C14303/A17197)
Royal Society (WM170023)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (766030)
Biotechnology and Biological Sciences Research Council (BB/R006563/1)
Innovate UK (74918)
Alan Turing Institute (TUR-000346)
Cancer Research UK (A22905)
Cancer Research UK (A15973)
Cancer Research UK (A11592)
Cancer Research UK (A15601)
Cancer Research UK (A19274)
Embargo Lift Date
2023-04-10
Identifiers
External DOI: https://doi.org/10.1158/1078-0432.CCR-21-1643
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332946
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