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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
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).
Peltomäki, P. et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science 260, 810–812 (1993).
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).
Parsons, R. et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75, 1227–1236 (1993).
Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).
Leach, F.S. et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993).
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).
Papadopoulos, N. et al. Mutation of a mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).
Nicolaides, N.C. et al. Mutations of two PMS homologues in hereditary non-polyposis colon cancer. Nature 371, 75–80 (1994).
Palombo, F., Hughes, M., Jiricny, J., Truong, O. & Hsuan, J. Mismatch repair and cancer. Nature 367, 417 (1994).
Palombo, F. et al. GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science 268, 1912–1914 (1995).
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).
Papadopoulos, N. et al. Mutation of in genetically unstable cells. Science 268, 1915–1917 (1995).
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).
Thibodeau, S.N., Bren, G. & Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260, 816–819 (1993).
Aaltonen, L.A. et al. Clues to the pathogenesis of familial colorectal cancer. Science 260, 812–816 (1993).
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).
Liu, B. et al. Genetic instability occurs in the majority of young patients with colorectal cancer. Nature Med. 1, 348–352 (1995).
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).
Liu, B. et al. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 54, 4590–4594 (1994).
Hamilton, S.R. et al. The molecular basis of Turcot's syndrome. N. Engl. J. Med. 332, 839–847 (1995).
Powell, S.M. et al. Molecular diagnosis of familial adenomatous polyposis. N. Engl. J. Med. 329, 1982–1987 (1993).
Roest, P.A.M. et al. Protein truncation test (PTT) for rapid detection of translation-terminating mutations. Hum. Mol. Genet. 2, 1719–1721 (1993).
Aaltonen, L.A. et al. Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients Cancer Res. 54, 1645–1648 (1994).
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).
Nystrmö-Lahti, M. et al. Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nature Med. 1, 1202–1206 (1995).
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).
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).
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).
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).
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).
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).
Liu, B. et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nature Genet. 9, 48–54 (1995).
Papadopoulos, N., Leach, F.S., Kinzler, K.W. & Vogelstein, B. Monoallelic mutation analysis (MAMA) for identifying germline mutations. Nature Genet. 11, 99–101 (1995).
Jen, J.J. et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N. Engl. J. Med. 331, 213–221 (1994).
About this article
Cite this article
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). https://doi.org/10.1038/nm0296-169
Expert Review of Molecular Diagnostics (2020)
Pathology - Research and Practice (2020)
Breast Cancer (2020)
Journal of Human Genetics (2019)
Seminars in Diagnostic Pathology (2019)