Identification of germline missense mutations and rare allelic variants in the ATM gene in early‐onset breast cancer

Abstract

Epidemiological studies have shown an increased risk of breast cancer in obligate ataxia telangiectasia (A-T) heterozygotes. We analyzed 100 samples from young breast cancer patients for mutations in ataxia-telangiectasia mutated (ATM), the gene responsible for the autosomal recessive condition, A-T, to determine whether A-T heterozygosity predisposes such individuals to develop breast cancer. These patients were selected from families with a moderate or absent family history of breast cancer and included a subset of 16 radiosensitive patients. Forty-four germline sequence variants were detected by fluorescent chemical cleavage of mismatch of RT-PCR products. These included seven rare variants found in nine patients (three described for the first time), but no truncating mutations. Although three variants were detected in the radiosensitive subset, this was not statistically significant compared to the nonradiosensitive group. One variant, G2765S, is likely to be a missense mutation, but the other six variants probably represent rare polymorphisms. However, five of the seven rare germline variants detected showed loss of heterozygosity of the wild-type ATM allele for one or more markers close to the ATM locus in matched tumor DNA. This high rate of somatic inactivation of ATM may indicate either that these rare variants play a role in breast cancer development or alternatively that a neighboring tumor suppressor gene is important for tumorigenesis. We found germline truncating ATM mutations to be rare in these young breast cancer patients and therefore they are unlikely to play a role in the etiology of their disease. Genes Chromosomes Cancer 26:286-294, 1999.

Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers

“…This missense alteration has not been previously described as a polymorphism in the ATM mutation database (http://www.benaroyaresearch.org/bri_investigators/ atm.htm). It has been reported as a rare variant (allele frequency 0.015) by Izatt et al (1999), and found in the heterozygous state in four out of 65 individuals of North African origin (Hall, unpublished data), and thus was considered as an ATM polymorphism in this present study. LCLs were routinely maintained at 371C, in a humidified incubator with 5% CO 2 , in exponential growth by dilution twice a week to 5 Â 10 5 cells ml À1 in RPMI1640 medium (Gibco, Invitrogen Corporation, Cergy-Pontoise, France) supplemented with 10% heat-inactivated foetal calf serum (Integro b.v, Zaandan, Holland) and penicillin and streptomycin (100 mg ml À1 , Gibco).…”

Investigation on the role of the ATM gene in chronic myeloid leukaemia

“…However, a non-conservative amino acid change H1380Y (C4138T) was discovered that lies directly within the Abl-binding motif DPAPNPPHFP in exon 30 and two samples had a nearby rare polymorphism, C4258T, causing a non-conservative amino acid change (L1420F) that has been reported previously. 22,23 Both nucleotide changes detected in the CML samples appeared to have arisen on one allele.…”

Screening breast cancer patients for Norwegian ATM mutations

“…No missense mutations were screened for in the present study. There are, however, several reports on germline amino acid substitutions in breast cancer patients with frequencies ranging from 7-41% (Vorechovsky et al, 1996a(Vorechovsky et al, , 1996bAppleby et al, 1997;Larson et al, 1998;Shayeghi et al, 1998;Izatt et al, 1999). Gatti et al (1999) hypothesize that both heterozygotes and homozygotes for the two types of ATM mutations, the truncating (ATM trunc ), resulting in no protein or truncated protein, and the missense (ATM mis ) resulting in reduced amounts of defective protein, may give different phenotypes.…”

“…This is in agreement with Vorechovsky et al (1996b). Recently, Izatt et al (1999) reported loss of the wild type allele in five breast cancer patients carrying different missense substitutions in the ATM protein, suggesting that LOH coincides with ATM missense mutations in breast cancer development.…”

“…Three of these patients carried the same intronic alteration, IVS10-6 G/T, the function of which is uncertain. Several studies did not find an excess of classical ATM mutations in breast cancer patients (Vorechovsky et al, 1996b;Appleby et al, 1997;Fitzgerald et al, 1997;Chen et al, 1998;Shayeghi et al, 1998;Bebb et al, 1999;Izatt et al, 1999;Oppitz et al, 1999). The statistical power is generally low in these studies due to small numbers of ATM mutation carriers (Bishop and Hopper, 1997) and most studies have screened for classical truncating mutations only.…”