Abstract
PurposeThe Ataxia-telangiectasia mutated (ATM) gene encodes a multifunctional kinase, which is linked to important cellular functions. Women heterozygous for ATM mutations have an estimated relative risk of developing breast cancer of 3.8. However, the pattern of ATM mutations and their role in breast cancer etiology has been controversial and remains unclear. In the present study, we investigated the frequency and spectrum of ATM mutations in a series of sporadic breast cancers and controls from the Brazilian population.MethodsUsing PCR-Single Strand Conformation Polymorphism (SSCP) analysis and direct DNA sequencing, we screened a panel of 100 consecutive, unselected sporadic breast tumors and 100 matched controls for all 62 coding exons and flanking introns of the ATM gene.ResultsSeveral polymorphisms were detected in 12 of the 62 coding exons of the ATM gene. These polymorphisms were observed in both breast cancer patients and the control population. In addition, evidence of potential ATM mutations was observed in 7 of the 100 breast cancer cases analyzed. These potential mutations included six missense variants found in exon 13 (p.L546V), exon 14 (p.P604S), exon 20 (p.T935R), exon 42 (p.G2023R), exon 49 (p.L2307F), and exon 50 (p.L2332P) and one nonsense mutation in exon 39 (p.R1882X), which was predicted to generate a truncated protein.ConclusionsOur results corroborate the hypothesis that sporadic breast tumors may occur in carriers of low penetrance ATM mutant alleles and these mutations confer different levels of breast cancer risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-0787-z) contains supplementary material, which is available to authorized users.
Highlights
The Ataxia-telangiectasia mutated (ATM) gene encodes a multifunctional kinase, which is linked to important cellular functions (Derheimer and Kastan 2010; Shiloh and Ziv 2013)
Our results corroborate the hypothesis that sporadic breast tumors may occur in carriers of low penetrance ATM mutant alleles and these mutations confer different levels of breast cancer risk
The amplified DNA fragments were screened by PCR-Single Strand Conformation Polymorphism (SSCP) analysis and the samples showing band mobility shifts were further analyzed by direct DNA sequencing
Summary
The Ataxia-telangiectasia mutated (ATM) gene encodes a multifunctional kinase, which is linked to important cellular functions (Derheimer and Kastan 2010; Shiloh and Ziv 2013). The frequency of individuals heterozygous for a mutation in ATM is estimated to be 0.5 - 1% in the general population (Swift et al 1986; Easton 1994). Individuals heterozygous for A-T mutations, who are phenotypically normal, may exhibit increased radio- and chemo-sensitivity and an increased relative risk of carcinogenesis (Swift et al 1991; West et al 1995). An increased relative risk of breast cancer was identified for female A-T heterozygotes; while, the proportion of sporadic breast cancers in the general population that is due to ATM mutations remains controversial (Swift et al 1987; Ahmed and Rahman 2006; Mavrou et al 2008). Occurring ATM mutations are prevalent in a number of sporadic human cancers, most notably leukemias and carcinomas of the breast and lung (Cremona and Behrens, 2014)
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