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ATM-Heterozygous Germline Mutations Contribute to Breast Cancer–Susceptibility
Ist Teil von
American journal of human genetics, 2000-02, Vol.66 (2), p.494-500
Ort / Verlag
Chicago, IL: Elsevier Inc
Erscheinungsjahr
2000
Quelle
ScienceDirect
Beschreibungen/Notizen
Approximately 0.5%–1% of the general population has been estimated to be heterozygous for a germline mutation in the
ATM gene. Mutations in the
ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T) (MIM
208900). The finding that
ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others. In view of this discrepancy, we examined the frequency of
ATM germline mutations in a selected group of Dutch patients with breast cancer. We have analyzed
ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of
ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer at age <45 and had survived ⩾5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients we identified seven (8.5%)
ATM germline mutations, of which five are distinct. One splice-site mutation (IVS10-6T→G) was detected three times in our series. Four heterozygous carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are “A-T disease–causing” mutations that might be associated with an increased risk of breast cancer in heterozygotes. We conclude that
ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. The specific characteristics of our population of patients may explain why such a high frequency was not found in other series.