Environmental Factors and Colorectal Tumor Risk in Individuals With Hereditary Nonpolyposis Colorectal Cancer

Background & Aims: Individuals with hereditary nonpolyposis colorectal cancer (HNPCC) are at increased risk for colorectal cancer. Environmental factors might play a role in HNPCC-associated carcinogenesis. The aim of this study was to gain insight into the effects of environmental factors on colorectal tumor risk in individuals with HNPCC. Methods: We examined associations between dietary factors, cigarette smoking, and HNPCC-associated colorectal tumors in a Dutch case-control study (145 cases, 103 tumor-free controls; all study participants were known or suspected carriers of a germline mutation in one of the DNA mismatch repair genes). We also assessed associations between the various environmental factors and occurrence of adenomatous polyposis coli (APC) mutations in HNPCC-associated polyps in a subset of the study population. Results: Fruit consumption was inversely associated with ever developing HNPCC-associated colorectal tumors (odds ratio [95% confidence interval] for highest vs lowest tertile, 0.4 [0.2–0.9]; Ptrend = .03); a borderline significant inverse association was observed for dietary fiber intake (0.5 [0.2–1.0]; Ptrend = .06). Cigarette smoking seemed to increase the risk of HNPCC-associated colorectal tumors. Truncating APC mutations were detected in 30 (37.5%) of the 80 available HNPCC-associated polyps; frameshift mutations were most common (73.3%). None of the evaluated environmental factors was distinctively associated with a specific APC status of the polyps. Conclusions: Our data suggest that fruit consumption and dietary fiber intake might decrease the risk of colorectal tumors in individuals with HNPCC, whereas cigarette smoking might increase the risk of HNPCC-associated colorectal tumors. The observed associations support the hypothesis that HNPCC-associated outcomes might be modified by environmental factors. Background & Aims: Individuals with hereditary nonpolyposis colorectal cancer (HNPCC) are at increased risk for colorectal cancer. Environmental factors might play a role in HNPCC-associated carcinogenesis. The aim of this study was to gain insight into the effects of environmental factors on colorectal tumor risk in individuals with HNPCC. Methods: We examined associations between dietary factors, cigarette smoking, and HNPCC-associated colorectal tumors in a Dutch case-control study (145 cases, 103 tumor-free controls; all study participants were known or suspected carriers of a germline mutation in one of the DNA mismatch repair genes). We also assessed associations between the various environmental factors and occurrence of adenomatous polyposis coli (APC) mutations in HNPCC-associated polyps in a subset of the study population. Results: Fruit consumption was inversely associated with ever developing HNPCC-associated colorectal tumors (odds ratio [95% confidence interval] for highest vs lowest tertile, 0.4 [0.2–0.9]; Ptrend = .03); a borderline significant inverse association was observed for dietary fiber intake (0.5 [0.2–1.0]; Ptrend = .06). Cigarette smoking seemed to increase the risk of HNPCC-associated colorectal tumors. Truncating APC mutations were detected in 30 (37.5%) of the 80 available HNPCC-associated polyps; frameshift mutations were most common (73.3%). None of the evaluated environmental factors was distinctively associated with a specific APC status of the polyps. Conclusions: Our data suggest that fruit consumption and dietary fiber intake might decrease the risk of colorectal tumors in individuals with HNPCC, whereas cigarette smoking might increase the risk of HNPCC-associated colorectal tumors. The observed associations support the hypothesis that HNPCC-associated outcomes might be modified by environmental factors. Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the most common cancer predisposition syndromes in humans. It is characterized by an autosomal dominant mode of inheritance and an early onset of carcinogenesis (mean age at diagnosis of colorectal cancer, ∼45 years). Colorectal tumors are the predominant form of cancer in HNPCC, but extracolonic cancers, endometrial, ovarian, and stomach cancer in particular, are also often observed.1Marra G. Boland C.R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives.J Natl Cancer Inst. 1995; 87: 1114-1125Crossref PubMed Scopus (482) Google Scholar, 2Lynch H.T. De la Chapelle A. Hereditary colorectal cancer.N Engl J Med. 2003; 348: 919-932Crossref PubMed Scopus (1672) Google Scholar Germline mutations in DNA mismatch repair (MMR) genes are responsible for HNPCC; most (∼90%) have been detected in hMLH1 and hMSH2 (see ICG-HNPCC/INSiGHT mutation database at www.insight-group.org). HNPCC is thought to account for 1%–5% of all colorectal cases,3Rodriguez-Bigas M.A. Boland C.R. Hamilton S.R. et al.A National Cancer Institute work shop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines.J Natl Cancer Inst. 1997; 89: 1758-1762Crossref PubMed Scopus (949) Google Scholar, 4Aaltonen L.A. Salovaara R. Kristo P. et al.Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease.N Engl J Med. 1998; 338: 1481-1487Crossref PubMed Scopus (989) Google Scholar, 5Samowitz W. Curtin K. Lin H.H. et al.The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer.Gastroenterology. 2001; 121: 830-838Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 6Cunningham J.M. Kim C.-Y. Christensen E.R. et al.The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.Am J Hum Genet. 2001; 69: 780-790Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar and mutation carriers might have a lifetime risk of developing colorectal cancer of 60%–80%.7Mitchell R.J. Farrington S.M. Dunlop M.G. et al.Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review.Am J Epidemiol. 2002; 156: 885-902Crossref PubMed Scopus (119) Google Scholar HNPCC-associated colorectal tumors are often located in the proximal part of the colon, have a more favorable prognosis than sporadic colorectal cancer, and most exhibit microsatellite instability (MSI).1Marra G. Boland C.R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives.J Natl Cancer Inst. 1995; 87: 1114-1125Crossref PubMed Scopus (482) Google Scholar, 2Lynch H.T. De la Chapelle A. Hereditary colorectal cancer.N Engl J Med. 2003; 348: 919-932Crossref PubMed Scopus (1672) Google Scholar Colorectal polyps in individuals with HNPCC progress into cancer more rapidly, within 2–3 years instead of the 10–15 years in the general population, but they do not seem to occur with obviously increased frequency. Several studies have reported the occurrence of inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor gene in HNPCC-associated colorectal tumors.8Huang J. Papadopoulos N. McKinley A.J. et al.APC mutations in colorectal tumors with mismatch repair deficiency.Proc Natl Acad Sci U S A. 1996; 93: 9049-9054Crossref PubMed Scopus (295) Google Scholar, 9Miyaki M. Iijima T. Kimura J. et al.Frequent mutation of β-Catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer.Cancer Res. 1999; 59: 4506-4509PubMed Google Scholar, 10Akiyama Y. Nagasaki H. Yagi K.O. et al.β-Catenin and adenomatous polyposis coli (APC) mutations in adenomas from hereditary nonpolyposis colorectal cancer patients.Cancer Lett. 2000; 157: 185-191Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 11Huang J. Zheng S. Jin S.-H. et al.Somatic mutations of APC gene in carcinomas from hereditary nonpolyposis colorectal cancer patients.World J Gastroenterol. 2004; 10: 834-836PubMed Google Scholar This suggests that as in sporadic colorectal carcinogenesis and familial adenomatous polyposis, loss of APC function might be an important initiating event in a subset of HNPCC-associated colorectal tumors. The incomplete penetrance of disease among mutation carriers and the observation that the clinical expression of HNPCC seems to vary between regions and to have changed over time suggest that environmental factors might play a role in HNPCC-associated carcinogenesis.1Marra G. Boland C.R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives.J Natl Cancer Inst. 1995; 87: 1114-1125Crossref PubMed Scopus (482) Google Scholar, 7Mitchell R.J. Farrington S.M. Dunlop M.G. et al.Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review.Am J Epidemiol. 2002; 156: 885-902Crossref PubMed Scopus (119) Google Scholar, 12Park J.-G. Park Y.J. Wijnen J.T. et al.Gene-environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and genetic testing.Int J Cancer. 1999; 82: 516-519Crossref PubMed Scopus (64) Google Scholar It is possible that dietary and lifestyle factors known to be relevant in sporadic colorectal carcinogenesis also play a role in HNPCC-associated colorectal cancer; however, epidemiologic data supporting this hypothesis are currently limited. Watson et al13Watson P. Ashwathnarayan R. Lynch H.T. et al.Tobacco use and increased colorectal cancer risk in patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome).Arch Intern Med. 2004; 164: 2429-2431Crossref PubMed Scopus (64) Google Scholar reported a positive association between cigarette smoking and HNPCC-associated colorectal cancer. To our knowledge, the only other study on associations between environmental factors and HNPCC-associated colorectal tumors in humans published to date looked at meat consumption and meat preparation only and observed no clear associations.14Voskuil D.W. Kampman E. Grubben M.J.A.L. et al.Meat consumption and meat preparation in relation to colorectal adenomas among sporadic and HNPCC family patients in the Netherlands.Eur J Cancer. 2002; 38: 2300-2308Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar It has been shown, however, that MMR-deficient cells are more resistant to the cytotoxic effects of various DNA-damaging agents and display a greater increase in induced mutations than MMR-proficient cells.15Glaad W.E. Skopek T.R. Cytotoxic and mutagenic response of mismatch repair- defective human cancer cells exposed to a food-associated heterocyclic amine.Carcinogenesis. 1999; 20: 391-394Crossref PubMed Scopus (21) Google Scholar, 16Glaad W.E. Kort K.L. Skopek T.R. Specificity of mutations induced by the food-associated heterocyclic amine 2-amino-1-1methyl-6-phenylimidazo-[4,5-b]-pyridine in colon cancer cell lines defective in mismatch repair.Cancer Res. 2000; 60: 4921-4925PubMed Google Scholar, 17Glaab W.E. Hill R.B. Skopek T.R. Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxidant ascorbate in mismatch repair-deficient human colon cancer cells.Carcinogenesis. 2001; 22: 1709-1713Crossref PubMed Scopus (36) Google Scholar The same response to DNA-damaging agents has been observed in MMR-deficient mice.18Wei K. Kucherlapati R. Edelmann W. Mouse models for human DNA mismatch repair gene defects.Trends Mol Med. 2002; 8: 346-352Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar The possibility that a simple change in diet and/or lifestyle might result in a decrease in colorectal tumor risk in individuals with HNPCC warrants further investigation, especially because even individuals with HNPCC who are participating in an intensive colorectal surveillance program still seem to have a substantial risk of developing colorectal cancer.19De Vos tot Nederveen Cappel W.H. Nagengast F.M. Griffioen G. et al.Surveillance for hereditary nonpolyposis colorectal cancer.Dis Colon 2002; PubMed Scopus Google Scholar this examined associations between dietary factors reported to be associated with sporadic colorectal cancer cigarette smoking, and of HNPCC-associated colorectal tumors. APC mutation was on from a subset of the study population, and to further the between environmental factors and HNPCC-associated colorectal also assessed associations between the various dietary factors, cigarette smoking, and the occurrence of APC mutations in HNPCC-associated colorectal polyps. for this case-control study on environmental factors and HNPCC-associated colorectal tumors were in the between participants to a family the for P. et al.The on Hereditary Colorectal Cancer Colon PubMed Scopus Google Scholar, Watson P. et clinical for hereditary nonpolyposis colorectal cancer Lynch by the on 1999; Full Text Full Text PDF PubMed Scopus Google Scholar and were known or suspected carriers of a germline mutation in one of the at with colorectal cancer or HNPCC-associated cancer endometrial, or and one of is a of the other at are at one of the is with cancer age and familial adenomatous polyposis is to all participants were between years to no known or and at one the and individuals who a were not the surveillance for known and suspected currently screening for colorectal tumors by at an of years or at years of study participants were at The for the of Hereditary The a for Dutch with HNPCC, or HNPCC surveillance at the of of The were by of at the participating of participants were the study by = of the to and and lifestyle were to who to were for on of colorectal cancer and and other relevant status was was a colorectal been detected the or a years to the from the of the in the study participants were of who to not the and were from the not the a of participants with dietary and lifestyle = were and ever with colorectal cancer or polyps. of the ever been with colorectal cancer. at one or a years as a result of various been by been from of was not available to were with was not available to not The with a or a years from the other only in intake was in the not = were and with colorectal cancer or of colorectal The time between and was years for and years for = The study was and by the of and on lifestyle factors smoking and family of colorectal cancer was by a smoking on cigarette smoking status of of years age at smoking was were for on of colorectal cancer and polyps and other relevant dietary intake was assessed with a frequency that was for the Dutch of the into Cancer and et al.The Dutch frequency of the and and for J Epidemiol. 1997; PubMed Google Scholar, M.A. et al.The Dutch frequency and for J Epidemiol. 1997; PubMed Google Scholar this on the consumption frequency for for the study was the in the the of most other the consumption frequency was in of or for a a was and were to for the consumption of was with the by the and were by an of the Dutch were study with the participants by on of was from and of colorectal tumors detected was from and The study the of all colorectal polyps DNA was from by the DNA was available from and also from participants who to and all but not the dietary and lifestyle individuals for was available from more than one colorectal detected the same the in was for mutation was by a and only tumor cells were was at in cell by at were with the to the DNA was with at for 30 The was with and the DNA was in DNA of the APC gene the mutation in most inactivating APC mutations have been Y. H. H. et al.Somatic mutations of the APC gene in colorectal mutation in the APC Mol Genet. PubMed Scopus Google Scholar, M. M. R. et of mutation of the adenomatous polyposis coli gene in colorectal Res. Google were for mutations and frameshift by The was into and were in as et factors and the occurrence of APC mutations in sporadic colon a Dutch 2003; PubMed Scopus (35) Google Scholar were on an and with the to the the were by and with DNA was in by the same as in the were on an DNA in all with and only no mutations were detected was for and We on mutations because mutations result in function loss of the APC whereas the of mutations in APC is We were to mutation on polyps from and from participants who not because of DNA and/or of were as mutation in or mutation in APC and all for intake was with the for and for intake in epidemiologic J 1997; Scopus Google Scholar To the of an the intake to for intake in epidemiologic J 1997; Scopus Google Scholar in between were assessed with for and or for were were The of the dietary factors in was on the of intake in the population. 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Fruit consumption the risk of ever developing HNPCC-associated colorectal and a borderline significant inverse association was observed for dietary fiber Cigarette smoking seemed to increase the risk of HNPCC-associated colorectal tumors. None of the evaluated environmental risk factors were distinctively associated with a specific APC status of the colorectal polyps. The primary function of the is the of and that DNA but also to be in and S.M. S.M. et DNA mismatch Genet. 1999; PubMed Scopus Google Scholar, R. The for mismatch repair in hereditary nonpolyposis colorectal cancer: the Res. 2001; Google Scholar loss of might cells with an increased mutation and a R. The for mismatch repair in hereditary nonpolyposis colorectal cancer: the Res. 2001; Google Scholar Individuals with HNPCC are at increased risk for colorectal cancer because they have a germline mutation in one of the to the general population, only one to be for the to Environmental factors might colorectal tumor risk in individuals with HNPCC for in the or of molecular in the in and/or in other genes in MMR-deficient cells or an that the of cells and not this fruit consumption and dietary fiber intake were to be inversely associated with ever developing HNPCC-associated colorectal tumors. might the occurrence of DNA and the of from a study in MMR-deficient cells suggest that dietary might decrease the risk of colorectal tumor in individuals with HNPCC by the for and the in mutation by W.E. Hill R.B. Skopek T.R. Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxidant ascorbate in mismatch repair-deficient human colon cancer cells.Carcinogenesis. 2001; 22: 1709-1713Crossref PubMed Scopus (36) Google Scholar of cancer of the colon and PubMed Scopus Google Scholar reported the association of dietary fiber intake with a of colon cancer in studies have the role of dietary fiber in colorectal but have been Cancer and the of cancer: a Institute for Cancer Scholar, Colorectal cancer: and Natl Cancer Inst. 1999; PubMed Scopus Google Scholar studies reported a inverse association between dietary fiber intake and sporadic colorectal adenomas and sporadic colorectal R. N. et and colorectal in a colorectal cancer early 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R. et in and colorectal cancer in the into Cancer and an 2003; Full Text Full Text PDF PubMed Scopus Google Scholar Several have been to the of dietary of of and the of and and dietary and to PubMed Scopus Google Scholar Our suggest that intake of dietary fiber might also the risk of colorectal tumors in individuals with HNPCC. Cigarette smoking seemed to increase the risk of ever developing HNPCC-associated colorectal tumors in our study population. with our Watson et al13Watson P. Ashwathnarayan R. Lynch H.T. et al.Tobacco use and increased colorectal cancer risk in patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome).Arch Intern Med. 2004; 164: 2429-2431Crossref PubMed Scopus (64) Google Scholar reported that use of increased the risk of colorectal cancer in carriers of germline mutations in hMLH1 or whereas et Curtin K. K. et between cigarette smoking, lifestyle factors, and microsatellite instability in colon Natl Cancer Inst. 2000; PubMed Scopus (294) Google Scholar reported a positive association between cigarette smoking and sporadic colon et D.W. Kampman E. Grubben M.J.A.L. et al.Meat consumption and meat preparation in relation to colorectal adenomas among sporadic and HNPCC family patients in the Netherlands.Eur J Cancer. 2002; 38: 2300-2308Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar who associations between meat consumption and HNPCC-associated colorectal no clear associations were observed with meat in was to of the APC gene for colorectal tumors in APC is exhibit at one mutation in the A.J. H. M. et al.APC mutations in sporadic colorectal a and of the Natl Acad Sci U S A. 2000; PubMed Scopus Google Scholar do not that our to on mutations in this has in Truncating APC mutations were in of the polyps; frameshift mutations were most This is in with reported by J. Papadopoulos N. McKinley A.J. et al.APC mutations in colorectal tumors with mismatch repair deficiency.Proc Natl Acad Sci U S A. 1996; 93: 9049-9054Crossref PubMed Scopus (295) Google Scholar, 9Miyaki M. Iijima T. Kimura J. et al.Frequent mutation of β-Catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer.Cancer Res. 1999; 59: 4506-4509PubMed Google Scholar, 10Akiyama Y. Nagasaki H. Yagi K.O. et al.β-Catenin and adenomatous polyposis coli (APC) mutations in adenomas from hereditary nonpolyposis colorectal cancer patients.Cancer Lett. 2000; 157: 185-191Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 11Huang J. Zheng S. Jin S.-H. et al.Somatic mutations of APC gene in carcinomas from hereditary nonpolyposis colorectal cancer patients.World J Gastroenterol. 2004; 10: 834-836PubMed Google Scholar and the that loss of APC function is also an important early event in a subset of HNPCC-associated colorectal tumors. Our study of known carriers and gene not to and suspected suspected carriers to a family the have the highest for the of germline mutations in hMLH1 or with other clinical for S. et and of clinical for hereditary colorectal cancer associated mutations in and Genet. 2000; PubMed Scopus Google Scholar of the suspected been with colorectal tumors at an early age adenomatous polyps years or colorectal cancer in to of the is a for the of mutations in hMLH1 or J.T. et with implications for genetic in with of colorectal cancer.N Engl J Med. 1998; PubMed Scopus Google Scholar a possible of this study is that might be individuals who do not have a germline mutation in one of the genes among the suspected Our study was especially the and is possible that associations were not detected because of It also be that might to of our by other studies is APC was possible that as a result of mutations were in polyps with APC mutation in the and of our To our data suggest that fruit consumption and dietary fiber intake might decrease the risk of colorectal tumors in individuals known or suspected of an mutation in one of the Cigarette smoking might increase the risk of HNPCC-associated colorectal tumors. The observed associations support the hypothesis that also HNPCC-associated outcomes might be modified by environmental factors. This for further of the effects of environmental factors on colorectal cancer risk in individuals with HNPCC is important because might result in the of dietary and lifestyle in with screening by the risk of colorectal cancer in this population. We for the of Hereditary for with for with data and Institute of and the for of dietary and for of The of the study participants and the that tumor are for We are to all study participants for and