The A allele of rs1801516, located at 11q22.3 in the coding region of the
ATM gene showed a reduction in the risk of breast cancer by 0.6-fold. ATM is a serine-threonine kinase that is known to be associated with risk of breast cancer through its regulatory effects on the cellular response to DNA DSB [
44]. In addition, active ATM is known to exert antineoplastic effects through the activation of checkpoints in the cell cycle, initiation of apoptosis, and accumulation of p53 [
44]. However, several studies have reported conflicting results on the relationship between
ATM genetic variants and breast cancer susceptibility [
42‐
45]. Mehdipour et al. reported that a common SNP (rs1801516) in exon 39 of the
ATM gene (5557G > A, D1853N) may serve to increase the risk for breast cancer, mainly in families with cancer predisposition [
45]. Shrauder et al. reported a marginal association between this variant and reduced breast cancer risk [OR for the heterozygous genotype = 0.70, 95% CI, 0.52–0.94,
P = 0.018] and for the homozygous variant, [OR = 0.63, 95% CI, 0.27–1.49,
P = 0.292] [
46]. However, a meta-analysis involving 9 epidemiological studies showed that the
ATM rs1801516 polymorphism had no association with risk of breast cancer. The authors concluded that this polymorphism acting alone may not influence breast cancer susceptibility [
47]. The published data on the role of
ATM as a marker of genetic susceptibility to breast cancer is rather inconsistent. Concannon et al. reported that carriers of common
ATM genetic variants had a reduction in the risk of cancer in the contralateral breast which was statistically significant [
48]. According to their findings, SNP rs1801673, c.5558A > T, p.Asp1853Val [RR = 0.2; 95% CI, 0.1–0.6] was associated with a substantial reduction in the risk of developing a contralateral breast cancer while rs1801516, 5557G > A, p.Asp1853Val was associated with a mere 0.9 fold reduction in risk [
48]. These findings indicate that certain
ATM alleles may produce an anti-tumour effect, either by modifying the activity of
ATM through its initial response to DNA damage or as a regulator of p53 [
48]. Functional studies of the cellular activity of
ATM in individuals who carry these variant alleles will aid in further elucidating their anti-tumour properties.
Our study had several strengths, including an adequate sample size from a homogenous ethnicity (100% of study participants were Sinhalese), thus minimizing any bias arising from population stratification. Study limitations include the fact that the analysis did not take into consideration probable differences in lifestyle factors and the selected SNPs may not give as comprehensive a view of genetic variation as sequencing does. It is possible that the other SNPs which showed a null association with breast cancer either do not modify the susceptibility to breast cancer in the Sri Lankan population or their effects are minimal and can be detected only with larger study samples. We plan to address these issues in subsequent studies. A detailed analysis of the phenotypic and clinical characteristics of this cohort in relation to the genotypic results is the subject of another study.