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01-11-2005 | Original Contribution

Mechanisms of Microsatellite Instability in Colorectal Cancer Patients in Different Age Groups

Authors: Raymond Yiu, M.D., Hongming Qiu, M.D., Suk-Hwan Lee, M.D., Julio García-Aguilar, M.D., Ph.D.

Published in: Diseases of the Colon & Rectum | Issue 11/2005

PURPOSE

The proportion of colorectal cancers located proximal to the splenic flexure increases with age. Colorectal cancers of the microsatellite instability phenotype are preferentially located in the proximal colon. We investigated the location of colorectal cancer with this phenotype in different age groups to determine whether different molecular mechanisms could account for the changes in distribution of colorectal cancers.

METHODS

A representative sample of 230 colorectal cancers from three age groups (<45 years, 60–70 years, >87 years) was selected from a subset of The Upper Midwest Oncology Medical Registries database. Microsatellite instability was determined by polymerase chain reaction using a panel of five microsatellite markers. The presence of new microsatellite alleles at two or more loci was scored as microsatellite instability. Tumors were otherwise considered microsatellite stable. MLH1 and MSH2 expression was determined by immunohistochemistry. Methylation of the MLH1 gene promotor was determined by methylation-specific polymerase chain reaction assay.

RESULTS

The proportion of tumors of the microsatellite instability phenotype was 21 percent in the young group, 15 percent in the middle group, and 33 percent in the old group. More tumors of the microsatellite instability phenotype were proximal compared with microsatellite-stable tumors in all three age groups, but the differences were significant only for the old group. Tumors of the microsatellite instability phenotype in the older group were associated with MLH1 inactivation (24/29 or 83 percent), MLH1 promoter methylation (18/29 or 62 percent), and proximal location (25/29 or 86 percent), while tumors in the young group were associated with MSH2 inactivation (8/18 or 44 percent) and distal location (11/18 or 62 percent).

CONCLUSION

The age-related proximal shift of colorectal cancers is associated with the microsatellite instability phenotype, MLH1 inactivation, and MLH1 promoter hypermethylation.

Ries L, Eisner M, Kosary C, et al. SEER Cancer Statistics Review, 1975–2001. Bethesda: National Cancer Institute, 2004

Cooper, GS, Yuan, Z, Landefeld, CS, Johanson, JF, Rimm, AA 1995A national population-based study of incidence of colorectal cancer and age. Implications for screening in older AmericansCancer7577581PubMed

Slattery, ML, Friedman, GD, Potter, JD, Edwards, S, Caan, BJ, Samowitz, W 1996A description of age, sex, and site distributions of colon carcinoma in three geographic areasCancer78166670PubMedCrossRef

Schub, R, Steinheber, FU 1986Rightward shift of colon cancer. A feature of the aging gutJ Clin Gastroenterol86304PubMed

Pfister, DG, Horwitz, RI 1987The rightward shift of colon cancer. Aging or artifact?J Clin Gastroenterol95861PubMed

Devesa, SS, Chow, WH 1993Variation in colorectal cancer incidence in the United States by subsite of originCancer71381926PubMed

Lengauer, C, Kinzler, KW, Vogelstein, B 1998Genetic instabilities in human cancersNature3966439PubMedCrossRef

Lengauer, C, Kinzler, KW, Vogelstein, B 1997Genetic instability in colorectal cancersNature3866237PubMedCrossRef

Ionov, Y, Peinado, MA, Malkhosyan, S, Shibata, D, Perucho, M 1993Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesisNature36355861PubMedCrossRef

10.

Thibodeau, SN, Bren, G, Schaid, D 1993Microsatellite instability in cancer of the proximal colonScience2608169PubMed

11.

Kim, H, Jen, J, Vogelstein, B, Hamilton, SR 1994Clinical and pathologic characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequencesAm J Pathol14514856PubMed

12.

Gryfe, R, Kim, H, Hsieh, ET, et al. 2000Tumor microsatellite instability and clinical outcome in young patients with colorectal cancerN Engl J Med3426977PubMedCrossRef

13.

Cunningham, JM, Christensen, ER, Tester, DJ, et al. 1998Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instabilityCancer Res58345560PubMed

14.

Herman, JG, Umar, A, Polyak, K, et al. 1998Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinomaProc Natl Acad Sci USA9568705PubMedCrossRef

15.

Toyota, M, Ahuja, N, Ohe-Toyota, M, Herman, JG, Baylin, SB, Issa, JP 1999CpG island methylator phenotype in colorectal cancerProc Natl Acad Sci USA9686816PubMedCrossRef

16.

Kuismanen, SA, Holmberg, MT, Salovaara, R, de la Chapelle, A, Peltomaki, P 2000Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancersAm J Pathol15617739PubMed

17.

Menigatti, M, Gregorio, C, Borghi, F, et al. 2001Methylation pattern of different regions of the MLH1 promoter and silencing of gene expression in hereditary and sporadic colorectal cancerGenes Chromosomes Cancer3135761PubMedCrossRef

18.

Issa, JP, Ottaviano, YL, Celano, P, Hamilton, SR, Davidson, NE, Baylin, SB 1994Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colonNat Genet753640PubMedCrossRef

19.

Ahuja, N, Li, Q, Mohan, AL, Baylin, SB, Issa, JP 1998Aging and DNA methylation in colorectal mucosa and cancerCancer Res58548994PubMed

20.

Samowitz, WS, Slattery, ML, Kerber, RA 1995Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancerGastroenterology109176571PubMedCrossRef

21.

Liu, B, Farrington, SM, Petersen, GM, et al. 1995Genetic instability occurs in the majority of young patients with colorectal cancerNat Med134852PubMed

22.

Lukish, JR, Muro, K, DeNobile, J, et al. 1998Prognostic significance of DNA replication errors in young patients with colorectal cancerAnn Surg227516PubMedCrossRef

23.

Boland, CR, Thibodeau, SN, Hamilton, SR, et al. 1998A 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 cancerCancer Res58524857PubMed

24.

Herman, JG, Graff, JR, Myohanen, S, Nelkin, BD, Baylin, SB 1996Methylation-specific PCR: a novel PCR assay for methylation status of CpG islandsProc Natl Acad Sci USA9398216PubMedCrossRef

25.

Fleshner, P, Slater, G, Aufses, AH,Jr 1989Age and sex distribution of patients with colorectal cancerDis Colon Rectum3210711PubMed

26.

Levi, F, Randimbison, L, Vecchia, C 1993Trends in subsite distribution of colorectal cancers and polyps from the Vaud Cancer RegistryCancer724650PubMed

27.

Axtell, LM, Chiazze, L,Jr 1966Changing relative frequency of cancers of the colon and rectum in the United StatesCancer197504PubMed

28.

Rosato, FE, Marks, G 1981Changing site distribution patterns of colorectal cancer at Thomas Jefferson University HospitalDis Colon Rectum24935PubMed

29.

Mamazza, J, Gordon, PH 1982The changing distribution of large intestinal cancerDis Colon Rectum2555862PubMed

30.

Beart, RW, Melton, LJ, Maruta, M, Dockerty, MB, Frydenberg, HB, O'Fallon, WM 1983Trends in right and left-sided colon cancerDis Colon Rectum263938PubMed

31.

Vobecky, J, Leduc, C, Devroede, G 1984Sex differences in the changing anatomic distribution of colorectal carcinomaCancer5430659PubMed

32.

Butcher, D, Hassanein, K, Dudgeon, M, Rhodes, J, Holmes, FF 1985Female gender is a major determinant of changing subsite distribution of colorectal cancer with ageCancer567146PubMed

33.

Jass, JR 1991Subsite distribution and incidence of colorectal cancer in New Zealand, 1974-1983Dis Colon Rectum34569PubMedCrossRef

34.

Obrand, DI, Gordon, PH 1998Continued change in the distribution of colorectal carcinomaBr J Surg852468PubMedCrossRef

35.

Chao, A, Gilliland, F, Willman, C, et al. 2000Patient and tumor characteristics of colon cancers with microsatellite instability: a population-based studyCancer Epidemiol Biomarkers Prev953944PubMed

36.

Ward, R, Meagher, A, Tomlinson, I, et al. 2001Microsatellite instability and the clinicopathologic features of sporadic colorectal cancerGut488219PubMedCrossRef

37.

Wright, CM, Dent, OF, Barker, M, et al. 2000Prognostic significance of extensive microsatellite instability in sporadic clinicopathologic stage C colorectal cancerBr J Surg871197202PubMed

38.

Parc, Y, Gueroult, S, Mourra, N, et al. 2004Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancerGut533715PubMedCrossRef

39.

Lim, SB, Jeong, SY, Lee, MR, et al. 2004Prognostic significance of microsatellite instability in sporadic colorectal cancerInt J Colorectal Dis195337PubMedCrossRef

40.

Ho, JW, Yuen, ST, Chung, LP, et al. 2000Distinct clinical features associated with microsatellite instability in colorectal cancers of young patientsInt J Cancer8935660PubMedCrossRef

41.

Roh, SA, Kim, HC, Kim, JS, Kim, JC 2003Characterization of mutator pathway in younger-age-onset colorectal adenocarcinomasJ Korean Med Sci1838791PubMed

42.

Salovaara, R, Loukola, A, Kristo, P, et al. 2000Population-based molecular detection of hereditary nonpolyposis colorectal cancerJ Clin Oncol182193200PubMed

43.

Brassett, C, Joyce, JA, Froggatt, NJ, et al. 1996Microsatellite instability in early onset and familial colorectal cancerJ Med Genet339815PubMedCrossRef

44.

Guillem, JG, Puig-La Calle, J,Jr, Cellini, C, et al. 1999Varying features of early age-of-onset “sporadic” and hereditary nonpolyposis colorectal cancer patientsDis Colon Rectum423642PubMedCrossRef

45.

Ferlay J, Parkin D, Pisani P. GLOBOCAN: Cancer incidence and mortality worldwide. Lyon: Agency for Research on Cancer, 1998

46.

Schottenfield D. Epidemiology. New York: McGraw-Hill, 1995

47.

Wynder, EL, Fujita, Y, Harris, RE, Hirayama, T, Hiyama, T 1991Comparative epidemiology of cancer between the United States and Japan. A second lookCancer6774663PubMed

48.

King, H, Li, JY, Locke, FB, Pollack, ES, Tu, JT 1985Patterns of site-specific displacement in cancer mortality among migrants: the Chinese in the United StatesAm J Public Health7523742PubMedCrossRef

49.

McMichael, AJ, McCall, MG, Hartshorne, JM, Woodings, TL 1980Patterns of gastro-intestinal cancer in European migrants to Australia: the role of dietary changeInt J Cancer254317PubMed

50.

Warshauer, ME, Silverman, DT, Schottenfeld, D, Pollack, ES 1986Stomach and colorectal cancers in Puerto Rican-born residents of New York CityJ Natl Cancer Inst765915PubMed

51.

Vukasin, AP, Ballantyne, GH, Flannery, JT, Lerner, E, Modlin, IM 1990Increasing incidence of cecal and sigmoid carcinoma. Data from the Connecticut Tumor RegistryCancer6624429PubMed

52.

Moore, LE, Huang, WY, Chung, J, Hayes, RB 2003Epidemiologic considerations to assess altered DNA methylation from environmental exposures in cancerAnn N Y Acad Sci98318196PubMed

53.

Ross, SA 2003Diet and DNA methylation interactions in cancer preventionAnn N Y Acad Sci983197207PubMedCrossRef

54.

Li, S, Hursting, SD, Davis, BJ, McLachlan, JA, Barrett, JC 2003Environmental exposure, DNA methylation, and gene regulation: lessons from diethylstilbesterol-induced cancersAnn N Y Acad Sci9831619PubMed

Title: Mechanisms of Microsatellite Instability in Colorectal Cancer Patients in Different Age Groups
Authors: Raymond Yiu, M.D.
Hongming Qiu, M.D.
Suk-Hwan Lee, M.D.
Julio García-Aguilar, M.D., Ph.D.
Publication date: 01-11-2005
Publisher: Springer-Verlag
Published in: Diseases of the Colon & Rectum / Issue 11/2005
Print ISSN: 0012-3706
Electronic ISSN: 1530-0358
DOI: https://doi.org/10.1007/s10350-005-0171-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Mechanisms of Microsatellite Instability in Colorectal Cancer Patients in Different Age Groups

PURPOSE

METHODS

RESULTS

CONCLUSION

Keynote webinar | Spotlight on medication adherence

Springer Medicine

PURPOSE

METHODS

RESULTS

CONCLUSION

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