Abstract
Biallelic inactivation of the ATM gene causes ataxia–telangiectasia (A–T), a complex neurological disease associated with a high risk of leukaemias and lymphomas. Mothers of A–T children, obligate ATM heterozygote mutation carriers, have a breast cancer (BC) relative risk of about 3. The frequency of ATM carriers in BC women with a BC family history has been estimated to be 2.70%. To further our clinical understanding of familial BC and examine whether haematological malignancies are predictive of ATM germline mutation, we estimated the frequency of heterozygote mutation carriers in a series of 122 BC women with a family history of both BC and haematological malignancy and without BRCA1/2 mutation. The gene screening was performed with a new high throughput method, EMMA (enhanced mismatch mutation analysis). Amongst 28 different ATM variants, eight mutations have been identified in eight patients: two mutations leading to a putative truncated protein and six being likely deleterious mutations. One of the truncating mutations was initially interpreted as a missense mutation, p.Asp2597Tyr, but is actually a splice mutation (c.7789G>T/p.Asp2597_Lys2643>LysfsX3). The estimated frequency of ATM heterozygote mutation carriers in our series is 6.56% (95% CI: 2.16–10.95), a significantly higher figure than that observed in the general population, estimated to be between 0.3 and 0.6%. Although a trend towards an increased frequency of ATM carriers was observed, it was not different from that observed in a population of familial BC women not selected for haematological malignancy as the frequency of ATM carriers was 2.70%, a value situated in the confidence interval of our study.
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Acknowledgments
We would like to thank the patients for their participation in this study. We thank Patricia Legoix-Né for her help in sequencing analyses, Catherine Dubois d’Enghien for her help in the selection of A–T DNA controls, and Nadine Andrieu for her critical reading of the manuscript. This work received financial support from ANR (Agence Nationale pour la Recherche), RNTS program.
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Paglia, L.L., Laugé, A., Weber, J. et al. ATM germline mutations in women with familial breast cancer and a relative with haematological malignancy. Breast Cancer Res Treat 119, 443–452 (2010). https://doi.org/10.1007/s10549-009-0396-z
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DOI: https://doi.org/10.1007/s10549-009-0396-z