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

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.

• Authors: Aung Ko Win, Joanne P Young, Noralane M Lindor, Katherine M Tucker, Dennis J Ahnen, Graeme P Young, Daniel D Buchanan, Mark Clendenning, Graham G Giles, Ingrid Winship, Finlay A Macrae, Jack Goldblatt, Melissa C Southey, Julie Arnold, Stephen N Thibodeau, Shanaka R Gunawardena, Bharati Bapat, John A Baron, Graham Casey, Steven Gallinger, Loïc Le Marchand, Polly A Newcomb, Robert W Haile, John L Hopper, Mark A Jenkins
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 30 Issue 9 Pg. 958-64 (Mar 20 2012) ISSN: 1527-7755 [Electronic] United States
• PMID: 22331944 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adenosine Triphosphatases (genetics)
• Adult
• Aged
• Aged, 80 and over
• Australia (epidemiology)
• Colorectal Neoplasms (epidemiology, etiology, 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, etiology, mortality)
• Nuclear Proteins (genetics)
• Prognosis
• Prospective Studies
• Risk Factors
• Survival Rate