Colorectal and Other Cancer Risks for Carriers and Noncarriers from Families with a DNA Mismatch Repair Gene Mutation: a Prospective Cohort Study

Overview

Journal J Clin Oncol

Specialty Oncology

Date 2012 Feb 15

PMID 22331944

Citations 149

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

Loic Le Marchand

Polly A Newcomb

Robert W Haile

John L Hopper

Mark A Jenkins

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Domchek S, Gaudet M, Stopfer J, Fleischaut M, Powers J, Kauff N . Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2. Breast Cancer Res Treat. 2009; 119(2):409-14. DOI: 10.1007/s10549-009-0611-y. View

Scott R, McPhillips M, Meldrum C, Fitzgerald P, Adams K, Spigelman A . Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet. 2000; 68(1):118-127. PMC: 1234904. DOI: 10.1086/316942. View

Umar A, Boland C, Terdiman J, Syngal S, de la Chapelle A, Ruschoff J . Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004; 96(4):261-8. PMC: 2933058. DOI: 10.1093/jnci/djh034. View

Taylor D, Burt R, Williams M, Haug P, Cannon-Albright L . Population-based family history-specific risks for colorectal cancer: a constellation approach. Gastroenterology. 2009; 138(3):877-85. PMC: 2831153. DOI: 10.1053/j.gastro.2009.11.044. View

Jarvinen H, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen L, Peltomaki P . Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology. 2000; 118(5):829-34. DOI: 10.1016/s0016-5085(00)70168-5. View

Wijnen J, Brohet R, van Eijk R, Jagmohan-Changur S, Middeldorp A, Tops C . Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome. Gastroenterology. 2008; 136(1):131-7. DOI: 10.1053/j.gastro.2008.09.033. View

Shanley S, Fung C, Milliken J, Leary J, Barnetson R, Schnitzler M . Breast cancer immunohistochemistry can be useful in triage of some HNPCC families. Fam Cancer. 2009; 8(3):251-5. DOI: 10.1007/s10689-008-9226-4. View

Campbell P, Edwards L, McLaughlin J, Green J, Younghusband H, Woods M . Cytochrome P450 17A1 and catechol O-methyltransferase polymorphisms and age at Lynch syndrome colon cancer onset in Newfoundland. Clin Cancer Res. 2007; 13(13):3783-8. DOI: 10.1158/1078-0432.CCR-06-2987. View

Reeves S, Rich D, Meldrum C, Colyvas K, Kurzawski G, Suchy J . IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer. Int J Cancer. 2008; 123(6):1339-43. DOI: 10.1002/ijc.23668. View

10.

Ou J, Niessen R, Vonk J, Westers H, Hofstra R, Sijmons R . A database to support the interpretation of human mismatch repair gene variants. Hum Mutat. 2008; 29(11):1337-41. DOI: 10.1002/humu.20907. View

11.

Korde L, Mueller C, Loud J, Struewing J, Nichols K, Greene M . No evidence of excess breast cancer risk among mutation-negative women from BRCA mutation-positive families. Breast Cancer Res Treat. 2010; 125(1):169-73. PMC: 3110729. DOI: 10.1007/s10549-010-0923-y. View

12.

Kruger S, Engel C, Bier A, Silber A, Gorgens H, Mangold E . The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in Lynch syndrome patients with pathogenic germline mutations in MSH2 or MLH1. Cancer Lett. 2007; 252(1):55-64. DOI: 10.1016/j.canlet.2006.12.006. View

13.

Boyd J, Rhei E, Federici M, Borgen P, Watson P, Franklin B . Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat. 1999; 53(1):87-91. DOI: 10.1023/a:1006030116357. View

14.

Southey M, Jenkins M, Mead L, Whitty J, Trivett M, Tesoriero A . Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol. 2005; 23(27):6524-32. DOI: 10.1200/JCO.2005.04.671. View

15.

Canto M, Goggins M, Yeo C, Griffin C, Axilbund J, Brune K . Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clin Gastroenterol Hepatol. 2004; 2(7):606-21. DOI: 10.1016/s1542-3565(04)00244-7. View

16.

Talseth-Palmer B, Brenne I, Ashton K, Evans T, McPhillips M, Groombridge C . Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in Lynch syndrome. J Med Genet. 2010; 48(4):279-84. DOI: 10.1136/jmg.2010.079962. View

17.

Baglietto L, Lindor N, Dowty J, White D, Wagner A, Gomez Garcia E . Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2009; 102(3):193-201. PMC: 2815724. DOI: 10.1093/jnci/djp473. View

18.

Watson P, Lynch H . Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993; 71(3):677-85. DOI: 10.1002/1097-0142(19930201)71:3<677::aid-cncr2820710305>3.0.co;2-#. View

19.

Kauff N, Mitra N, Robson M, Hurley K, Chuai S, Goldfrank D . Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families. J Natl Cancer Inst. 2005; 97(18):1382-4. DOI: 10.1093/jnci/dji281. View

20.

Hutter P, Couturier A, Scott R, Alday P, DeLozier-Blanchet C, Cachat F . Complex genetic predisposition to cancer in an extended HNPCC family with an ancestral hMLH1 mutation. J Med Genet. 1996; 33(8):636-40. PMC: 1050695. DOI: 10.1136/jmg.33.8.636. View