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Constitutional alterations of the ATM gene in early onset sporadic breast cancer
  1. P Maillet1,
  2. H Bonnefoi2,
  3. G Vaudan-Vutskits1,
  4. B Pajk3,
  5. T Cufer3,
  6. W D Foulkes4,
  7. P O Chappuis5,
  8. A-P Sappino1
  1. 1Unit of Identification of Genetic Predispositions to Cancer, Division of Oncology, Geneva University Hospital, Switzerland
  2. 2Department of Gynaecology and Obstetrics, Geneva University Hospital, Switzerland
  3. 3Institute of Oncology, Ljubljana, Slovenia
  4. 4Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada
  5. 5Divisions of Oncology and Medical Genetics, Geneva University Hospital, Switzerland
  1. Correspondence to:
 Dr P Maillet, Unit of Identification of Genetic Predispositions to Cancer, CMU/Laboratory of Oncology 5216, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland;
 Philippe.Maillet{at}medecine.unige.ch

https://doi.org/10.1136/jmg.39.10.751

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    Ataxia-telangiectasia (AT) is a recessive disorder caused by mutations in the ATM gene (ataxia-telangiectasia mutated) located on chromosome 11q22-23 (OMIM 208900). AT is characterised by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, radiosensitivity, and cancer predisposition with a predominance of lymphoid tumours and less frequently other tumours including breast cancer. The 13 kb mRNA of ATM is assembled from 66 exons distributed across a genomic region of 150 kb. It codes for a 350 kDa protein with a C-terminus phosphatidylinositol 3-kinase domain involved in the recognition and repair of radiation induced DNA double strand breaks.1–5 Oncoproteins, including the tumour suppressors p53, BRCA1, and CHK2, are regulated by ATM.6 Epidemiological evidence suggests that ATM heterozygotes, representing 0.5-1% of the general population, have a 5 to 8-fold increased risk of developing breast cancer.7,8 These estimations raised the possibility that germline mutations of ATM may account for ∼5% of all breast cancer cases. Furthermore, since breast cancer reported in obligate carriers among AT family members affects predominantly younger women, an age specific relative risk model has been proposed.9 In this model, up to 8% of breast cancer diagnosed in women under the age of 40 may arise in ATM mutation carriers, compared with 2% of cases diagnosed between 40 and 59 years. However, recent data suggest that this model may overestimate the true allele frequency in women with breast cancer.10–12 Moreover, direct molecular examination of ATM in selected breast cancer patients outside AT families has led to conflicting results. Fitzgerald et al13 showed that ATM mutations were present in only 2/401 (0.5%) women with early onset breast cancer, but they only looked for truncating mutations. In a recent study, Broeks et al14 identified seven germline ATM truncating mutations among 82 patients who developed breast …

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