ATM germline mutations in women with familial breast cancer and a relative with haematological malignancy

Breast Cancer Res Treat. 2010 Jan;119(2):443-52. doi: 10.1007/s10549-009-0396-z. Epub 2009 Apr 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics*
  • Cell Cycle Proteins / genetics*
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Germ-Line Mutation*
  • Heterozygote
  • Humans
  • Leukemia / genetics*
  • Lymphoma / genetics*
  • Molecular Sequence Data
  • Pedigree
  • Predictive Value of Tests
  • Protein Serine-Threonine Kinases / genetics*
  • Risk Assessment
  • Risk Factors
  • Tumor Suppressor Proteins / genetics*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases