期刊
CLINICAL CANCER RESEARCH
卷 28, 期 13, 页码 2911-2922出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-21-1643
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类别
资金
- Imperial/China Scholarship Council scholarship
- NIHR Imperial Biomedical Research Centre [P77646]
- Cancer Research UK [A15973, A15601, A18072, A17197, A19274, A19694]
- Wellcome Trust [006]
- Ovarian Cancer Action [RG92770]
- Cancer Research UK Imperial Centre
Late-stage and early-stage high-grade serous carcinomas (HGSCs) of the ovary exhibit highly similar patterns of mutation and copy-number alterations. However, late-stage HGSCs show distinct copy-number signature exposures consistent with whole-genome duplication. Further analysis is needed to determine whether these differences reflect genuine biological disparities between early-stage and late-stage disease or simply markers of evolutionary fitness over time.
? 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 sig-nature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further anal-yses will be required to ascertain whether these differences refiect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness.
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