The spectrum of ATM missense variants and their contribution to contralateral breast cancer

Abstract

Heterozygous carriers of ATM mutations are at increased risk of breast cancer. In this case-control study, we evaluated the significance of germline ATM missense variants to the risk of contralateral breast cancer (CBC). We have determined the spectrum and frequency of ATM missense variants in 443 breast cancer patients diagnosed before age 50, including 247 patients who subsequently developed CBC. Twenty-one per cent of the women with unilateral breast cancer and 17% of the women with CBC had at least one ATM germline missense variant, indicating no significant difference in variant frequency between these two groups. We have found that carriers of an ATM missense mutation, who were treated with radiotherapy for the first breast tumour, developed their second tumour on average in a 92-month interval compared to a 136-month mean interval for those CBC patients who neither received RT nor carried a germline variant, (p = 0.029). Our results indicate that the presence of ATM variants does not have a major impact on the overall risk of CBC. However, the combination of RT and (certain) ATM missense variants seems to accelerate tumour development.

ATMGene Variants in Patients with Idiopathic Perifoveal Telangiectasia

“…Interestingly, this fraction perfectly correlates with the fraction of Dutch patients with breast cancer who carried AT-causing mutations. 33 The frequency of possibly disease-associated ATM missense alleles, excluding the common D1853N SNP, is approximately 20% in European breast cancer patients, 34 which is again lower than the analogous fraction (35%, 8 of 23; P ϭ 0.05) in this study. The association of ATM missense alleles with cancer has varied between studies.…”

Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: A genotype-phenotype study

“…For all patients, ATM mutation analysis was performed using methods as previously described [Broeks et al, 1998[Broeks et al, , 2000[Broeks et al, , 2008. Large genomic deletions and insertions were assessed by MLPA (multiplex ligation-dependent probe amplification; kit P041 and P042, MRC-Holland).…”

Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry

“…Several methods have previously been used to screen for ATM mutations to overcome the complexity of analyzing ATM gene, such as a non-isotopic RNase cleavage-based assay (NIRCA) [29], denaturating gradient gel electrophoresis (DGGE) [30], single-strand conformational polymorphism (SSCP) [31], denaturing high-performance liquid chromatography (DHPLC) [32], and more recently enhanced mismatch mutation analysis (EMMA) [33]. Despite the availability of all these techniques for ATM analysis, Sanger sequencing of the entire coding and flanking sequences of ATM gene remains standard making ATM mutation identification expensive and labor intensive.…”