Abstract
Genomic instability has been proposed as a new mechanism of carcinogenesis involved in hereditary non-polyposis colorectal cancer (HNPCC) and in a large number of sporadic cancers like pancreatic and colon tumours. Mutations in human mismatch repair genes have been found in HNPCC patients, but their involvement in sporadic cancer has not been clarified yet. In this study we screened 21 pancreatic and 23 colorectal sporadic cancers for microsatellite instability by ten and six different microsatellite markers respectively. Microsatellite alterations were observed at one or more loci in 66.6% (14/21) of pancreatic cancers and in 26% (6/23) colon tumours, but all the pancreatic and half of the colon samples showed a low rate of microsatellite instability. All the unstable samples were further analysed for mutations in the hMLH1 and hMSH2 genes and for hypermethylation of the hMLH1 promoter region. Alterations in the hMLH1 gene were found only in colorectal tumours with a large presence of microsatellite instability. None of the pancreatic tumours showed any alteration in the two genes analysed. Our results demonstrate that microsatellite instability is unlikely to play a role in the tumorigenesis of sporadic pancreatic cancers and confirm the presence of mismatch repair gene alterations only in sporadic colon tumours with a highly unstable phenotype.
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16 November 2011
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Aaltonen, L. A., PeltomĂ€ki, P., Leach, F. S., Sistönen, P., PylkkĂ€nen, L., Mecklin, J., JĂ€rvinen, H., Powell, S. M., Jen, J., Hamilton, S. R., Petersen, G. M., Kinzler, K. W., Vogelstein, B. & De la Chapelle, A. (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260: 812â816.
Aquilina, G., Hess, P., Branch, P., MacGeoch, C., Casciano, I., Karran, P. & Bignami, M. (1994) A mismatch recognition defect in colon carcinoma confers DNA microsatellite instability and a mutator phenotype. Proc Natl Acad Sci USA 91: 8905â8909.
Bhattacharyya, N. P., Skandalis, A., Ganesh, A., Groden, J. & Meuth, M. (1994) Mutator phenotypes in human colorectal carcinoma cell lines. Proc Natl Acad Sci USA 91: 6319â6123.
BĂžrresenn, A-L, Lothe, R. A., Meling, G. I., Lystad, P., Morrison, P., Lipford, J., Kane, M. F., Rognum, T. O. & Kolodner, R. D. (1995) Somatic mutations in the hMSH2 gene in microsatellite unstable colorectal carcinomas. Hum Mol Genet 4: 2065â2072.
Brentnall, T. A., Chen, R., Lee, J. G., Kimmey, M. B., Bronner, M. P., Haggitt, R. C., Kowdley, K. V., Hecker, L. M. & Byrd, D. R. (1995) Microsatellite instability and K-ras mutations associated with pancreatic adenocarcinoma and pancreatitis. Cancer Res 55: 4264â4267.
Dietmaier, W., Wallinger, S., Bocker, T., Kullmann, F., Fishel, R. & RĂŒschoff, J. (1997) Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res 57: 4749â4756.
Dunlop, M. G. (1996) Mutator genes and mosaicism in colorectal cancer. Curr Opin Genet Dev 6: 75â80.
Eshleman, J. R. & Markowitz, S. D. (1995) Microsatellite instability in inherited and sporadic neoplasms. Curr Opin Oncol 7: 83â89.
Eshleman, J. R., Lang, E. Z., Bowerfind, G. K., Parsons, R., Vogelstein, B., Willson, J. K. V., Veigl, M. L., Sedwick, W. D. & Markowitz, S. D. (1995) Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogene 10: 33â37.
Fishel, R. A., Lescoe, M. K., Rao, M. R. S., Copeland, N., Jenkins, N., Garber, J., Kane, M. & Kolodner, R. (1993) The human mutator gene homolog MSH2 and its association with hereditary non-polyposis colon cancer. Cell 75: 1027â1038.
Fodde, R. & Losekoot, M. (1994) Mutation detection by denaturing gradient gel electrophoresis (DGGE). Hum Mutat 3: 83â94.
Fujita, M., Enomoto, T., Yoshino, K., Nomura, T., Buzard, G. S., Inoue, M. & Okudaira, Y. (1995) Microsatellite instability and alterations in the hMSH2 gene in human ovarian cancer. Int J Cancer 64: 361â366.
Futreal, P. A., Soderkvist, P., Marks, J. R., Inglehart, J. D., Cochran, C., Barrett, J. C. & Wiseman, R. W. (1992) Detection of frequent allelic loss on proximal chromosome 17q in sporadic breast carcinoma using microsatellite length polymorphisms. Cancer Res 52: 2624â2627.
Han, H. J., Yanagisawa, A., Kato, Y., Park, J. G. & Nakamura, Y. (1993) Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res 53: 5087â5089.
Honchel, R., Halling, K. C. & Thibodeau, S. N. (1995) Genomic instability in neoplasia. Semin Cell Biol 6: 45â52.
Ionov, Y., Peinado, M. A., Malkhosyan, S., Shibata, D. & Perucho, M. (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363: 558â561.
Kane, M. F., Loda, M., Gaida, G. M., Lipman, J., Mishra, R., Goldman, H., Jessup, J. M. & Kolodner, R. (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57: 808â811.
Katabuchi, H., Van Rees, B., Lambers, A. R., Ronnett, B. M., Blazes, M. S., Leach, F. S., Cho, K. R. & Hedrick, L. (1995) Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas. Cancer Res 55: 5556â5560.
Keller, G., Roter, M., Vogelsang, H., Bischoff, P., Becker, K-F, Mueller, J., Brauch, H., Siewert, J. R. & Höfler, H. (1995) Microsatellite instability in adenocarcinomas of the upper gastrointestinal tract. Am J Pathol 147: 593â600.
Kim, H., Jen, J., Vogelstein, B. & Hamilton, S. R. (1994) Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 145: 148â156.
Kolodner, R. (1996) Biochemistry and genetics of eukaryotic mismatch repair. Genes Dev 10: 1433â1442.
Leach, F. S., Nicolaides, N. C., Papadopoulos, N., Liu, B., Jen, J., Parsons, R. E., PeltomĂ€ki, P., Sistönen, P., Aaltonen, L. A., Nyström-Lahti, M., Guan, X. Y., Zang, J., Meltzer, P. S., Yu, J. W., Kao, F. T., Chen, D. J., Cerosaletti, K. M., Fournier, R. E. K., Todd, S., Lewis, T., Leach, R. G., Naylor, S. L., Weissenbach, J., Mecklin, J-P, JĂ€rvinen, H., Petersen, G. M., Hamilton, S. R., Green, J., Jass, J., Watson, P., Lynch, H. T., Trent, J. M., De la Chapelle, A., Kinzler, K. W. & Vogelstein, B. (1993) Mutations of a mutS homolog in hereditary non-polyposis colorectal cancer. Cell 75: 1215â1225.
Liu, B., Nicolaides, N. C., Markowitz, S., Willson, J. K. V., Parsons, R. E., Jen, J., Papadopoulos, N., Peltomaki, P., De la Chapelle, A., Hamilton, S. R., Kinzler, K. W. & Vogelstein, B. (1995) Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nature Genet 9: 48â55.
Liu, B., Parsons, R., Papadopoulos, N., Nicolaides, N. C., Lynch, H. T., Watson, P., Jass, J. R., Dunlop, M., Wyllie, A., PeltomĂ€ki, P., De la Chapelle, A., Hamilton, S. R., Vogelstein, B. & Kinzler, K. W. (1996) Analysis of the mismatch repair genes in the hereditary non-polyposis colorectal cancer patients. Nature Med 2: 169â174.
Loeb, L. A. (1994) Microsatellite instability: marker of a mutator phenotype in cancer. Cancer Res 54: 5059â5063.
Modrich, P. & Lahue, R. (1996) Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Ann Rev Biochem 65: 101â133.
Moslein, G., Tester, D. J., Lindor, N. M., Honchel, R., Cunningham, J. M., French, A. J., Halling, K. C., Schwab, M., Goretzki, P. & Thibodeau, S. N. (1996) Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and herediatary colorectal cancer. Hum Mol Genet 5: 1245â1252.
Muzeau, F., Flejou, J-F, Belghiti, J., Thomas, G. & Hamelin, R. (1997) Infrequent microsatellite instability in oesophageal cancers. Br J Cancer 75: 1336â1339.
Myers, R. M., Maniatis, T. & Lerman, L. S. (1987) Detection and localization of single base changes by denaturating gradient gel electrophoresis. Nucleic Acids Res 17: 501â528.
Nicolaides, N. C., Littman, S. J., Modrich, P., Kinzler, K. W. & Vogelstein, B. (1998) A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype. Mol Cell Biol 18: 1635â1641.
Nyström-Lahti, M., Parsons, R., Sistönen, P., PylkkĂ€nen, L., Aaltonen, L. A., Leach, F. S., Hamilton, S. R., Watson, P., Bronson, E., Fusaro, R., Cavalieri, J., Lynch, J., Lanspa, S., Smyrk, T., Lynch, P., Drouhard, T., Kinzler, K. W., Vogelstein, B., Lynch, H. T., De la Chapelle, A. & PeltomĂ€ki, P. (1994) Mismatch repair genes on chromosomes 2p and 3p account for major share of hereditary non-polyposis colorectal cancer families evaluable by linkage. Am J Hum Genet 55: 659â665.
Papadopoulos, N., Nicolaides, N. C., Wei, Y., Ruben, S. N., Carter, K. C., Rosen, C. A., Haseltine, W. A., Fleischmann, R. D., Fraser, C. N., Adams, M. D., Venter, J. C., Hamilton, S. R., Petersen, G. M., Watson, P., Lynch, H. T., Peltomaki, P., De la Chapelle, A., Kinzler, K. W. & Vogelstein, B. (1994) Mutation of mutL homolog in hereditary colon cancer. Science 263: 1625â1629.
Parsons, R., Li, G-M, Longley, M., Fang, W. H., Papadopoulos, N., Jen, J., de la Chapelle, A., Kinzler, K. W., Vogelstein, B. & Modrich, P. (1993) Hypermutability and mismatch repair deficency in RER+ tumor cells. Cell 75: 1227â1236.
Sambrook, J., Fritsch, E. F. & Maniatis, T. (1989). Molecular Cloning: a Laboratory Manual, 2nd Edn. Cold Spring Harbor Laboratory Press: Cold Spring Harbor
Seifert, M., Seib, T., Engel, M., Dooley, S. & Welter, C. (1996) Characterization of the human NM23.H2 promoter region and localization of the microsatellite D17S396. Biochem Biophys Res Commun 215: 910â914.
Strand, M., Prolla, T. A., Liskay, R. M. & Petes, T. D. (1993) Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 365: 274â276.
TannergĂ„rd, P., Lipford, J. R., Kolodner, R., Frödin, J. E., Nordenskjöld, M. & Lindblom, A. (1995) Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer families. Cancer Res 55: 6092â6096.
Wahlberg, S., Nyström-Lahti, M., Kane, M. F., Kolodner, R. D., PeltomĂ€ki, P. & Lindblom, A. (1997) Few mutations in the hMSH2 gene in Swedish HNPCC families found by denaturing gradient gel electrophoresis. Int J Cancer 74: 134â137.
Weissenbach, J., Gyapay, G., Dib, C., Vignal, A., Morissette, J., Milasseau, P., Vaysseix, G. & Lathrop, M. A. (1992) A second-generation linkage map of the human genome. Nature 359: 794â801.
Wijnen, J., Fodde, R. & Kahn, P. M. (1994) DGGE polymorphism in intron 10 of MSH2, the HNPCC gene. Hum Mol Genet 3: 2263â2268.
Wu, Y., Nyström-Lahti, M., Osinga, J., Looman, M. W. G., PeltomĂ€ki, P., Alatonen, L. A., de la Chapelle, A., Hofstra, R. M. W. & Buys, CHCM (1997) MSH2 and MLH1 mutations in sporadic replication error-positive colorectal carcinoma as assessed by two-dimensional DNA electrophoresis. Gene Chrom Cancer 18: 269â278.
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Ghimenti, C., TannergĂ„rd, P., Wahlberg, S. et al. Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours. Br J Cancer 80, 11â16 (1999). https://doi.org/10.1038/sj.bjc.6690314
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DOI: https://doi.org/10.1038/sj.bjc.6690314
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