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

J Med Genet. 2019 Sep;56(9):574-580. doi: 10.1136/jmedgenet-2018-105930. Epub 2019 Apr 12.


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.

Keywords: germline variant; methylation; ovarian cancer; somatic variant; targeted therapy.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA1 Protein
  • BRCA2 Protein
  • Biomarkers, Tumor
  • Computational Biology / methods
  • DNA Copy Number Variations
  • DNA Methylation
  • Female
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Germ-Line Mutation
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Ovarian Neoplasms / diagnosis
  • Ovarian Neoplasms / epidemiology
  • Ovarian Neoplasms / genetics*
  • Prevalence
  • Promoter Regions, Genetic
  • Sequence Deletion*


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Biomarkers, Tumor

Associated data