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

Abstract

For individuals with ovarian cancer (OC), therapy options mainly depend on <i>BRCA1/2</i> 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? Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (<i>ATM</i>, <i>BRCA1/2, BRIP1</i>, <i>MSH2/6</i>, <i>PALB2</i>, <i>RAD51C/D</i> and <i>TP53</i>) and the <i>PIK3CA</i> and <i>PTEN</i> genes in individuals with OC (AGO-TR1 study, NCT02222883). Results were complemented by <i>BRCA1</i>, <i>PALB2</i> and <i>RAD51C</i> promoter methylation analyses and stratified by histological subtype; 473 individuals were included. The combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; <i>BRCA1/2</i>: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding <i>TP53</i> (all: 39/473, 8.2%; <i>BRCA1/2</i>: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; <i>BRCA1</i>: 57/473, 12.1%; <i>RAD51C</i>: 10/473, 2.1%; <i>PALB2</i>: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic <i>PIK3CA</i> and/or <i>PTEN</i> 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. Tumour sequencing of the <i>BRCA1, BRCA2, PIK3CA</i> and <i>PTEN</i> genes along with <i>BRCA1</i> and <i>RAD51C</i> 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. NCT02222883.