TwoATM variants and breast cancer risk

Cancer Research United Kingdom Genetic Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
Human Mutation (Impact Factor: 5.14). 06/2005; 25(6):594-5. DOI: 10.1002/humu.9344
Source: PubMed


The ATM gene is mutated in ataxia-telangiectasia (AT). Heterozygote female relatives of AT cases have a 2-7fold increased risk of breast cancer. We previously reported high risks of breast cancer associated with certain ATM variants. To estimate the risks more precisely, we have examined two ATM variants, c.1066-6T>G (IVS10-6T>G) and c.4258C>T (p.Leu1420Phe), in additional cases and controls from the same Australian cohorts previously used to estimate the risk of breast cancer associated with c.1066-6T>G. A total of 775 and 84 population-based controls were genotyped for the c.1066-6T>G and c.4258C>T ATM variants respectively, as were index cases from 378 and 373 non-BRCA1/2 breast cancer families. Penetrance was estimated by Bayes factor analysis. The allele frequencies of ATM c.1066-6T>G and c.4258C>T estimated from controls were 0.005 (95% CI=0.002 to 0.009) and 0.012 (95% CI=0.001 to 0.042), respectively. We identified three new breast cancer families with c.1066-6T>G, and seven families with c.4258C>T. Combining with the two c.1066-6T>G families previously reported, the estimated penetrance to age 70 of c.1066-6T>G was 17.2% (95% CI=4.7% to 37.5%). For c.4258C>T, the estimated average penetrance was 4.8% (95% CI 1.7% to 10.1%). In conclusion, we found no evidence that the ATM c.4258C>T variant increases breast cancer risk, and little evidence that c.1066-6T>G confers an elevated risk. Analysis of additional families will be necessary to define more precisely the risk, if any, associated with c.1066-6T>G.

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Available from: Graham G Giles, Sep 18, 2014
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    • "2008). Although AT is rare, with a frequency of ∼1/40,000, up to 1% of the population could be heterozygous carriers of ATM mutations, and these carrier individuals are estimated to have an increased risk of pancreatic cancer and breast cancer (Savitsky et al. 1995; Thompson et al. 2005; Renwick et al. 2006; Roberts et al. 2012). In addition to hereditary cancer, ATM mutations are frequently detected in diverse sporadic cancers (Stankovic et al. 2002; Gumy-Pause et al. 2004; Hall. "
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    ABSTRACT: Many tumors contain mutations that confer defects in the DNA damage response and genome stability. DNA damaging agents are powerful therapeutic tools that can differentially kill cells with an impaired DNA damage response. The response to DNA damage is complex and comprised of a network of coordinated pathways, often with a degree of redundancy. Tumor-specific somatic mutations in DNA damage response genes could be exploited by inhibiting the function of a second gene product to increase the sensitivity of tumor cells to a sub-lethal concentration of a DNA damaging therapeutic agent, resulting in a class of conditional synthetic lethality we call Synthetic Cytotoxicity. We used the Saccharomyces cerevisiae non-essential gene deletion collection to screen for synthetic cytotoxic interactions with camptothecin, a topoisomerase I inhibitor, and a null mutation in TEL1, the S. cerevisiae orthologue of the mammalian tumor suppressor gene, ATM. We found and validated 14 synthetic cytotoxic interactions that define at least five epistasis groups. One class of synthetic cytotoxic interaction was due to telomere defects. We also found that at least one synthetic cytotoxic interaction was conserved in Caenorhabditis elegans. We have demonstrated that synthetic cytotoxicity could be a useful strategy to expand the sensitivity of certain tumors to DNA damaging therapeutics.
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    • "A number of studies have reported ATM mutation carriers to have a 2–7-fold increased risk of breast cancer (Swift et al, 1991; Easton, 1994; Athma et al, 1996; Stankovic et al, 1998; Inskip et al, 1999; Janin et al, 1999; Geoffroy-Perez et al, 2001; Olsen et al, 2001; Bernstein et al, 2003; Thompson et al, 2005a, 2005b; Reiman et al, 2011), with increased risk presumably associated with loss of heterozygosity, the sporadic loss of the normal ATM allele, resulting in either total loss of or a large reduction in functional ATM protein. Interestingly, this is the fourth time that neurologically milder A-T has been diagnosed following radiotherapy for breast cancer (Stankovic et al, 1998; Fang et al, 2010; Mandigers et al, 2011). "
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    • "Studies based on relatives of ataxia-telangiectasia patients, and breast cancer case– control studies, have estimated that the relative risk of breast cancer in heterozygous carriers of ATM mutations is approximately 2 (Olsen et al., 2001; Cavaciuti et al., 2005; Thompson et al., 2005b), with some evidence of higher relative risk under the age of 50 years. Specific mutations, notably 7271T>G, may confer higher breast cancer risks (Chenevix-Trench et al., 2002), although the evidence is limited (Bernstein et al., 2003; Thompson et al., 2005a). More recently, a truncating variant in CHEK2, 1100delC, has also been shown to confer an approximately twofold risk of breast cancer (Meijers-Heijboer et al., 2002). "
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