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TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.

ABSTRACT: To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC.

SUBMITTER: Chien J

PROVIDER: S-EPMC4538798 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.

Chien Jeremy J Sicotte Hugues H Fan Jian-Bing JB Humphray Sean S Cunningham Julie M JM Kalli Kimberly R KR Oberg Ann L AL Hart Steven N SN Li Ying Y Davila Jaime I JI Baheti Saurabh S Wang Chen C Dietmann Sabine S Atkinson Elizabeth J EJ Asmann Yan W YW Bell Debra A DA Ota Takayo T Tarabishy Yaman Y Kuang Rui R Bibikova Marina M Cheetham R Keira RK Grocock Russell J RJ Swisher Elizabeth M EM Peden John J Bentley David D Kocher Jean-Pierre A JP Kaufmann Scott H SH Hartmann Lynn C LC Shridhar Viji V Goode Ellen L EL

Nucleic acids research 20150427 14

To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis wit ...[more]

PMID: 25916844

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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.

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TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.

Publications

TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.

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