Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study

J Clin Oncol. 2012 Mar 20;30(9):958-64. doi: 10.1200/JCO.2011.39.5590. Epub 2012 Feb 13.

Abstract

Purpose: To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population.

Patients and methods: We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.

Results: Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97).

Conclusion: We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adenosine Triphosphatases / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Australia / epidemiology
  • Colorectal Neoplasms / epidemiology
  • Colorectal Neoplasms / etiology*
  • Colorectal Neoplasms / mortality
  • DNA Mismatch Repair / genetics*
  • DNA Repair Enzymes / genetics
  • DNA-Binding Proteins / genetics
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease*
  • Heterozygote
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / genetics
  • Mutation / genetics*
  • Neoplasms / epidemiology
  • Neoplasms / etiology*
  • Neoplasms / mortality
  • Nuclear Proteins / genetics
  • Prognosis
  • Prospective Studies
  • Risk Factors
  • Survival Rate

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • Nuclear Proteins
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • MSH2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • DNA Repair Enzymes