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BRCA1 mutations in high-grade serous ovarian cancer are associated with proteomic changes in DNA repair, splicing, transcription regulation and signaling.

ABSTRACT: Despite recent advances in the management of BRCA1 mutated high-grade serous ovarian cancer (HGSC), the physiology of these tumors remains poorly understood. Here we provide a comprehensive molecular understanding of the signaling processes that drive HGSC pathogenesis with the addition of valuable ubiquitination profiling, and their dependency on BRCA1 mutation-state directly in patient-derived tissues. Using a multilayered proteomic approach, we show the tight coordination between the ubiquitination and phosphorylation regulatory layers and their role in key cellular processes related to BRCA1-dependent HGSC pathogenesis. In addition, we identify key bridging proteins, kinase activity, and post-translational modifications responsible for molding distinct cancer phenotypes, thus providing new opportunities for therapeutic intervention, and ultimately advance towards a more personalized patient care.

SUBMITTER: Bradbury M

PROVIDER: S-EPMC8924168 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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BRCA1 mutations in high-grade serous ovarian cancer are associated with proteomic changes in DNA repair, splicing, transcription regulation and signaling.

Bradbury Melissa M Borràs Eva E Castellví Josep J Méndez Olga O Sánchez-Iglesias José Luis JL Pérez-Benavente Assumpció A Gil-Moreno Antonio A Sabidó Eduard E Santamaria Anna A

Scientific reports 20220315 1

Despite recent advances in the management of BRCA1 mutated high-grade serous ovarian cancer (HGSC), the physiology of these tumors remains poorly understood. Here we provide a comprehensive molecular understanding of the signaling processes that drive HGSC pathogenesis with the addition of valuable ubiquitination profiling, and their dependency on BRCA1 mutation-state directly in patient-derived tissues. Using a multilayered proteomic approach, we show the tight coordination between the ubiquiti ...[more]

PMID: 35292711

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Project description:BackgroundStudies on the prevalence of BRCA1/2 mutations in ovarian cancer mainly focused on germline single-nucleotide variant (SNV)/insertion/deletion (indel). The status of large genomic rearrangement (LRG) and somatic mutation were poorly investigated.MethodsPaired blood and tumor DNA from an unselected cohort of 115 Chinese high grade serous ovarian cancer (HGSOC) patients were collected and analyzed for BRCA1/2 SNV and indel by NGS. BRCA1/2 LRG was detected by MLPA. Clinicopathological characteristics including age at diagnosis, FIGO stage, family history and follow-up data were collected for further analysis.ResultsA total of 115 HGSOC patients were screened. Among them, 30 (26.1%) had germline BRCA1/2 mutations, including 19 (16.5%) SNV/indels, 5 (4.3%) LGRs in BRCA1, and 6 (5.2%) SNV/indels in BRCA2. Ten (8.7%) had somatic BRCA1/2 mutations, including 5 (4.3%) in BRCA1 and 5 (4.3%) in BRCA2. The entire tumor BRCA1/2 mutation frequency was 34.8%. No patients were found with two or more deleterious BRCA1/2 mutations. The proportion of germline (66.7%) and tumor (75%) mutation carriers was significantly increased for patients with family history when compared with those without (P<0.05). Patients with germline BRCA1/2 mutation appeared to be younger than non-carriers (mean age, 50.9 vs. 54.4 years, P=0.004) and somatic mutation carriers (mean age, 50.9 vs. 58.7 years, P=0.009). No significant association was found between BRCA1/2 status and clinicopathological characteristics including stage and family history of other cancer than breast and ovarian cancer. In univariate and Cox regression analysis, patients with tumor BRCA1/2 mutations had significant improvements than non-carriers in overall survival in the first two years after surgery (P<0.05). No significant impacts were found between various mutation status in PFS.ConclusionsThere is a high germline and tumor BRCA1/2 mutation incidences in Chinese HGSOC patients. Germline mutations were associated with family history and age at diagnosis, whereas somatic mutations were not. In our study, tumor BRCA1/2 mutations showed a time-depended improved survival outcome. A larger cohort should be examined to clarify the relation between BRCA1/2 mutation and survival outcomes.

Dataset Information

BRCA1 mutations in high-grade serous ovarian cancer are associated with proteomic changes in DNA repair, splicing, transcription regulation and signaling.

Publications

BRCA1 mutations in high-grade serous ovarian cancer are associated with proteomic changes in DNA repair, splicing, transcription regulation and signaling.

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