Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

Hum Mutat. 2015 Nov;36(11):1088-99. doi: 10.1002/humu.22845. Epub 2015 Aug 14.

Abstract

Somatic mosaicism for DNA copy-number alterations (SMC-CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC-CNAs can undergo clonal expansion, it has been proposed that SMC-CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array-based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC-CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC-CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC-CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co-occurrence of gross SMC-CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.

Keywords: CNA; CNV; breast cancer; driver mutations; genome stability; rearrangement; somatic mosaicism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations*
  • DNA Mutational Analysis
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Genetic Association Studies
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genomic Instability*
  • Humans
  • Middle Aged
  • Mutation*
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Reproducibility of Results
  • Tumor Burden

Substances

  • Biomarkers, Tumor