Abstract
BackgroundThe gene CHEK2 encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though CHEK2 has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. Alteration in gene expression regulation provides a potential mechanism for generating disease susceptibility. The detection of differential allelic expression (DAE) represents a sensitive assay to direct the search for a functional sequence variant within the transcriptional regulatory elements of a candidate gene. We aimed to assess whether CHEK2 was subject to DAE in lymphoblastoid cell lines (LCLs) from high-risk breast cancer patients for whom no mutation in BRCA1 or BRCA2 had been identified.MethodsWe implemented an assay based on high-resolution melting (HRM) curve analysis and developed an analysis tool for DAE assessment.ResultsWe observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of CHEK2 that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs.ConclusionsOur results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms.
Highlights
The gene CHEK2 encodes a checkpoint kinase playing a key role in the DNA damage pathway
In order to fully assess the contribution of CHEK2 in breast cancer susceptibility, we aimed to test whether the gene was subject to differential allelic expression (DAE)
Lymphoblastoid cell lines We used a total of 89 lymphoblastoid cell lines (LCLs) derived from breast cancer patients, who were considered to be at high risk of carrying a genetic predisposition to cancer due to an early age at onset and/or family history, and for whom no mutation in BRCA1 or BRCA2
Summary
The gene CHEK2 encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though CHEK2 has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. The CHEK2-Breast Cancer Consortium reported a frequency of 5.1% for the CHEK2*1100delC variant in familial breast cancer cases who tested negative for BRCA1 and BRCA2 (Breast cancer 2, early onset) mutations, as opposed to 1.1% of carriers in the control population [3]. This intermediate-risk breast cancer susceptibility allele almost triples the risk of developing the disease in unselected breast cancer cases (OR = 2.34; 95% CI[1.72 - 3.20]) [4]. Though first discovered in breast cancer patients, CHEK2 mutations have since been reported to predispose to a range of cancer types, including ovarian, prostate, kidney and colorectal cancers [6], supporting the hypothesis that CHEK2 is a multiorgan cancer susceptibility gene [5]
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