title: Genomic profiling of CHEK2*1100delC-mutated breast carcinomas.
abstract: BACKGROUND
  CHEK2*1100delC is a moderate-risk breast cancer susceptibility allele with a high prevalence in the Netherlands. We performed copy number and gene expression profiling to investigate whether CHEK2*1100delC breast cancers harbor characteristic genomic aberrations, as seen for BRCA1 mutated breast cancers.
  
  
  METHODS
  We performed high-resolution SNP array and gene expression profiling of 120 familial breast carcinomas selected from a larger cohort of 155 familial breast tumors, including BRCA1, BRCA2, and CHEK2 mutant tumors. Gene expression analyses based on a mRNA immune signature was used to identify samples with relative low amounts of tumor infiltrating lymphocytes (TILs), which were previously found to disturb tumor copy number and LOH (loss of heterozygosity) profiling. We specifically compared the genomic and gene expression profiles of CHEK2*1100delC breast cancers (n = 14) with BRCAX (familial non-BRCA1/BRCA2/CHEK2*1100delC mutated) breast cancers (n = 34) of the luminal intrinsic subtypes for which both SNP-array and gene expression data is available.
  
  
  RESULTS
  High amounts of TILs were found in a relatively small number of luminal breast cancers as compared to breast cancers of the basal-like subtype. As expected, these samples mostly have very few copy number aberrations and no detectable regions of LOH. By unsupervised hierarchical clustering of copy number data we observed a great degree of heterogeneity amongst the CHEK2*1100delC breast cancers, comparable to the BRCAX breast cancers. Furthermore, copy number aberrations were mostly seen at low frequencies in both the CHEK2*1100delC and BRCAX group of breast cancers. However, supervised class comparison identified copy number loss of chromosomal arm 1p to be associated with CHEK2*1100delC status.
  
  
  CONCLUSIONS
  In conclusion, in contrast to basal-like BRCA1 mutated breast cancers, no apparent specific somatic copy number aberration (CNA) profile for CHEK2*1100delC breast cancers was found. With the possible exception of copy number loss of chromosomal arm 1p in a subset of tumors, which might be involved in CHEK2 tumorigenesis. This difference in CNAs profiles might be explained by the need for BRCA1-deficient tumor cells to acquire survival factors, by for example specific copy number aberrations, to expand. Such factors may not be needed for breast tumors with a defect in a non-essential gene such as CHEK2.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. m.massink@vumc.nl.
authors.forename: Maarten P G
authors.initials: MP
authors.lastname: Massink
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. ei.kooi@vumc.nl.
authors.forename: Irsan E
authors.initials: IE
authors.lastname: Kooi
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, The Netherlands. j.martens@erasmusmc.nl.
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. q.waisfisz@vumc.nl.
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. h.meijers-heijboer@vumc.nl.
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
mesh_terms: D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008875:Middle Aged; D009426:Netherlands; D017384:Sequence Deletion
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human