Cancer risks and mortality in heterozygous ATM mutation carriers

Deborah Thompson, Silvia Duedal, Jennifer Kirner, Lesley McGuffog, James Last, Anne Reiman, Philip Byrd, Malcolm Taylor, Douglas F Easton

Research output: Contribution to journalArticlepeer-review

355 Citations (Scopus)

Abstract

BACKGROUND: Homozygous or compound heterozygous mutations in the ATM gene are the principal cause of ataxia telangiectasia (A-T). Several studies have suggested that heterozygous carriers of ATM mutations are at increased risk of breast cancer and perhaps of other cancers, but the precise risk is uncertain.

METHODS: Cancer incidence and mortality information for 1160 relatives of 169 UK A-T patients (including 247 obligate carriers) was obtained through the National Health Service Central Registry. Relative risks (RRs) of cancer in carriers, allowing for genotype uncertainty, were estimated with a maximum-likelihood approach that used the EM algorithm. Maximum-likelihood estimates of cancer risks associated with three groups of mutations were calculated using the pedigree analysis program MENDEL. All statistical tests were two-sided.

RESULTS: The overall relative risk of breast cancer in carriers was 2.23 (95% confidence interval [CI] = 1.16 to 4.28) compared with the general population but was 4.94 (95% CI = 1.90 to 12.9) in those younger than age 50 years. The relative risk for all cancers other than breast cancer was 2.05 (95% CI = 1.09 to 3.84) in female carriers and 1.23 (95% CI = 0.76 to 2.00) in male carriers. Breast cancer was the only site for which a clear risk increase was seen, although there was some evidence of excess risks of colorectal cancer (RR = 2.54, 95% CI = 1.06 to 6.09) and stomach cancer (RR = 3.39, 95% CI = 0.86 to 13.4). Carriers of mutations predicted to encode a full-length ATM protein had cancer risks similar to those of people carrying truncating mutations.

CONCLUSION: These results confirm a moderate risk of breast cancer in A-T heterozygotes and give some evidence of an excess risk of other cancers but provide no support for large mutation-specific differences in risk.

Original languageEnglish
Pages (from-to)813-822
Number of pages10
JournalJournal of the National Cancer Institute
Volume97
Issue number11
DOIs
Publication statusPublished - 1 Jun 2005

Keywords

  • Adult
  • Aged
  • Algorithms
  • Ataxia Telangiectasia
  • Ataxia Telangiectasia Mutated Proteins
  • Breast Neoplasms
  • Cell Cycle Proteins
  • Confidence Intervals
  • DNA-Binding Proteins
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Heterozygote Detection
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Mutation
  • Neoplasms
  • Pedigree
  • Phenotype
  • Protein-Serine-Threonine Kinases
  • Risk Assessment
  • Risk Factors
  • Tumor Suppressor Proteins
  • United Kingdom
  • Journal Article
  • Research Support, Non-U.S. Gov't

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