Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 1996 Dec;33(12):981–985. doi: 10.1136/jmg.33.12.981

Microsatellite instability in early onset and familial colorectal cancer.

C Brassett 1, J A Joyce 1, N J Froggatt 1, G Williams 1, D Furniss 1, S Walsh 1, R Miller 1, D G Evans 1, E R Maher 1
PMCID: PMC1050806  PMID: 9004127

Abstract

Hereditary non-polyposis colorectal cancer syndrome (HNPCC) is often considered to be the most common form of inherited colorectal cancer, although its precise incidence is unknown. The clinical diagnosis of HNPCC relies on a combination of family history and young age of onset of colorectal cancer, but as many familial aggregations of colorectal cancer do not fulfil the strict diagnostic criteria, HNPCC might be underdiagnosed. The majority of HNPCC families have germline mutations in mismatch repair (MMR) genes, such as MSH2 or MLH1, so that HNPCC cancers characteristically exhibit DNA replication errors (RERs) at microsatellite loci. Although an RER positive phenotype in tumours can also result from somatic mutations in an MMR gene, the prevalence of RER + tumours should provide a maximum estimate of the incidence of germline MMR gene mutations in patients with early onset and familial colorectal cancer. We investigated colorectal cancers for RERs from (1) a population based study of 33 patients with colorectal cancer aged 45 years or less, (2) 65 kindreds with familial colorectal cancer which only partially fulfilled the criteria for the diagnosis of HNPCC, and (3) 18 cancers from 12 HNPCC kindreds. Seven of 33 patients (21%) with colorectal cancer aged 45 years or less had an RER + cancer, with only two of these having a clear family history of HNPCC. A greater proportion of RER + tumours (5/7) occurred proximal to the splenic flexure than RER - tumours (4/26; chi2 = 6.14, p < 0.025). RERs were detected in all 18 cancers from HNPCC patients but in only six of 65 non-HNPCC familial colorectal cancer kindreds (9%; chi2 = 52.2, p < 0.0005). These findings suggest that most cancers in patients diagnosed at 45 years of age or less and familial aggregations of colorectal cancer which do not fulfil HNPCC diagnostic criteria do not have germline mutations in MSH2 and MLH1. Hence population screening for germline mutations in these genes is unlikely to be an efficient strategy for identifying people at high risk of developing colorectal cancer.

Full text

PDF
981

Images in this article

982Image
on p.982

Selected References

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

  1. Aaltonen L. A., Peltomäki P., Mecklin J. P., Järvinen H., Jass J. R., Green J. S., Lynch H. T., Watson P., Tallqvist G., Juhola M. Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res. 1994 Apr 1;54(7):1645–1648. [PubMed] [Google Scholar]
  2. Alitalo T., Kruse T. A., Ahrens P., Albertsen H. M., Eriksson A. W., de la Chapelle A. Genetic mapping of 12 marker loci in the Xp22.3-p21.2 region. Hum Genet. 1991 Apr;86(6):599–603. doi: 10.1007/BF00201548. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Buerstedde J. M., Alday P., Torhorst J., Weber W., Müller H., Scott R. Detection of new mutations in six out of 10 Swiss HNPCC families by genomic sequencing of the hMSH2 and hMLH1 genes. J Med Genet. 1995 Nov;32(11):909–912. doi: 10.1136/jmg.32.11.909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cannon-Albright L. A., Skolnick M. H., Bishop D. T., Lee R. G., Burt R. W. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med. 1988 Sep 1;319(9):533–537. doi: 10.1056/NEJM198809013190902. [DOI] [PubMed] [Google Scholar]
  6. Drummond J. T., Li G. M., Longley M. J., Modrich P. Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells. Science. 1995 Jun 30;268(5219):1909–1912. doi: 10.1126/science.7604264. [DOI] [PubMed] [Google Scholar]
  7. 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. 1993 Dec 3;75(5):1027–1038. doi: 10.1016/0092-8674(93)90546-3. [DOI] [PubMed] [Google Scholar]
  8. Froggatt N. J., Brassett C., Koch D. J., Evans D. G., Hodgson S. V., Ponder B. A., Maher E. R. Mutation screening of MSH2 and MLH1 mRNA in hereditary non-polyposis colon cancer syndrome. J Med Genet. 1996 Sep;33(9):726–730. doi: 10.1136/jmg.33.9.726. [DOI] [PMC free article] [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. Froggatt N. J., Koch J., Davies R., Evans D. G., Clamp A., Quarrell O. W., Weissenbach J., Hodgson S. V., Ponder B. A., Barton D. E. Genetic linkage analysis in hereditary non-polyposis colon cancer syndrome. J Med Genet. 1995 May;32(5):352–357. doi: 10.1136/jmg.32.5.352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  12. Hall N. R., Finan P. J., Ward B., Turner G., Bishop D. T. Genetic susceptibility to colorectal cancer in patients under 45 years of age. Br J Surg. 1994 Oct;81(10):1485–1489. doi: 10.1002/bjs.1800811029. [DOI] [PubMed] [Google Scholar]
  13. Houlston R. S., Collins A., Slack J., Morton N. E. Dominant genes for colorectal cancer are not rare. Ann Hum Genet. 1992 May;56(Pt 2):99–103. doi: 10.1111/j.1469-1809.1992.tb01136.x. [DOI] [PubMed] [Google Scholar]
  14. Jass J. R., Cottier D. S., Jeevaratnam P., Pokos V., Holdaway K. M., Bowden M. L., Van de Water N. S., Browett P. J. Diagnostic use of microsatellite instability in hereditary non-polyposis colorectal cancer. Lancet. 1995 Nov 4;346(8984):1200–1201. doi: 10.1016/s0140-6736(95)92902-9. [DOI] [PubMed] [Google Scholar]
  15. Jones M. H., Yamakawa K., Nakamura Y. Isolation and characterization of 19 dinucleotide repeat polymorphisms on chromosome 3p. Hum Mol Genet. 1992 May;1(2):131–133. doi: 10.1093/hmg/1.2.131. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Liu B., Farrington S. M., Petersen G. M., Hamilton S. R., Parsons R., Papadopoulos N., Fujiwara T., Jen J., Kinzler K. W., Wyllie A. H. Genetic instability occurs in the majority of young patients with colorectal cancer. Nat Med. 1995 Apr;1(4):348–352. doi: 10.1038/nm0495-348. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Nagase H., Nakamura Y. Mutations of the APC (adenomatous polyposis coli) gene. Hum Mutat. 1993;2(6):425–434. doi: 10.1002/humu.1380020602. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Nyström-Lahti M., Parsons R., Sistonen P., Pylkkänen L., Aaltonen L. A., Leach F. S., Hamilton S. R., Watson P., Bronson E., Fusaro R. 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. 1994 Oct;55(4):659–665. [PMC free article] [PubMed] [Google Scholar]
  22. Palombo F., Gallinari P., Iaccarino I., Lettieri T., Hughes M., D'Arrigo A., Truong O., Hsuan J. J., Jiricny J. GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science. 1995 Jun 30;268(5219):1912–1914. doi: 10.1126/science.7604265. [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. Scapoli C., Ponz De Leon M., Sassatelli R., Benatti P., Roncucci L., Collins A., Morton N. E., Barrai I. Genetic epidemiology of hereditary non-polyposis colorectal cancer syndromes in Modena, Italy: results of a complex segregation analysis. Ann Hum Genet. 1994 Jul;58(Pt 3):275–295. doi: 10.1111/j.1469-1809.1994.tb01891.x. [DOI] [PubMed] [Google Scholar]
  25. Spirio L., Nelson L., Ward K., Burt R., White R., Leppert M. A CA-repeat polymorphism close to the adenomatous polyposis coli (APC) gene offers improved diagnostic testing for familial APC. Am J Hum Genet. 1993 Feb;52(2):286–296. [PMC free article] [PubMed] [Google Scholar]
  26. Spirio L., Olschwang S., Groden J., Robertson M., Samowitz W., Joslyn G., Gelbert L., Thliveris A., Carlson M., Otterud B. Alleles of the APC gene: an attenuated form of familial polyposis. Cell. 1993 Dec 3;75(5):951–957. doi: 10.1016/0092-8674(93)90538-2. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Weissenbach J., Gyapay G., Dib C., Vignal A., Morissette J., Millasseau P., Vaysseix G., Lathrop M. A second-generation linkage map of the human genome. Nature. 1992 Oct 29;359(6398):794–801. doi: 10.1038/359794a0. [DOI] [PubMed] [Google Scholar]
  29. Wijnen J., Vasen H., Khan P. M., Menko F. H., van der Klift H., van Leeuwen C., van den Broek M., van Leeuwen-Cornelisse I., Nagengast F., Meijers-Heijboer A. Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis. Am J Hum Genet. 1995 May;56(5):1060–1066. [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES