Abstract
PURPOSE: The present study was designed to determine the frequency of germline mutations in the hMLH1 and hMSH2 genes in 31 families suspected of having hereditary nonpolyposis colorectal cancer who do not fulfill the criteria of the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer but in whom a genetic basis for colon cancer is strongly suspected and 45 patients with sporadic early-onset colorectal cancer who developed colorectal cancer before the age of 40 years without any family history of colorectal cancer. METHODS: Genomic DNAs were prepared from peripheral blood samples of patients who were tested. All coding exons and exon-intron borders of these two genes were screened, first with the polymerase chain reaction-single-strand conformation polymorphism method, followed by sequencing of the DNA fragments displaying an abnormal single-strand conformation polymorphism pattern. RESULTS: In 31 families with suspected hereditary nonpolyposis colorectal cancer, we found six different germline mutations in seven unrelated families, including one missense mutation and three frame-shift mutations in the hMLH1 gene and one missense mutation and one frame-shift mutation in the hMSH2 gene. Totally, frequency of mutation was 23 percent, 16 percent and 7 percent in the hMLH1 and hMSH2, respectively. Only one missense mutation of the hMSH2 gene was identified in 45 patients (2 percent) with sporadic early-onset colorectal cancer. The mutation detection rate in families with suspected hereditary nonpolyposis colorectal cancer was significantly higher than that of patients with sporadic early-onset colorectal cancer (P<0.05). CONCLUSION: Our definition of suspected hereditary nonpolyposis colorectal cancer is useful in the diagnosis of hereditary nonpolyposis colorectal cancer and for identifying those families who need genetic presymptomatic diagnosis. Our results indicate that it may be important to perform DNA testing in families suspected of having hereditary nonpolyposis colorectal cancer. On the other hand, we only detected a low mutation rate (2 percent) in 45 patients with sporadic early-onset colorectal cancer.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Powell SM, Zilz N, Beazer-Barclay Y,et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992;359:235–7.
Baker SJ, Fearon ER, Nigro JM,et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 1989;244:217–21.
Fearon ER, Cho KR, Nigro JM,et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 1990;247:49–56.
Vogelstein B, Fearon ER, Hamilton SR,et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319:525–32.
Fearon ER, Vogelstein B. A genetic model for coloretcal tumorigenesis. Cell 1990;61:759–67.
Boland CR. Roles of the DNA mismatch repair genes in colorectal tumorigenesis. Int J Cancer 1996;69:47–9.
Jiricny J. Colon cancer and DNA repair: have mismatches met their match? Trends Genet 1994;10:164–8.
Fishel R, Lescoe MK, Rao MR,et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993;75:1027–38.
Leach FS, Nicolaides NC, Papadopoulos N,et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993;75:1215–25.
Bronner CE, Baker SM, Morrison PT,et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary nonpolyposis colon cancer. Nature 1994;368:258–61.
Papadopoulos N, Nicolaides NC, Wei YF,et al. Mutation of a mutL homolog in hereditary colon cancer. Science 1994;263:1625–9.
Nicolaides NC, Papadopoulos N, Liu B,et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 1994;371:75–80.
Liu B, Parsons RE, Hamilton SR,et al. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res 1994;54:4590–4.
Han HJ, Maruyama M, Baba S, Park JG, Nakamura Y. Genomic structure of human mismatch repair gene, hMLH1, and its mutation analysis in patients with hereditary nonpolyposis colorectal cancer (HNPCC). Hum Mol Genet 1995;4:237–42.
Nystrom-Lahti M, Parsons R, Sistonen P,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 1994;55:659–65.
Lindblom A, Tannergard P, Werelius B, Nordenskjold M. Genetic mapping of a second locus predisposing to hereditary nonpolyposis colon cancer. Nat Genet 1993;5:279–82.
Vasen HF, Mecklin J-P, Kahn PM, Lynch HT. The International Collaborative Group on hereditary nonpolyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 1991;34:424–5.
Ponz DL, Sassatelli R, Benatti P, Roncucci L. Identification of hereditary nonpolyposis colorectal cancer in general population. Cancer 1993;71:3493–501.
Percesepe A, Anti M, Marra G,et al. Role of clinical criteria in the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC): result of a multivariate analysis. Int J Cancer 1994;58:799–802.
Han HJ, Yuan Y, Ku JL,et al. Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancer. J Natl Cancer Inst 1996;88:1317–9.
Han HJ, Yanagisawa A, Kato Y, Park JG, Nakamura Y. Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res 1993;53:5087–9.
Loeb LA. Microsatellite instability: marker of a mutator phenotype in cancer. Cancer Res 1994;54:5059–63.
Aaltonen LA, Peltomaki P, Mecklin JP,et al. Replications errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 1994;54:1645–8.
Blin N, Nicklen S, Coulson AR. DNA sequencing with chain terminating inhibitors. Proc Natl Acad Sci U S A 1977;74:5463–6.
Orita M, Iwahana H, Kanazawa H, Sekiya T. Detection of polymorphism of human DNA by gel electrophoresis as single strand confirmation polymorphism. Proc Natl Acad Sci U S A 1989;86:2766–70.
Orita M, Suzuki Y, Sekiya T, Hayashi K. A rapid and sensitive detection of point mutations and genetic polymorphism using polymerase chain reaction. Genomics 1989;5:874–9.
Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain terminating inhibitors. Proc Natl Acad Sci U S A 1977;74:5463–6.
Beck NE, Tomlinson IP, Homfray T, Hodgson SV, Harocopos CJ, Bodmer WF. Genetic testing important in families with a history suggestive of hereditary nonpolyposis colorectal cancer even if the Amsterdam criteria are not fulfilled. Br J Surg 1997;84:233–7.
Maliaka YK, Chudina AP, Belev NF, Alday P, Bochkov NP, Buerstedde JM. CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations. Hum Genet 1996;97:251–5.
Wijnen J, Khan PM, Vasen H,et al. Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15–16. Am J Hum Genet 1996;58:300–7.
Liu B, Farrington SM, Petersen GM,et al. Genetic instability occurs in the majority of young patiens with colorectal cancer. Nat Med 1995;1:348–52.
Author information
Authors and Affiliations
Additional information
Supported, in part, by the 1997 Good Health R & D Project, the Ministry of Health and Welfare of the Republic of Korea, and the Korea Science and Engineering Foundation (KOSEF-CRC-94K2-0402-04-00-3) through the Cancer Research Center at Seoul National University.
Read at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, June 22 to 26, 1997. Winner of the Southern California Society of Colon and Rectal Surgeons Award.
About this article
Cite this article
Yuan, Y., Han, HJ., Zheng, S. et al. Germline mutations of hMLH1 and hMSH2 genes in patients with suspected hereditary nonpolyposis colorectal cancer and sporadic early-onset colorectal cancer. Dis Colon Rectum 41, 434–440 (1998). https://doi.org/10.1007/BF02235756
Issue Date:
DOI: https://doi.org/10.1007/BF02235756