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

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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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  • Cite this

    Thompson, D., Duedal, S., Kirner, J., McGuffog, L., Last, J., Reiman, A., ... Easton, D. F. (2005). Cancer risks and mortality in heterozygous ATM mutation carriers. Journal of the National Cancer Institute, 97(11), 813-822. https://doi.org/10.1093/jnci/dji141