Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1997 Jul;61(1):129–138. doi: 10.1086/513896

Reduced frequency of extracolonic cancers in hereditary nonpolyposis colorectal cancer families with monoallelic hMLH1 expression.

A C Jäger 1, M L Bisgaard 1, T Myrhøj 1, I Bernstein 1, J F Rehfeld 1, F C Nielsen 1
PMCID: PMC1715882  PMID: 9245993

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease caused by mutations in one of at least four different DNA mismatch repair genes, hMLH1, hMSH2, hPMS1, and hPMS2. Phenotypically, HNPCC is characterized by the early onset of colorectal cancers and various extracolonic cancers. Depending on the presence or absence of extracolonic tumors, HNPCG-has been divided into two syndromes (Lynch syndrome I and Lynch syndrome II), but, so far, no correlation to distinct genotypes has been demonstrated. In this study, we present a frequent hMLH1 intron 14 founder mutation that is associated with a highly reduced frequency of extracolonic tumors. The mutation disrupts the splice donor site and silences the mutated allele. Tumors exhibited microsatellite instability, and loss of the wild-type hMLH1 allele was prevalent. We propose that the mutation results in a milder phenotype, because the mutated hMLH1 protein is prevented from exerting a dominant negative effect on the concerted action of the mismatch repair system.

Full text

PDF
129

Images in this article

132Figure 1
on p.132
132Figure 2
on p.132
134Figure 3
on p.134

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aoufouchi S., Yélamos J., Milstein C. Nonsense mutations inhibit RNA splicing in a cell-free system: recognition of mutant codon is independent of protein synthesis. Cell. 1996 May 3;85(3):415–422. doi: 10.1016/s0092-8674(00)81119-8. [DOI] [PubMed] [Google Scholar]
  2. Bronner C. E., Baker S. M., Morrison P. T., Warren G., Smith L. G., Lescoe M. K., Kane M., Earabino C., Lipford J., Lindblom A. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994 Mar 17;368(6468):258–261. doi: 10.1038/368258a0. [DOI] [PubMed] [Google Scholar]
  3. Canzian F., Salovaara R., Hemminki A., Kristo P., Chadwick R. B., Aaltonen L. A., de la Chapelle A. Semiautomated assessment of loss of heterozygosity and replication error in tumors. Cancer Res. 1996 Jul 15;56(14):3331–3337. [PubMed] [Google Scholar]
  4. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  5. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  6. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  7. Fishel R., Kolodner R. D. Identification of mismatch repair genes and their role in the development of cancer. Curr Opin Genet Dev. 1995 Jun;5(3):382–395. doi: 10.1016/0959-437x(95)80055-7. [DOI] [PubMed] [Google Scholar]
  8. Fishel R., Lescoe M. K., Rao M. R., Copeland N. G., Jenkins N. A., Garber J., Kane M., Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 1994 Apr 8;77(1):1–166. [PubMed] [Google Scholar]
  9. Froggatt N. J., Joyce J. A., Davies R., Gareth D., Evans R., Ponder B. A., Barton D. E., Maher E. R. A frequent hMSH2 mutation in hereditary non-polyposis colon cancer syndrome. Lancet. 1995 Mar 18;345(8951):727–727. doi: 10.1016/s0140-6736(95)90900-1. [DOI] [PubMed] [Google Scholar]
  10. Hemminki A., Peltomäki P., Mecklin J. P., Järvinen H., Salovaara R., Nyström-Lahti M., de la Chapelle A., Aaltonen L. A. Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nat Genet. 1994 Dec;8(4):405–410. doi: 10.1038/ng1294-405. [DOI] [PubMed] [Google Scholar]
  11. Kolodner R. D., Hall N. R., Lipford J., Kane M. F., Morrison P. T., Finan P. J., Burn J., Chapman P., Earabino C., Merchant E. Structure of the human MLH1 locus and analysis of a large hereditary nonpolyposis colorectal carcinoma kindred for mlh1 mutations. Cancer Res. 1995 Jan 15;55(2):242–248. [PubMed] [Google Scholar]
  12. Kolodner R. D., Hall N. R., Lipford J., Kane M. F., Rao M. R., Morrison P., Wirth L., Finan P. J., Burn J., Chapman P. Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Genomics. 1994 Dec;24(3):516–526. doi: 10.1006/geno.1994.1661. [DOI] [PubMed] [Google Scholar]
  13. Leach F. S., Nicolaides N. C., Papadopoulos N., Liu B., Jen J., Parsons R., Peltomäki P., Sistonen P., Aaltonen L. A., Nyström-Lahti M. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell. 1993 Dec 17;75(6):1215–1225. doi: 10.1016/0092-8674(93)90330-s. [DOI] [PubMed] [Google Scholar]
  14. Legrain P., Rosbash M. Some cis- and trans-acting mutants for splicing target pre-mRNA to the cytoplasm. Cell. 1989 May 19;57(4):573–583. doi: 10.1016/0092-8674(89)90127-x. [DOI] [PubMed] [Google Scholar]
  15. Liu B., Parsons R. E., Hamilton S. R., Petersen G. M., Lynch H. T., Watson P., Markowitz S., Willson J. K., Green J., de la Chapelle A. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 1994 Sep 1;54(17):4590–4594. [PubMed] [Google Scholar]
  16. Liu B., Parsons R., Papadopoulos N., Nicolaides N. C., Lynch H. T., Watson P., Jass J. R., Dunlop M., Wyllie A., Peltomäki P. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med. 1996 Feb;2(2):169–174. doi: 10.1038/nm0296-169. [DOI] [PubMed] [Google Scholar]
  17. Lynch H. T., Watson P., Kriegler M., Lynch J. F., Lanspa S. J., Marcus J., Smyrk T., Fitzgibbons R. J., Jr, Cristofaro G. Differential diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome I and Lynch syndrome II). Dis Colon Rectum. 1988 May;31(5):372–377. doi: 10.1007/BF02564888. [DOI] [PubMed] [Google Scholar]
  18. Maquat L. E. When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. RNA. 1995 Jul;1(5):453–465. [PMC free article] [PubMed] [Google Scholar]
  19. Moisio A. L., Sistonen P., Weissenbach J., de la Chapelle A., Peltomäki P. Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer. Am J Hum Genet. 1996 Dec;59(6):1243–1251. [PMC free article] [PubMed] [Google Scholar]
  20. Nakamura Y., Lathrop M., Leppert M., Dobbs M., Wasmuth J., Wolff E., Carlson M., Fujimoto E., Krapcho K., Sears T. Localization of the genetic defect in familial adenomatous polyposis within a small region of chromosome 5. Am J Hum Genet. 1988 Nov;43(5):638–644. [PMC free article] [PubMed] [Google Scholar]
  21. Nicolaides N. C., Papadopoulos N., Liu B., Wei Y. F., Carter K. C., Ruben S. M., Rosen C. A., Haseltine W. A., Fleischmann R. D., Fraser C. M. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature. 1994 Sep 1;371(6492):75–80. doi: 10.1038/371075a0. [DOI] [PubMed] [Google Scholar]
  22. Nyström-Lahti M., Kristo P., Nicolaides N. C., Chang S. Y., Aaltonen L. A., Moisio A. L., Järvinen H. J., Mecklin J. P., Kinzler K. W., Vogelstein B. Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nat Med. 1995 Nov;1(11):1203–1206. doi: 10.1038/nm1195-1203. [DOI] [PubMed] [Google Scholar]
  23. Papadopoulos N., Nicolaides N. C., Wei Y. F., Ruben S. M., Carter K. C., Rosen C. A., Haseltine W. A., Fleischmann R. D., Fraser C. M., Adams M. D. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994 Mar 18;263(5153):1625–1629. doi: 10.1126/science.8128251. [DOI] [PubMed] [Google Scholar]
  24. Spirio L., Joslyn G., Nelson L., Leppert M., White R. A CA repeat 30-70 KB downstream from the adenomatous polyposis coli (APC) gene. Nucleic Acids Res. 1991 Nov 25;19(22):6348–6348. doi: 10.1093/nar/19.22.6348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tannergård P., Lipford J. R., Kolodner R., Frödin J. E., Nordenskjöld M., Lindblom A. Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer families. Cancer Res. 1995 Dec 15;55(24):6092–6096. [PubMed] [Google Scholar]
  26. Vasen H. F., Mecklin J. P., Khan P. M., Lynch H. T. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991 May;34(5):424–425. doi: 10.1007/BF02053699. [DOI] [PubMed] [Google Scholar]
  27. Vasen H. F., Offerhaus G. J., den Hartog Jager F. C., Menko F. H., Nagengast F. M., Griffioen G., van Hogezand R. B., Heintz A. P. The tumour spectrum in hereditary non-polyposis colorectal cancer: a study of 24 kindreds in the Netherlands. Int J Cancer. 1990 Jul 15;46(1):31–34. doi: 10.1002/ijc.2910460108. [DOI] [PubMed] [Google Scholar]
  28. Vasen H. F., Wijnen J. T., Menko F. H., Kleibeuker J. H., Taal B. G., Griffioen G., Nagengast F. M., Meijers-Heijboer E. H., Bertario L., Varesco L. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996 Apr;110(4):1020–1027. doi: 10.1053/gast.1996.v110.pm8612988. [DOI] [PubMed] [Google Scholar]
  29. Watson P., Lynch H. T. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993 Feb 1;71(3):677–685. doi: 10.1002/1097-0142(19930201)71:3<677::aid-cncr2820710305>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  30. Wijnen J., Khan P. M., Vasen H., Menko F., van der Klift H., van den Broek M., van Leeuwen-Cornelisse I., Nagengast F., Meijers-Heijboer E. J., Lindhout D. Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16. Am J Hum Genet. 1996 Feb;58(2):300–307. [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES