Background For individuals with ovarian cancer (OC), therapy options mainly depend on BRCA1/2 germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy?
Methods Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (ATM, BRCA1/2, BRIP1, MSH2/6, PALB2, RAD51C/D and TP53) and the PIK3CA and PTEN genes in individuals with OC (AGO-TR1 study, NCT02222883). Results were complemented by BRCA1, PALB2 and RAD51C promoter methylation analyses and stratified by histological subtype; 473 individuals were included.
Results The combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; BRCA1/2: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding TP53 (all: 39/473, 8.2%; BRCA1/2: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; BRCA1: 57/473, 12.1%; RAD51C: 10/473, 2.1%; PALB2: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic PIK3CA and/or PTEN variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles.
Conclusion Tumour sequencing of the BRCA1, BRCA2, PIK3CA and PTEN genes along with BRCA1 and RAD51C promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors.
Trial registration number NCT02222883
- ovarian cancer
- targeted therapy
- somatic variant
- germline variant
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Contributors JH and EH contributed equally to this work; study concept and design: JH, EH, ADB, RKS and PH; acquisition, analysis and interpretation of data: JH, EH, StS, AR, LR, SK, AH, FM, SaS, KP, HG, AdB, JB, NDG, PN, AE-B, HT, FH, JA, WM, DD, RK, BS-M, KK, EB, KB, CJ, T-WP-S, CE, LH, JP and AS; drafting the manuscript: JH and EH; critical revision of the manuscript for important intellectual content: StS, AR, LR, SK, AH, FM, SaS, KP, HG, AB, JB, NDG, PN, AE-B, HT, FH, JA, WM, DD, RK, BS-M, KK, EB, KB, CJ, T-WP-S, CE, LH, JP, AS, AdB, RKS and PH; accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors; final approval of the submitted manuscript: all authors; obtained funding: PH; study supervision: EH and PH; administrative, technical or material support: all authors.
Funding The study was funded by AstraZeneca, AGO Research GmbH.
Competing interests EH: honoraria: AstraZeneca; consulting or advisory role: AstraZeneca; research funding: Astra Zeneca (Inst). SS: honoraria: Roche; consulting or advisory role: Tesaro. KK: honoraria: Roche, Pfizer and AstraZeneca. JP: honoraria: Roche Pharma AG; consulting or advisory role: Amgen, AstraZeneca, Coherus Bioscience, DeciBio, F. Hoffmann-La Roche, Pharmamar, Shield Therapeutics, Simon Kucher & Partner, Taylor Wessing LLP and Tesaro; research funding: Astra Zeneca, Hoffmann-La Roche and Tesaro; travel, accommodations and expenses: Amgen, Astra Zeneca, F. Hoffmann-La Roche and Tesaro. AS: honoraria: TEVA and Gedeon Richter; consulting or advisory role: Astra Zeneca and Roche. SK: honoraria: AstraZeneca and Roche; consulting or advisory role: Roche. KP: travel and research funding: Medac Oncology; honoraria: AstraZeneca and Roche. DD is a consultant for AJ Innuscreen GmbH (Berlin, Germany), a 100% daughter company of Analytik Jena AG (Jena, Germany) and receives royalties from product sales (innuCONVERT kits). AdB: consulting or advisory role: AstraZeneca, Pfizer, Pharmamar, Roche/Genentech, Advaxis, Tesaro, Genmab, Clovis and Biocad. RKS: honoraria: AstraZeneca; consulting or advisory role: AstraZeneca; research funding: AstraZeneca (Inst); patents, royalties, other intellectual property: University of Cologne. CK: consulting and advisory role: AstraZeneca and Roche/Genentech. PH: consulting or advisory role: AstraZeneca, Roche/Genentech, Tesaro, Clovis, Pharmamar Lilly and Sotio; research funding: AstraZeneca (Inst); travel, accommodations and expenses: Medac.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.