Abstract
Mutations in hMSH2 and hMLH1 genes were analyzed in patients from 11 Japanese families that had been diagnosed as carrying hereditary nonpolyposis colorectal cancer (HNPCC) by clinical examination. Germ line mutations of hMSH2 gene were identified in 5 independent families in which colorectal (87% of patients), endometrial (30%), ovarian (17%), gastric (14%), and other cancers existed. Five mutations detected between codons 136 and 811 included single-base substitutions (C→T and T→G), a T deletion, and an A insertion, all of which produced stop codons resulting in truncated proteins, and an A→T substitution at splice donor site of exon 5 which resulted in deletion of this exon. Moreover, one HNPCC family was presumed to have germ line mutation of hMSH2 gene because a somatic mutation of hMSH2 gene was detected in a cancer from a patient in this family. In addition to these 11 families already diagnosed with HNPCC, 3 new families with germ line mutations of hMSH2 gene and hMLH1 gene were found through analysis of DNA from patients who had multiple cancers with alteration in microsatellite DNA. These mutations included an AG deletion at codons 877–878 of hMSH2 gene, an AAG deletion at codons 616–618 of hMLH1 gene, and a C→T single-base substitution at codon 217 of hMLH1 gene. Seven of eight germ line mutations found in this study are new mutations that have not been reported previously. In families in which germ line mutations were identified presymptomatic examination was then carried out using polymerase chain reaction single-strand conformation polymorphism analysis of DNA from peripheral blood, and the result was the detection of family members predisposed to HNPCC who did not yet show signs of cancer. These results indicate the value of DNA analysis in the screening and diagnosis of HNPCC patients and families.
Similar content being viewed by others
Abbreviations
- HNPCC :
-
Hereditary nonpolyposis colorectal cancer
- PCR :
-
Polymerase chain reaction
- SSCP :
-
Single-strand conformation polymorphism
References
Lynch HT, Kimberling W, Albano WA, Lynch JF, Biscone K, Schuelke GS, Sandberg AA, Lipkin M, Deschner EE, Mikol YB, Elston RC, Bailey-Wilson JE, Danes S (1985) Hereditary nonpolyposis colorectal cancer (Lynch syndrome I and II) I. Clinical description of resource. Cancer 56:934–938
Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch JF, Lynch PM, Cavalieri RJ, Boland CR (1993) Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104: 1535–1549
Fishel R, Lescoe MK, Rao MRS, Copeland NG, Jenkins NA, Garber J, Kane M, Kolonder R (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038
Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomaki P, Sistonen P, Aaltonen LA, Nyströmlahti M, Guan XY, Zhang J, Meltzer PS, Yu J-W, Kao FT, Chen DJ, Cerosaletti KM, Fournier REK, Todd S, Lewis T, Leach RJ, Naylor SL, Weissenbach J, Mecklin JP, Järvinen H, Petersen GM, Hamilton SR, Green J, Jass J, Watson P, Lynch HT, Trent JM, La Chapelle A, Kinzler KW, Vogelstein B (1993) Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–1225
Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A, Tannergård P, Bollag RJ, Godwin AR, Ward DC, Nordenskjold M, Fishel R, Kolonder R, Liskay RM (1994) Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368:258–261
Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MK, Venter JC, Hamilton SR, Peterson GM, Watson P, Lynch HT, Peltomäki P, Mecklin JP, de la Chapelle A, Kinzler KW, Vogelstein B. (1994) Mutation of a mutL homolog in hereditary colon cancer. Science 263:1625–1628
Nicolaidis NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Dunlop MG, Hamilton SR, Petersen GM, de la Chapelle A, Vogelstein B, Kinzler KW (1994) Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371:75–80
Vasen HFA, Mecklin J-P, Meera Khan P, Lynch HT (1991) The international collaborative group on hereditary non-polyposis colorectal cancer, dis. Colon Ret 34:424–425
Miyaki M, Konishi M, Kikuchi-Yanoshita R, Enomoto M, Igari T, Tanaka K, Muraoka M, Takahashi H, Amada Y, Fukayama M, Maeda Y, Iwama T, Mishima Y, Mori T, Koike M. (1994) Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res 54:3011–3020
Liu B, Parsons RE, Hamilton SR, Petersen GM, Lynch HT, Watson P, Markowitz S, Willson JKV, Green J, de la Chapelle A, Kinzler KW, Vogelstein B (1994) hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res 54:4590–4594
Kolodner RD, Hall NR, Lipford J, Kane MF, Rao MRS, Morrison P, Wirth L, Finan PJ, Burn J, Chapman P, Earabino C, Merchant E, Bishop DT (1994) Structure of the human MSH2 locus and analysis of two Muir-Torre kinders for msh2 mutations. Genomics 24:516–526
Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5: 874–879
Chong J-M, Fukayama M, Hayashi Y, Takizawa T, Koike M, Konishi M, Kikuchi-Yanoshita R, Miyaki M (1994) Microsatellite instability in the progression of gastric carcinoma. Cancer Res 54:4595–4597
Froggatt NJ, Joyce JA, Davis R, Evans DGR, Ponder BA, Barton DE, Maher ER (1995) A frequent hMSH2 mutation in hereditary non-polyposis colon cancer syndrome. Lancet 345: 727
Aaltonen LA, Peltomäki P, Leach FS, Sistonen P, Pylkkänen L, Mecklin J-P, Järvinen H, Powell SM, Jen J, Hamilton SR, Petersen GM, Kinzler KW, Vogelstein B, de la Chapelle A (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816
Peltomäki P, Lothe RA, Aaltonen LA, Pylkkänen L, Nyströmlahti M, Seruca R, David L, Holm R, Ryberg D, Haugen A, Brøgger A, Børresen A-L, de la Chapelle A (1993) Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 53:5853–5855
Nyströmlahti M, Parsons R, Sistonen P, Pylkkänen L, Aaltonen LA, Leach FS, Hamilton SR, Watson P, Bronson E, Fusaro R, Cavalieri J, Lynch J, Lanspa S, Smyrk T, Lyncj P, Drouhard T, Kinzler KW, Vogelstein B, Lynch HT, dela Chapelle A, Peltomäki P (1994) Mismatch repair genes on chromosomes 2p and 3p account for a major share of hereditary nonpolyposis colorectal cancer families evaluable by linkage. Am J Hum Genet 55:659–665
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Miyaki, M., Konishi, M., Muraoka, M. et al. Germ line mutations of hMSH2 and hMLH1 genes in Japanese families with hereditary nonpolyposis colorectal cancer (HNPCC): usefulness of DNA analysis for screening and diagnosis of HNPCC patients. J Mol Med 73, 515–520 (1995). https://doi.org/10.1007/BF00198903
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00198903