Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel

J Mol Diagn. 2020 Apr;22(4):544-554. doi: 10.1016/j.jmoldx.2020.01.013. Epub 2020 Feb 15.

Abstract

Differences in the mutation spectrum across ethnicities suggest the importance of identifying genes in addition to common high penetrant genes to estimate the associated breast cancer risk in China. A total of 1338 high-risk breast cancer patients who tested negative for germline BRCA1, BRCA2, TP53, and PTEN mutations between 2007 and 2017 were selected from the Hong Kong Hereditary Breast Cancer Family Registry. Patient samples were subjected to next-generation DNA sequencing using a multigene panel (Color Genomics). All detected pathogenic variants were validated by bidirectional DNA sequencing. The sequencing data were coanalyzed by a bioinformatics pipeline developed in-house. Sixty-one pathogenic variants (4.6%) were identified in this cohort in 11 cancer predisposition genes. Most carriers (77.1%) had early onset of breast cancer (age <45 years), 32.8% had family members with breast cancer, and 11.5% had triple-negative breast cancer. The most common mutated genes were PALB2 (1.4%), RAD51D (0.8%), and ATM (0.8%). A total of 612 variants of unknown significance were identified in 494 patients, and 87.4% of the variants of unknown significance were missense mutations. Pathogenic variants in cancer predisposition genes beyond BRCA1, BRCA2, TP53, and PTEN were detected in an additional 4.6% of patients using the multigene panel. PALB2 (1.4%) and RAD51D (0.8%) were the most commonly mutated genes in patients who tested mutation negative by a four-gene panel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Biomarkers, Tumor*
  • Computational Biology / methods
  • Female
  • Genetic Association Studies / methods
  • Genetic Predisposition to Disease*
  • Genetic Testing / methods
  • Genotype
  • Germ-Line Mutation*
  • Hereditary Breast and Ovarian Cancer Syndrome / diagnosis
  • Hereditary Breast and Ovarian Cancer Syndrome / epidemiology*
  • Hereditary Breast and Ovarian Cancer Syndrome / genetics*
  • Humans
  • Middle Aged
  • Neoplasm Grading
  • PTEN Phosphohydrolase / genetics
  • Prevalence
  • Young Adult

Substances

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