Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer

JAMA Oncol. 2017 Sep 1;3(9):1190-1196. doi: 10.1001/jamaoncol.2017.0424.

Abstract

Importance: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined.

Objective: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes.

Design, setting, and participants: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016.

Main outcomes and measures: Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes.

Results: The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer.

Conclusions and relevance: This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.

MeSH terms

  • Acid Anhydride Hydrolases
  • Adult
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Cell Cycle Proteins / genetics
  • Checkpoint Kinase 2 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18 / genetics
  • DNA Repair Enzymes / genetics
  • DNA-Binding Proteins / genetics*
  • Fanconi Anemia Complementation Group N Protein
  • Fanconi Anemia Complementation Group Proteins
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Germ-Line Mutation
  • Humans
  • MRE11 Homologue Protein
  • Middle Aged
  • Mismatch Repair Endonuclease PMS2 / genetics
  • MutL Protein Homolog 1 / genetics
  • MutS Homolog 2 Protein / genetics
  • Neurofibromin 1 / genetics
  • Nuclear Proteins / genetics*
  • Ovarian Neoplasms / genetics*
  • Phenotype
  • RNA Helicases / genetics
  • Risk Factors
  • Tumor Suppressor Proteins / genetics*
  • Ubiquitin-Protein Ligases / genetics*
  • White People / genetics

Substances

  • CDKN2A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • Fanconi Anemia Complementation Group Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • MRE11 protein, human
  • NBN protein, human
  • Neurofibromin 1
  • Nuclear Proteins
  • PALB2 protein, human
  • RAD51C protein, human
  • RAD51D protein, human
  • Tumor Suppressor Proteins
  • BARD1 protein, human
  • Ubiquitin-Protein Ligases
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • RAD50 protein, human
  • PMS2 protein, human
  • MSH2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • BRIP1 protein, human
  • RNA Helicases
  • DNA Repair Enzymes