Dataset Information

Homologous recombination repair gene mutations show no survival benefits in Chinese high-grade serous ovarian cancer patients.

ABSTRACT:

Background

The purpose of our study was to identify germline and somatic homologous recombination repair (HRR) pathway gene mutations and their clinical-prognostic impact in Chinese high-grade serous ovarian cancer (HGSC) patients.

Methods

We applied next-generation sequencing (NGS) in consecutive patients who underwent primary surgery for HGSC in November and December 2015 at our institution. Paired peripheral blood (or para-carcinoma tissue) samples and tumor samples from 42 Chinese women were tested to identify both germline and somatic deleterious mutations through all exons in BRCA1/2 and 22 other core HRR genes. Clinic-pathological data were collected until February, 2020. Associations between HRR gene mutations and clinical characters and outcomes were also evaluated.

Results

Deleterious germline HRR mutations were identified in 16.7% (7/42) of the HGSC patients. One patient had both germline BRCA2 and ATM mutations. Six patients had only somatic mutations, increasing the HRR mutation rate to 31.0% (13/42). Neither germline nor somatic HRR gene mutations were related with residual disease (P=0.233) nor platinum sensitivity (P=0.851). In the univariate and multivariate analyses, germline HRR gene mutation status was not associated with progression-free survival (PFS) or overall survival (OS). In addition, no prognostic differences between somatic HRR mutated patients and wild-type patients were found.

Conclusions

Our results suggest that the HRR gene defect was not associated with improved survival in our Chinese HGSC patient cohort.

SUBMITTER: Feng Z

PROVIDER: S-EPMC8033363 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Homologous recombination repair gene mutations show no survival benefits in Chinese high-grade serous ovarian cancer patients.

Feng Zheng Z Wen Hao H Ju Xingzhu X Bi Rui R Chen Xiaojun X Yang Wentao W Wu Xiaohua X

Annals of translational medicine 20210301 5

<h4>Background</h4>The purpose of our study was to identify germline and somatic homologous recombination repair (HRR) pathway gene mutations and their clinical-prognostic impact in Chinese high-grade serous ovarian cancer (HGSC) patients.<h4>Methods</h4>We applied next-generation sequencing (NGS) in consecutive patients who underwent primary surgery for HGSC in November and December 2015 at our institution. Paired peripheral blood (or para-carcinoma tissue) samples and tumor samples from 42 Chi ...[more]

PMID: 33842585

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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

Homologous recombination repair gene mutations show no survival benefits in Chinese high-grade serous ovarian cancer patients.

Background

Methods

Results

Conclusions

Publications

Homologous recombination repair gene mutations show no survival benefits in Chinese high-grade serous ovarian cancer patients.

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