title: Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications.
abstract: BACKGROUND
  Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers.
  
  
  METHODS
  In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method.
  
  
  RESULTS
  We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels.Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time.
  
  
  CONCLUSIONS
  We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation.
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 8, Helsinki, FI-00029, Finland.
authors.forename: Taru A
authors.initials: TA
authors.lastname: Muranen
authors.forename: Dario
authors.initials: D
authors.lastname: Greco
authors.forename: Rainer
authors.initials: R
authors.lastname: Fagerholm
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: Kati
authors.initials: K
authors.lastname: Kämpjärvi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D001499:Bayes Theorem; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics; D064447:Checkpoint Kinase 2; D018118:Chloride Channels / Q000235:genetics; D002878:Chromosomes, Human, Pair 1; D055028:Comparative Genomic Hybridization; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017384:Sequence Deletion; D014157:Transcription Factors; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C495392:CALCOCO1 protein, human; C492109:CLCA1 protein, human; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018118:Chloride Channels; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D014157:Transcription Factors; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases