Absence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapy

Abstract

The effectiveness of cancer radiotherapy is compromised by the small proportion (approximately 5%) of patients who sustain severe normal tissue damage after standard radiotherapy treatments. Predictive tests are required to identify these highly radiosensitive cases. Patients with the rare, recessively inherited, cancer-prone syndrome ataxia-telangiectasia (A-T) sustain extremely severe normal tissue necrosis after radiotherapy and their cultured cells are also highly radiosensitive. Clinically normal carriers (heterozygotes) of the A-T gene have an increased risk of breast cancer, account for approximately 4% of all breast cancer cases and show a modest increase in cellular radiosensitivity in vitro. It has been suggested that a substantial proportion of highly radiosensitive (HR) breast cancer patients may be A-T heterozygotes, and that screening for mutations in the A-T gene could be used as a predictive test. We have tested this hypothesis in a group of cancer patients who showed adverse reactions to radiotherapy. Sixteen HR breast cancer patients showing mainly acute reactions (and seven HR patients with other cancers) were tested for ATM mutations using the restriction endonuclease fingerprinting assay. No mutations typical of those found in obligate A-T heterozygotes were detected. If the estimate that 4% of breast cancer cases are A-T gene carriers is correct, then ATM mutations do not confer clinical radiosensitivity. These early results suggest that screening for ATM mutations in cancer patients may not be of value in predicting adverse reactions.

Radiation-hypersensitive cancer patients do not manifest protein expression abnormalities in components of the nonhomologous end-joining (NHEJ) pathway

“…Screening for heterozygous mutations in the gene homozygously mutated in the cancer-prone, radiosensitivity disorder, ataxia-telangiectasia (ATM: AT mutated) in radiosensitive patients has been vigorously pursued during the past few years. However, data from several studies suggest that ATM gene defects are not a major cause of radiation hypersensitivity (Appleby et al, 1997;Clarke et al, 1998;Hall et al, 1998;Ramsay et al, 1998;Shayeghi et al, 1998;Oppitz et al, 1999). We have previously reported the results of mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in a cohort of radiationhypersensitive cancer patients (Leong et al, 2000).…”

Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families

“…However, the previous suggestion that the ATM heterozygotes would be highly ionizingradiation sensitive (Swift et al, 1987) is still unconfirmed. Indeed, studies on highly clinical-radiosensitive BC patients did not show evidence for an elevated ATM heterozygote rate (Appleby et al, 1997;Shayeghi et al, 1998). Thus it does not appear necessary, so far, to subject women with ATM het status to any different screening program which is not already available to women with a first-degree relative affected by BC.…”

Screening breast cancer patients for Norwegian ATM mutations

“…A subgroup of patients found to carry ATM mutations is those with radiationinduced bilateral breast cancer at young age with good prognosis (Broeks et al, 2000). However, no excess of truncating ATM mutations were found in three small cohorts of breast cancer patients showing tissue radiation side-effects (Appleby et al, 1997;Shayeghi et al, 1998;Oppitz et al, 1999).…”

“…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.…”

“…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.…”