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Cancer susceptibility in ATM heterozygotes: do two distinct carrier populations exist?

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The failure to find an increased frequency of ATM mutations in large cancer cohorts, especially breast cancer, is contrary to what was anticipated based on the increased cancer susceptibility of obligate ATM heterozygotes from families with ataxia telangiectasia. This apparent contradiction might be resolved if two types of ATM heterozygotes were to exist and their phenotypes were to differ, ie, those with truncating types of mutations (ATM trunc) that make no protein, and those with missense types of mutations (ATM mis) that make reduced amounts of defective protein; the latter could create a dominant negative effect that could be more detrimental than having no protein at all. The phenotype of ATM trunc/truncmutations is the AT syndrome; the phenotype of ATM mis/mis mutations, judging from the few homozygous patients that have been documented, appears to include some neurological features and cancer susceptibility but not the typical AT syndrome. Evidence will be presented which suggests that ATM mis/wt mutations are technically more difficult to detect than ATM trunc/wt mutations. Despite this, most large cancer cohort studies have identified mainly missense mutations and few truncating mutations. If substantiated, this model would require a paradigm shift for cancer risk analyses that would recognize the existence of different allelic frequencies for the missense and truncating ATM heterozygotes.

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Gatti, R., Concannon, P. Cancer susceptibility in ATM heterozygotes: do two distinct carrier populations exist?. Breast Cancer Res 2 (Suppl 1), S.23 (2000).

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