Genetic and epigenetic profiling of BRCA1/2 in ovarian tumors reveals additive diagnostic yield and evidence of a genomic BRCA1/2 DNA methylation signature

J Hum Genet. 2020 Oct;65(10):865-873. doi: 10.1038/s10038-020-0780-4. Epub 2020 Jun 1.

Abstract

Poly-ADP-ribose-polymerase inhibitor (PARPi) treatment is indicated for advanced-stage ovarian tumors with BRCA1/2 deficiency. The "BRCAness" status is thought to be attributed to a tumor phenotype associated with a specific epigenomic DNA methylation profile. Here, we examined the diagnostic impact of combined BRCA1/2 sequence, copy number, and promoter DNA methylation analysis, and evaluated whether genomic DNA methylation patterns can predict the BRCAness in ovarian tumors. DNA sequencing of 172 human tissue samples of advanced-stage ovarian adenocarcinoma identified 36 samples with a clinically significant tier 1/2 sequence variants (point mutations and in/dels) and 9 samples with a CNV causing a loss of function in BRCA1/2. DNA methylation analysis of the promoter of BRCA1/2 identified promoter hypermethylation of BRCA1 in two mutation-negative samples. Computational modeling of genome-wide methylation markers, measured using Infinium EPIC arrays, resulted in a total accuracy of 0.75, sensitivity: 0.83, specificity: 0.64, positive predictive value: 0.76, negative predictive value: 0.74, and area under the receiver's operating curve (AUC): 0.77, in classifying tumors harboring a BRCA1/2 defect from the rest. These findings indicate that the assessment of CNV and promoter DNA methylation in BRCA1/2 increases the cumulative diagnostic yield by 10%, compared with the 20% yield achieved by sequence variant analysis alone. Genomic DNA methylation data can partially predict BRCAness in ovarian tumors; however, further investigation in expanded BRCA1/2 cohorts is needed, and the effect of other double strand DNA repair gene defects in these tumors warrants further investigations.

MeSH terms

  • Adenocarcinoma / diagnosis
  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics*
  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • DNA Copy Number Variations
  • DNA Methylation*
  • DNA, Neoplasm / chemistry
  • DNA, Neoplasm / genetics
  • Female
  • Genes, BRCA1*
  • Genes, BRCA2*
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Humans
  • INDEL Mutation
  • Middle Aged
  • Molecular Diagnostic Techniques*
  • Neoplastic Syndromes, Hereditary / diagnosis
  • Neoplastic Syndromes, Hereditary / drug therapy
  • Neoplastic Syndromes, Hereditary / genetics*
  • Ovarian Neoplasms / diagnosis
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Point Mutation
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Predictive Value of Tests
  • Promoter Regions, Genetic / genetics
  • ROC Curve
  • Sensitivity and Specificity

Substances

  • Antineoplastic Agents
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • DNA, Neoplasm
  • Poly(ADP-ribose) Polymerase Inhibitors