RT Journal Article
SR Electronic
T1 Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 574
OP 580
DO 10.1136/jmedgenet-2018-105930
VO 56
IS 9
A1 Hauke, Jan
A1 Hahnen, Eric
A1 Schneider, Stephanie
A1 Reuss, Alexander
A1 Richters, Lisa
A1 Kommoss, Stefan
A1 Heimbach, André
A1 Marmé, Frederik
A1 Schmidt, Sandra
A1 Prieske, Katharina
A1 Gevensleben, Heidrun
A1 Burges, Alexander
A1 Borde, Julika
A1 De Gregorio, Nikolaus
A1 Nürnberg, Peter
A1 El-Balat, Ahmed
A1 Thiele, Holger
A1 Hilpert, Felix
A1 Altmüller, Janine
A1 Meier, Werner
A1 Dietrich, Dimo
A1 Kimmig, Rainer
A1 Schoemig-Markiefka, Birgid
A1 Kast, Karin
A1 Braicu, Elena
A1 Baumann, Klaus
A1 Jackisch, Christian
A1 Park-Simon, Tjoung-Won
A1 Ernst, Corinna
A1 Hanker, Lars
A1 Pfisterer, Jacobus
A1 Schnelzer, Andreas
A1 du Bois, Andreas
A1 Schmutzler, Rita K
A1 Harter, Philipp
YR 2019
UL http://jmg.bmj.com/content/56/9/574.abstract
AB 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