PT  - JOURNAL ARTICLE
AU  - Hauke, Jan
AU  - Hahnen, Eric
AU  - Schneider, Stephanie
AU  - Reuss, Alexander
AU  - Richters, Lisa
AU  - Kommoss, Stefan
AU  - Heimbach, André
AU  - Marmé, Frederik
AU  - Schmidt, Sandra
AU  - Prieske, Katharina
AU  - Gevensleben, Heidrun
AU  - Burges, Alexander
AU  - Borde, Julika
AU  - De Gregorio, Nikolaus
AU  - Nürnberg, Peter
AU  - El-Balat, Ahmed
AU  - Thiele, Holger
AU  - Hilpert, Felix
AU  - Altmüller, Janine
AU  - Meier, Werner
AU  - Dietrich, Dimo
AU  - Kimmig, Rainer
AU  - Schoemig-Markiefka, Birgid
AU  - Kast, Karin
AU  - Braicu, Elena
AU  - Baumann, Klaus
AU  - Jackisch, Christian
AU  - Park-Simon, Tjoung-Won
AU  - Ernst, Corinna
AU  - Hanker, Lars
AU  - Pfisterer, Jacobus
AU  - Schnelzer, Andreas
AU  - du Bois, Andreas
AU  - Schmutzler, Rita K
AU  - Harter, Philipp
TI  - Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)
AID  - 10.1136/jmedgenet-2018-105930
DP  - 2019 Sep 01
TA  - Journal of Medical Genetics
PG  - 574--580
VI  - 56
IP  - 9
4099  - http://jmg.bmj.com/content/56/9/574.short
4100  - http://jmg.bmj.com/content/56/9/574.full
SO  - J Med Genet2019 Sep 01; 56
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