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

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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., Hahnen, E., Schneider, S., Reuss, A., Richters, L., Kommoss, S., Heimbach, A., Marmé, F., Schmidt, S., Prieske, K., Gevensleben, H., Burges, A., Borde, J., De Gregorio, N., Nürnberg, P., El-Balat, A., Thiele, H., Hilpert, F., Altmüller, J., Meier, W., Dietrich, D., Kimmig, R., Schoemig-Markiefka, B., Kast, K., Braicu, E., Baumann, K., Jackisch, C., Park-Simon, T.W., Ernst, C., Hanker, L., Pfisterer, J., Schnelzer, A., du Bois, A., 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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