Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)

Item Type:	Article
Title:	Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)
Creators Name:	Hauke, J. and Hahnen, E. and Schneider, S. and Reuss, A. and Richters, L. and Kommoss, S. and Heimbach, A. and Marmé, F. and Schmidt, S. and Prieske, K. and Gevensleben, H. and Burges, A. and Borde, J. and De Gregorio, N. and Nürnberg, P. and El-Balat, A. and Thiele, H. and Hilpert, F. and Altmüller, J. and Meier, W. and Dietrich, D. and Kimmig, R. and Schoemig-Markiefka, B. and Kast, K. and Braicu, E. and Baumann, K. and Jackisch, C. and Park-Simon, T.W. and Ernst, C. and Hanker, L. and Pfisterer, J. and Schnelzer, A. and du Bois, A. and Schmutzler, R.K. and Harter, P.
Abstract:	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.
Keywords:	Germline Variant, Methylation, Ovarian Cancer, Somatic Variant, Targeted Therapy
Source:	Journal of Medical Genetics
ISSN:	1468-6244
Publisher:	BMJ Publishing Group
Volume:	56
Number:	9
Page Range:	574-580
Date:	September 2019
Official Publication:	https://doi.org/10.1136/jmedgenet-2018-105930
PubMed:	View item in PubMed

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