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

Abstract

BackgroundFor 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?MethodsPaired 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.ResultsThe 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.ConclusionTumour 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 numberNCT02222883

Year 1: Experiences of a tertiary cancer centre following implementation of reflex BRCA1 and BRCA2 tumor testing for all high-grade serous ovarian cancers in a universal healthcare system

“…When tumor testing is completed, follow-up genetic counseling and germline testing of patients with identified PVs is critical to clarify whether family members may be at risk. This is particularly important for HGSOC, as 57-85% of BRCA1/2 PVs identified in tumor tissues are germline in origin [25,[33][34][35]. In this study, 94% (16/17) of HGSOC patients with a BRCA1/2 PV in their tumor were referred for genetic counseling, all of whom provided a blood sample for germline testing.…”

PTEN and Gynecological Cancers

“…The reported prevalence of deleterious somatic PIK3CA and/or PTEN variants in germline mutation-negative OC individuals (13%), together with encouraging data from Phase 1 trials on gynaecological patients receiving PI3K/AKT/mTOR inhibitors, suggest that this pathway will be more investigated in the future [39,40].…”

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

“…5 In ovarian cancer, mutation of PTEN has been a reported driver in endometrioid and clear cell subtypes. [6][7][8][9][10] Homozygous loss of PTEN is found in 6% of HGSOC 11 and loss-of-function mutations of Pten allow for accelerated tumour growth in mouse and in vitro models of HGSOC and ENOC. [12][13][14] We previously demonstrated that PTEN loss is prevalent in HGSOC using bioinformatics and image analysis methods that corrected for cellularity in gene expression signatures from The Cancer Genome Atlas.…”