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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.

Breast tumors from CHEK2 1100delC- mutation carriers: genomic landscape and clinical implications