Dataset Information

Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma.

ABSTRACT:

Purpose

In this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.

Materials and methods

Tissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and TP53 gene and their relationships with patient survival were examined. Additionally, we analyzed BRCA germline variants in blood samples from 47 of the patients for comparison.

Results

BRCA1, BRCA2, and TP53 mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in RAD50, ATR, MSH6, MSH2, and FANCA were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic BRCA mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without TP53mutation, exhibited better disease-free survival than those with TP53 mutation alone.

Conclusion

DNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic BRCA mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

SUBMITTER: Choi MC

PROVIDER: S-EPMC7176973 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma.

Choi Min Chul MC Hwang Sohyun S Kim Sewha S Jung Sang Geun SG Park Hyun H Joo Won Duk WD Song Seung Hun SH Lee Chan C Kim Tae-Heon TH Kang Haeyoun H An Hee Jung HJ

Cancer research and treatment 20200106 2

<h4>Purpose</h4>In this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.<h4>Materials and methods</h4>Tissue samples from 77 Korean patients with ovarian high-grade serous carcinom ...[more]

PMID: 32019284

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Project description:BackgroundHigh-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs.Experimental designWe tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo.ResultsWe show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts.ConclusionOur findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

Project description:BackgroundApproximately half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well-characterized in Black individuals.ObjectiveTo characterize HGSC HRD by self-reported race and evaluate whether differences in HRD are associated with ovarian cancer mortality.Study populationCohort study using data collected from two population-based case-control studies of ovarian cancer. Cases were selected based on self-reported race (178 Black, 123 White) and pathologically-confirmed HGSC.ExposuresHRD features identified using matched tumor-normal whole-exome DNA sequencing and categorized as germline or somatic variants in homologous recombination pathway genes, or the SBS3 HRD-associated signature.OutcomesMedian difference and 95% confidence intervals (CI) for age at diagnosis and tumor mutation burden, and age and stage-adjusted hazard ratios (HR) and 95%CIs for survival, comparing individuals with an HRD feature to those without, separately by self-reported race.ResultsMore of the germline and somatic variants detected among Black individuals compared with White individuals were unannotated or variants of uncertain significance (VUS; germline 65% versus 45%; somatic 62% versus 50%, respectively). While the prevalences of many HRD features were similar between Black individuals and White individuals, Black individuals had a higher prevalence of the HRD signature identified using de novo mutational signature analysis (40% versus 29%) and germline BRCA2 variants (8% versus 2%) compared with White individuals. We observed that among Black individuals, BRCA2 variants were associated with better survival (somatic HR=0.23, 95%CI 0.07-0.76; germline HR=0.48, 95%CI 0.22-1.03), while germline BRCA1 variants were associated with worse survival (HR=2.11, 95%CI 1.14-3.88). When we restricted to VUS and unannotated variants, we observed similar associations with survival for BRCA2 among Black individuals (somatic HR=0.18, 95%CI 0.04-0.75; germline HR=0.40, 95%CI 0.15-1.09).Conclusions and relevanceHRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care. Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.

Dataset Information

Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma.

Purpose

Materials and methods

Results

Conclusion

Publications

Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma.

Similar Datasets

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