Abstract
BackgroundThe ATM gene has been frequently involved in hereditary breast cancer as a low-penetrance susceptibility gene but evidence regarding the role of ATM as a breast cancer susceptibility gene has been contradictory.MethodsIn this study, a full mutation analysis of the ATM gene was carried out in patients from 137 Chilean breast cancer families, of which 126 were BRCA1/2 negatives and 11 BRCA1/2 positives. We further perform a case-control study between the subgroup of 126 cases BRCA1/2 negatives and 200 controls for the 5557G>A missense variant and the IVS38-8T>C and the IVS24-9delT polymorphisms.ResultsIn the full mutation analysis we detected two missense variants and eight intronic polymorphisms. Carriers of the variant IVS24-9delT, or IVS38-8T>C, or 5557G>A showed an increase in breast cancer risk. The higher significance was observed in the carriers of IVS38-8T>C (OR = 3.09 [95%CI 1.11–8.59], p = 0.024). The IVS24-9 T/(-T), IVS38-8 T/C, 5557 G/A composite genotype confered a 3.19 fold increase in breast cancer risk (OR = 3.19 [95%CI 1.16–8.89], p = 0.021). The haplotype estimation suggested a strong linkage disequilibrium between the three markers (D' = 1). We detected only three haplotypes in the cases and control samples, some of these may be founder haplotypes in the Chilean population.ConclusionThe IVS24-9 T/(-T), IVS38-8 T/C, 5557 G/A composite genotype alone or in combination with certain genetic background and/or environmental factors, could modify the cancer risk by increasing genetic inestability or by altering the effect of the normal DNA damage response.
Highlights
The Ataxia-Telangiectasia Mutated gene (ATM) gene has been frequently involved in hereditary breast cancer as a lowpenetrance susceptibility gene but evidence regarding the role of ATM as a breast cancer susceptibility gene has been contradictory
A number of studies have searched for germ line ATM mutations in breast cancer cases and/or compared the frequency of common ATM variants among breast cancer cases to population controls, but evidence regarding the role of ATM as a breast cancer susceptibility gene has been contradictory [6,7]
We further evaluated the 5557G>A missense variant and the IVS38-8T>C and the IVS24-9delT polymorphisms, for breast cancer risk in a subgroup of 126 familial breast cancer cases without BRCA1/2 mutations and in 200 healthy controls
Summary
The ATM gene has been frequently involved in hereditary breast cancer as a lowpenetrance susceptibility gene but evidence regarding the role of ATM as a breast cancer susceptibility gene has been contradictory. Mutations in BRCA1 and BRCA2 genes (BRCA1/2) have been identified as high penetrance alleles These alleles explain only a small fraction of familial breast cancers [1,2]. The most widely accepted model proposes that familial breast cancer susceptibility is a consequence of a small number of mutations in BRCA1/2 and a much larger variability in ethnic-specific genes of moderate and/or low penetrance [4]. The Ataxia-Telangiectasia Mutated gene (ATM) has been frequently involved in hereditary breast cancer as a low-penetrance susceptibility gene. A number of studies have searched for germ line ATM mutations in breast cancer cases and/or compared the frequency of common ATM variants among breast cancer cases to population controls, but evidence regarding the role of ATM as a breast cancer susceptibility gene has been contradictory [6,7]. The 5557G>A variant has previously been reported in the homozygous state to associate with enhanced clinical radiosensitivity in breast cancer patients [10,11,12]
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