Analysis of mismatch repair genes in hereditary non–polyposis colorectal cancer patients


Hereditary non–polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer and linked to germline defects in at least four mismatch repair genes. Although much has been learned about the molecular pathogenesis of this disease, questions related to effective presymptomatic diagnosis are largely unanswered because of its genetic complexity. In this study, we evaluated tumors from 74 HNPCC kindreds for genomic instability characteristic of a mismatch repair deficiency and found such instability in 92% of the kindreds. The entire coding regions of the five known human mismatch repair genes were evaluated in 48 kindreds with instability, and mutations were identified in 70%. This study demonstrates that a combination of techniques can be used to genetically diagnose tumor susceptibility in the majority of HNPCC kindreds and lays the foundation for genetic testing of this relatively common disease.

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  1. 1

    Warthin A.S. Heredity with reference to carcinoma: As shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895-1913. Arch. Intern. Med. 12, 546–555 (1913).

    Article  Google Scholar 

  2. 2

    Lynch, H.T. et al. Genetics, natural history, rumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: An updated review. Gastroenterology 104, 1535–1549 (1993).

    CAS  Article  Google Scholar 

  3. 3

    Peltomäki, P. et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science 260, 810–812 (1993).

    Article  Google Scholar 

  4. 4

    Lindblom, A., Tannergård, P., Werelius, B. & Nordenskjöld, M. Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nature Genet. 5, 279–282 (1993).

    CAS  Article  Google Scholar 

  5. 5

    Parsons, R. et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75, 1227–1236 (1993).

    CAS  Article  Google Scholar 

  6. 6

    Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).

    CAS  Article  Google Scholar 

  7. 7

    Leach, F.S. et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993).

    CAS  Article  Google Scholar 

  8. 8

    Bronner, C.E. et al. Mutation in the DNA mismatch repair gene homologue hMLHl is associated with hereditary non-polyposis colon cancer. Nature 368, 258–261 (1994).

    CAS  Article  Google Scholar 

  9. 9

    Papadopoulos, N. et al. Mutation of a mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).

    CAS  Article  Google Scholar 

  10. 10

    Nicolaides, N.C. et al. Mutations of two PMS homologues in hereditary non-polyposis colon cancer. Nature 371, 75–80 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Palombo, F., Hughes, M., Jiricny, J., Truong, O. & Hsuan, J. Mismatch repair and cancer. Nature 367, 417 (1994).

    CAS  Article  Google Scholar 

  12. 12

    Palombo, F. et al. GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science 268, 1912–1914 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Dmmmond, J.T., Li, G.-M. Longley, M.J. & Modrich, P. Isolation of an hMSH2-p160 herterodimer that restores DNA mismatch repair to tumor cells. Science 268, 1909–1912 (1995).

    Article  Google Scholar 

  14. 14

    Papadopoulos, N. et al. Mutation of in genetically unstable cells. Science 268, 1915–1917 (1995).

    CAS  Article  Google Scholar 

  15. 15

    Ionov, Y. M., Peinado, A., Malkhosyan, S., Shibata, D. & Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363, 558–561 (1993).

    CAS  Article  Google Scholar 

  16. 16

    Thibodeau, S.N., Bren, G. & Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260, 816–819 (1993).

    CAS  Article  Google Scholar 

  17. 17

    Aaltonen, L.A. et al. Clues to the pathogenesis of familial colorectal cancer. Science 260, 812–816 (1993).

    CAS  Article  Google Scholar 

  18. 18

    Vasen, H.F., Mecklin, J.P., Meera Khan, P. & Lynch, H.T. The international collaborative group on hereditary nonpolyposis colorectal cancer (ICG-HNPCC). Dis. Colon Rectum 34, 424–425 (1991).

    CAS  Article  Google Scholar 

  19. 19

    Liu, B. et al. Genetic instability occurs in the majority of young patients with colorectal cancer. Nature Med. 1, 348–352 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Goelz, S.E., Hamilton, S.R. & Vogelstein, B. Purification of DNA from formaldehyde fixed and paraffin embedded human tissue. Biochem. Biophys. Res. Commun. 130, 118–126 (1985).

    CAS  Article  Google Scholar 

  21. 21

    Liu, B. et al. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 54, 4590–4594 (1994).

    CAS  Google Scholar 

  22. 22

    Hamilton, S.R. et al. The molecular basis of Turcot's syndrome. N. Engl. J. Med. 332, 839–847 (1995).

    CAS  Article  Google Scholar 

  23. 23

    Powell, S.M. et al. Molecular diagnosis of familial adenomatous polyposis. N. Engl. J. Med. 329, 1982–1987 (1993).

    CAS  Article  Google Scholar 

  24. 24

    Roest, P.A.M. et al. Protein truncation test (PTT) for rapid detection of translation-terminating mutations. Hum. Mol. Genet. 2, 1719–1721 (1993).

    CAS  Article  Google Scholar 

  25. 25

    Aaltonen, L.A. et al. Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients Cancer Res. 54, 1645–1648 (1994).

    CAS  Google Scholar 

  26. 26

    Nyström-Lahti, M. et al. Close linkage to chromosome 3p and conservation of ancestral founding haplotype in hereditary nonpolyposis colorectal cancer families. Proc. Natl. Acad. Sci. USA 91, 6054–6058 (1994).

    Article  Google Scholar 

  27. 27

    Nystrmö-Lahti, M. et al. Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nature Med. 1, 1202–1206 (1995).

    Google Scholar 

  28. 28

    Prolla, T.A., Pang, Q., Alani, E., Kolodner, R.D. & Liskay, R.M. MLH1, PMS1, and MSH2 interactions during the initiation of DNA mismatch repair in yeast. Science 265, 1091–1093 (1995).

    Article  Google Scholar 

  29. 29

    Li G.-M. & Modrich, P. Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs. Proc. Natl. Acad. Sci. USA 92, 1950–1954 (1995).

    CAS  Article  Google Scholar 

  30. 30

    Hall, N.R. et al. Genetic-linkage in muirtorre syndrome to the same chromosomal region as cancer family syndrome. Eur. J. Can. 30(A), 180–182 (1994).

    Article  Google Scholar 

  31. 31

    Honchel, R., Hailing, K.C., Schaid, D.J., Pittelkow, M. & Thibodeau, S.N. Microsatellite instability in Muir-Torre syndrome. Cancer Res. 54, 1159–1163 (1994).

    CAS  Google Scholar 

  32. 32

    Turcot, J., Despres J-P. & Pierre, F. Malignant tumors of the central nervous system associated with familial polyposis of the colon: Report of two cases. Dis. Colon Rectum 2, 456–458 (1959).

    Article  Google Scholar 

  33. 33

    Nyström-Lahti, M. et al. Mismatch repair genes on chromosome 2p and 3p account for a major share of hereditary nonpolyposis colorectal cancer families evaluable by linkage. Am. J. Hum. Genet. 55, 659–665 (1994).

    PubMed  PubMed Central  Google Scholar 

  34. 34

    Liu, B. et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nature Genet. 9, 48–54 (1995).

    CAS  Article  Google Scholar 

  35. 35

    Papadopoulos, N., Leach, F.S., Kinzler, K.W. & Vogelstein, B. Monoallelic mutation analysis (MAMA) for identifying germline mutations. Nature Genet. 11, 99–101 (1995).

    CAS  Article  Google Scholar 

  36. 36

    Jen, J.J. et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N. Engl. J. Med. 331, 213–221 (1994).

    CAS  Article  Google Scholar 

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Liu, B., Parsons, R., Papadopoulos, N. et al. Analysis of mismatch repair genes in hereditary non–polyposis colorectal cancer patients. Nat Med 2, 169–174 (1996).

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