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Open Access 01-12-2009 | Research

Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario

Authors: Yun-Hee Choi, Michelle Cotterchio, Gail McKeown-Eyssen, Monga Neerav, Bharati Bapat, Kevin Boyd, Steven Gallinger, John McLaughlin, Melyssa Aronson, Laurent Briollais

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2009

Abstract

Background

Several DNA mismatch repair (MMR) genes, responsible for the majority of Lynch Syndrome cancers, have been identified, predominantly MLH1 and MSH2, but the risk associated with these mutations is still not well established. The aim of this study is to provide population-based estimates of the risks of colorectal cancer (CRC) by gender and mutation type from the Ontario population.

Methods

We analyzed 32 families segregating MMR mutations selected from the Ontario Familial Colorectal Cancer Registry and including 199 first-degree and 421 second-degree relatives. The cumulative risks were estimated using a modified segregation-based approach, which allows correction for the ascertainment of the Lynch Syndrome families and permits account to be taken for missing genotype information.

Results

The risks of developing CRC by age 70 were 60% and 47% among men and women carriers of any MMR mutation, respectively. Among MLH1 mutation carriers, males had significantly higher risks than females at all ages (67% vs. 35% by age 70, p-value = 0.02), while the risks were similar in MSH2 carriers (about 54%). The relative risk associated with MLH1 was almost constant with age (hazard ratio (HR) varied between 5.5-5.1 over age 30–70), while the HR for MSH2 decreased with age (from 13.1 at age 30 to 5.4 at age 70).

Conclusion

This study provides a unique population-based study of CRC risks among MSH2/MLH1 mutation carriers in a Canadian population and can help to better define and understand the patterns of risks among members of Lynch Syndrome families.

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Lynch HT, Watson P, Shaw TG, Lynch JF, Harty AE, Franklin BA, Kapler CR, Tinley ST, Liu B, Lerman C: Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer. Part II: Hereditary nonpolyposis colorectal carcinoma as a model. Cancer 1999, 86(11 Suppl):2457–2463. 10.1002/(SICI)1097-0142(19991201)86:11+<2457::AID-CNCR2>3.0.CO;2-ICrossRefPubMed

Bocker T, Ruschoff J, Fishel R: Molecular diagnostics of cancer predisposition: HNPCC and mismatch repair defects. Biochimica Biophysica Acta 1999, 1423: 1–10.

Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, Peltomäki P, Mecklin J-P, Järvinen H: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999, 81: 214–218. 10.1002/(SICI)1097-0215(19990412)81:2<214::AID-IJC8>3.0.CO;2-LCrossRefPubMed

Lin KM, Shashidharan M, Thorson AG, Ternent CA, Blatchford GJ, Christensen MA, Watson P, Lemon SJ, Franklin B, Karr B, Lynch J, Lynch HT: Cumulative incidence of colorectal and extracolonic cancers in MLH1 and MSH2 mutation carriers of hereditary nonpolyposis colorectal cancer. J Gastrointest Surg 1998, 2: 67–71. 10.1016/S1091-255X(98)80105-4CrossRefPubMed

Vasen HFA, Wijnen JT, Menko FH, Kleibeuker JH, Taal BG, Griffioen G, Nagengast FM, Meijers-Heijboer EH, Bertario L, Varesco L, Bisgaard M-L, Mohr J, Fodde R, Meera Khan P: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996, 110: 1020–1027. 10.1053/gast.1996.v110.pm8612988CrossRefPubMed

Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, Liu B, Kinzler KW, Vogelstein B: Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 1997, 6: 105–110. 10.1093/hmg/6.1.105CrossRefPubMed

Cotterchio M, McKeown-Eyssen G, Sutherland H, Buchan G, Aronson M, Easson AM, Macey J, Holowaty E, Gallinger S: Ontario familial colon cancer registry: methods and first year response rates. Chron Dis Canada 2000, 21: 81–86.

Dunlop MG, Farrington SM, Nicholl I, Aaltonen L, Petersen G, Porteous M, Carothers A: Population carrier frequency of hMSH2 and hMLH1 mutations. Br J Cancer 2000, 83: 1643–5. 10.1054/bjoc.2000.1520CrossRefPubMedPubMedCentral

Woods MO, Hyde AJ, Curtis FK, Stuckless S, Green JS, Pollett AF, Robb JD, Green RC, Croitoru ME, Careen A, Chaulk JAW, Jegathesan J, McLaughlin JR, Gallinger SS, Younghusband HB, Bapat BV, Parfrey PS: High frequency of hereditary colorectal cancer in Newfoundland likely involves novel susceptibility genes. Clin Cancer Res 2005, 11: 6853–61. 10.1158/1078-0432.CCR-05-0726CrossRefPubMed

10.

Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Amer Statist Assoc 1958, 53: 457–481. 10.2307/2281868CrossRef

11.

Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani N, Srivastava S: A national Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998, 58: 5248–5257.PubMed

12.

Bapat BV, Madlensky L, Temple LKF, Hiruki T, Redston M, Baron DL, Ling X, Marcus VA, Soravia C, Mitri A, Shen W, Gryfe R, Berk T, Chodirker BN, Cohen Z, Gallinger S: Family history characteristics, tumour microsatellite instability and germline MSH2 , and MLH1 mutations in hereditary colorectal cancer. Hum Genet 1999, 104: 167–176. 10.1007/s004390050931CrossRefPubMed

13.

Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 2002, 30: e57. 10.1093/nar/gnf056CrossRefPubMedPubMedCentral

14.

Ramensky V, Bork P, Sunyaev S: Human non-synonymous SNPs: server and survey. Nucleic Acids Res 2002, 30: 3894–3900. 10.1093/nar/gkf493CrossRefPubMedPubMedCentral

15.

Ng PC, Henikoff S: Predicting deleterious amino acid substitutions. Genome Res 2001, 11: 863–74. 10.1101/gr.176601CrossRefPubMedPubMedCentral

16.

Kraft P, Thomas DC: Bias and efficiency in family-based gene-characterization studies: conditional, prospective, retrospective, and joint likelihoods. Am J Hum Genet 2000, 66: 1119–1131. 10.1086/302808CrossRefPubMedPubMedCentral

17.

Choi YH, Kopciuk K, Briollais L: Estimating disease risk associated with mutated genes in family-based designs. Hum Hered 2008, 66: 238–251. 10.1159/000143406CrossRefPubMed

18.

Jenkins MA, Baglietto L, Dowty JG, Van Vliet CM, Smith L, Mead LJ, Macrae FA, St John DJ, Jass JR, Giles GG, Hopper JL, Southey MC: Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study. Clin Gastroenterol Hepatol 2006, 4: 489–98. 10.1016/j.cgh.2006.01.002CrossRefPubMed

19.

Lange K, Sinsheimer JS, Sobel E: Association testing with Mendel. Genet Epidemiol 2005, 29: 36–50. 10.1002/gepi.20073CrossRefPubMed

20.

Quehenberger F, Vasen HFA, van Houwelingen HC: Risk of colorectal and endometrial cancer for carriers of mutations of the h MLH1 and h MSH2 gene: correction for ascertainment. J Med Genet 2005, 42: 491–496. 10.1136/jmg.2004.024299CrossRefPubMedPubMedCentral

21.

Green J, O'Driscoll M, Barnes A, Maher ER, Bridge P, Shields K, Parfrey PS: Impact of gender and parent of origin on the phenotypic expression of hereditary nonpolyposis colorectal cancer in a large Newfoundland kindred with a common MSH2 mutation. Dir Colon Rectum 2002, 45: 1223–1232. 10.1007/s10350-004-6397-4CrossRef

22.

Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ: Life-time risk of different cancers in HNPCC syndrome. Int J Cancer 1995, 64: 430–433. 10.1002/ijc.2910640613CrossRefPubMed

23.

Froggart NJ, Green J, Brassett C, Evans E, Bishop D, Kolodner R, Maher E: A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer risk. J Med Genet 1999, 36: 97–102.

24.

Vasen HFA, Stormorken A, Menko FH, Nagengast FM, Kleibeuker JH, Griffioen G, Taal BG, Moller P, Wijnen JT: MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol 2001, 19: 4074–4080.PubMed

25.

Parc Y, Boisson C, Thomas G, Olschwang S: Cancer risk in 348 French MSH2 or MLH1 gene carriers. J Med Genet 2003, 40: 208–213. 10.1136/jmg.40.3.208CrossRefPubMedPubMedCentral

26.

Hampel H, Stephens JA, Pukkala E, Sankila R, Aaltonen LA, Mecklin JP, de la Chapelle A: Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 2005, 129: 415–21.CrossRefPubMed

27.

Vasen HFA, Watson P, Mecklin JP, Lynch HT: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch Syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999, 116: 1453–1456. 10.1016/S0016-5085(99)70510-XCrossRefPubMed

28.

Begg CB: On the use of familial aggregation in population-based case probands for calculating penetrance. J Nat Cancer Inst 2002, 94: 1221–1226.CrossRefPubMed

29.

Carayol J, Bonaïti-Pellié C: Estimating penetrance from family data using a retrospective likelihood when ascertainment depends on genotype and age of onset. Gen Epidemiol 2004, 27: 109–117. 10.1002/gepi.20007CrossRef

30.

Theis B, Boyd N, Lockwood G, Tritchler D: Accuracy of family cancer history in breast cancer patients. Eur J Cancer Prev 1994, 3: 321–327. 10.1097/00008469-199407000-00004CrossRefPubMed

Title: Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario
Authors: Yun-Hee Choi
Michelle Cotterchio
Gail McKeown-Eyssen
Monga Neerav
Bharati Bapat
Kevin Boyd
Steven Gallinger
John McLaughlin
Melyssa Aronson
Laurent Briollais
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: Hereditary Cancer in Clinical Practice / Issue 1/2009
Electronic ISSN: 1897-4287
DOI: https://doi.org/10.1186/1897-4287-7-14

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