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Genomic Rearrangement Signatures and Clinical Outcomes in High-Grade Serous Ovarian Cancer.

ABSTRACT: Background:To identify clinically relevant genomic rearrangement signatures in high-grade serous ovarian cancer (HGSOC), we conducted a retrospective analysis of sequenced HGSOC whole-tumor genomes. Methods:Clinical data and whole-genome sequencing (WGS) reads were obtained for primary HGSOC tumors sequenced by the Australian Ovarian Cancer Study (AOCS; n?=?80). Genomic rearrangements were identified, and non-negative matrix factorization (NMF) was used to extract rearrangement signatures. The cohort was then dichotomized around the median signature contribution, and overall survival (OS) was analyzed. An independent cohort from The Cancer Genome Atlas (TCGA) ovarian cancer study (n?=?490) was also examined. The TCGA cohort was dichotomized around the median similarity between tumor copy number profile and a prognostic rearrangement signature, and OS was analyzed. Outcomes were assessed using Kaplan-Meier and multivariable Cox regression methods. All statistical tests were two-sided. Results:We identified five genomic rearrangement signatures (Ov.RS1-5) in HGSOC. Ov.RS3 exhibited 10 kilobase to 10 megabase deletions and tandem duplications, and patients whose tumors exhibited a high contribution from Ov.RS3 had poor OS. The median OS was 22.7?months (95% confidence interval [CI] = 20.2 to 39.0?months) in the Ov.RS3-high group vs 38.2?months (95% CI?=?22.7 to 69.1?months) in the Ov.RS3-low group (hazard ratio [HR] = 1.86, 95% CI?=?1.12 to 3.09, P = .02). For the independent TCGA cohort, median OS rates were 38.0?months (95% CI?=?35.3 to 41.4?months) in the Ov.RS3 high-similarity group vs 48.9?months (95% CI?=?44.1 to 57.1?months) in the Ov.RS3 low-similarity group (HR?=?1.54, 95% CI?=?1.21 to 1.97, P < .001). Conclusion:A novel genomic rearrangement signature is associated with poor prognosis in HGSOC.

SUBMITTER: Hillman RT

PROVIDER: S-EPMC6054271 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Genomic Rearrangement Signatures and Clinical Outcomes in High-Grade Serous Ovarian Cancer.

Hillman R Tyler RT Chisholm Gary B GB Lu Karen H KH Futreal P Andrew PA

Journal of the National Cancer Institute 20180301 3

<h4>Background</h4>To identify clinically relevant genomic rearrangement signatures in high-grade serous ovarian cancer (HGSOC), we conducted a retrospective analysis of sequenced HGSOC whole-tumor genomes.<h4>Methods</h4>Clinical data and whole-genome sequencing (WGS) reads were obtained for primary HGSOC tumors sequenced by the Australian Ovarian Cancer Study (AOCS; n = 80). Genomic rearrangements were identified, and non-negative matrix factorization (NMF) was used to extract rearrangement si ...[more]

PMID: 29584920

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Project description:Purpose To investigate the associations between BRCA mutation status and computed tomography (CT) phenotypes of high-grade serous ovarian cancer (HGSOC) and to evaluate CT indicators of cytoreductive outcome and survival in patients with BRCA-mutant HGSOC and those with BRCA wild-type HGSOC. Materials and Methods This HIPAA-compliant, institutional review board-approved retrospective study included 108 patients (33 with BRCA mutant and 75 with BRCA wild-type HGSOC) who underwent CT before primary debulking. Two radiologists independently reviewed the CT findings for various qualitative CT features. Associations between CT features, BRCA mutation status, cytoreductive outcome, and progression-free survival (PFS) were evaluated by using logistic regression and Cox proportional hazards regression, respectively. Results Peritoneal disease (PD) pattern, presence of PD in gastrohepatic ligament, mesenteric involvement, and supradiaphragmatic lymphadenopathy at CT were associated with BRCA mutation status (multiple regression: P < .001 for each CT feature). While clinical and CT features were not associated with cytoreductive outcome for patients with BRCA-mutant HGSOC, presence of PD in lesser sac (odds ratio [OR] = 2.40) and left upper quadrant (OR = 1.19), mesenteric involvement (OR = 7.10), and lymphadenopathy in supradiaphragmatic (OR = 2.83) and suprarenal para-aortic (OR = 4.79) regions were associated with higher odds of incomplete cytoreduction in BRCA wild-type HGSOC (multiple regression: P < .001 each CT feature). Mesenteric involvement at CT was associated with significantly shorter PFS for both patients with BRCA-mutant HGSOC (multiple regression: hazard ratio [HR] = 26.7 P < .001) and those with BRCA wild-type HGSOC (univariate analysis: reader 1, HR = 2.42, P < .001; reader 2, HR = 2.61; P < .001). Conclusion Qualitative CT features differed between patients with BRCA-mutant HGSOC and patients with BRCA wild-type HGSOC. CT indicators of cytoreductive outcome varied according to BRCA mutation status. Mesenteric involvement at CT was an indicator of significantly shorter PFS for both patients with BRCA-mutant HGSOC and those with BRCA wild-type HGSOC. © RSNA, 2017 Online supplemental material is available for this article.

Dataset Information

Genomic Rearrangement Signatures and Clinical Outcomes in High-Grade Serous Ovarian Cancer.

Publications

Genomic Rearrangement Signatures and Clinical Outcomes in High-Grade Serous Ovarian Cancer.

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