@article {Hauke574, author = {Jan Hauke and Eric Hahnen and Stephanie Schneider and Alexander Reuss and Lisa Richters and Stefan Kommoss and Andr{\'e} Heimbach and Frederik Marm{\'e} and Sandra Schmidt and Katharina Prieske and Heidrun Gevensleben and Alexander Burges and Julika Borde and Nikolaus De Gregorio and Peter N{\"u}rnberg and Ahmed El-Balat and Holger Thiele and Felix Hilpert and Janine Altm{\"u}ller and Werner Meier and Dimo Dietrich and Rainer Kimmig and Birgid Schoemig-Markiefka and Karin Kast and Elena Braicu and Klaus Baumann and Christian Jackisch and Tjoung-Won Park-Simon and Corinna Ernst and Lars Hanker and Jacobus Pfisterer and Andreas Schnelzer and Andreas du Bois and Rita K Schmutzler and Philipp Harter}, title = {Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)}, volume = {56}, number = {9}, pages = {574--580}, year = {2019}, doi = {10.1136/jmedgenet-2018-105930}, publisher = {BMJ Publishing Group Ltd}, 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}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/56/9/574}, eprint = {https://jmg.bmj.com/content/56/9/574.full.pdf}, journal = {Journal of Medical Genetics} }