Skip to main content
SpringerLink
Log in

Microsatellite instability: new aspects in the carcinogenesis of colorectal carcinoma

  • Review Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Very recently a new molecular mechanism in the tumorigenesis of colorectal carcinoma has been described which is closely linked to hereditary non-polyposis colonic cancer (HNPCC). Ubiquitous changes in the length of simple repetitive DNA sequences between constitutional and tumour DNA occur in about 90% of cases of HNPCC and in about 15% of cases of non-familial, sporadic colorectal carcinoma. Such microsatellite instabilities have been shown to be the phenotypical marker of mutations in the human homologues of prokaryotic mismatch repair genes (MutS, MutL, MutH). These data provide crucial new tools in the detection of patients at high risk of developing colon cancer and other HNPCC-related carcinomas. In addition, these developments provide new insights into a new, presumably primary event in oncogenesis, i.e. the occurrence of mutations in genomic stability genes leading to an increased cellular mutation rate (“mutator phenotype”) and thus to cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Aaltonen LA, Peltomäki P, Leach FS, Sistonen P, Pylkkänen L, Mecklin JP, Järvinen H, Powell SM, Jen J, Hamilton SR, Peterson GM, Kinzler KW, Vogelstein B, Chapelle A de la (1993) Clues of the pathogenesis of familial colorectal cancer. Science 260:812–816

    Google Scholar 

  2. Aaltonen LA, Peltomäki P, Mecklin JP, Järvinen H, Jass JR, Green JS, Lynch HT, Watson P, Tallqvist G, Juhola M, Sistonen P, Hamilton SR, Kinzler KW, Vogelstein B, Chapelle A de la (1994) Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 54:1645–1648

    Google Scholar 

  3. Bhattacharyya NP, Skandalis A, Ganesh A, Groden J, Meuth M (1994) Mutator phenotypes in human colorectal carcinoma cell lines. Proc Natl Acad Sci USA 91:6319–1623

    Google Scholar 

  4. Bodmer W, Bishop T, Karran P (1994) Genetic steps in colorectal cancer. Nature Genetics 6:217–219

    Google Scholar 

  5. Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A, Tannergard P, Bollag RJ, Godwin AR, Ward DC, Nordenskjold M, Fishel R, Kolodner 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

    Google Scholar 

  6. Burks RT, Kessis TD, Cho KR, Hedrick L (1994) Microsatellite instability in endometrial carcinoma. Oncogene 9:1163–1166

    Google Scholar 

  7. Charlesworth B, Sniegowski P, Stephan W (1994) The evoluationary dynamics of repetitive DNA in eukaryotes. Nature 371:215–220

    Google Scholar 

  8. Chong JM, 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

    Google Scholar 

  9. Cleaver JE (1994) It was a very good year for DNA repair. Cell 76:1–4

    Google Scholar 

  10. Correa P, Shiao Y (1994) Phenotypic and genotypic events in gastric carcinogenesis. Cancer Res [Suppl] 54:1941s-1943s

    Google Scholar 

  11. Fearon E, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767

    Google Scholar 

  12. Fishel R, Lescoe MK, Rao MRS, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R (1993) The human mutator gene homologue MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038

    Google Scholar 

  13. Friedl W (1994) Familiäre adenomatöse Polyposis. Dtsch Artzebl 91(C):92–94

    Google Scholar 

  14. Gonzalez-Zulueta M, Ruppert JM, Tokino K, Tsai YC, Spruck III CH, Miyao N, Nichols PW, Hermann GG, Horn T, Steven K, Summerhayes IC, Sidransky D, Jones PA (1993) Microsatellite instability in bladder cancer. Cancer Res 53:5620–5623

    Google Scholar 

  15. Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, Bernardi G, Lathrop M, Weissenbach J (1994) The 1993–94 Généthon human genetic linkage map. Nature Genetics 7:246–339

    Google Scholar 

  16. Han HJ, Yanagisawa A, Kato Y, Park JG, Nakamura Y (1993) Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res 53:5087–5089

    Google Scholar 

  17. Honchel R, Halling KC, Schaid DJ, Pittelkow M, Thibodeau SN (1994) Microsatellite instability in Muir-Torre syndrome. Cancer Res 54:1159–1163

    Google Scholar 

  18. Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561

    Google Scholar 

  19. Jiricny J (1994) Colon cancer and DNA repair: have mismatches met their match? Trends Genet 10:164–168

    Google Scholar 

  20. Kim H, Jen J, Vogelstein B, Hamilton SR (1994) Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 145:148–156

    Google Scholar 

  21. Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomäki P, Sistonen P, Aaltonen LA, Nyström-Lahti M, Guan XY, Zhang J, Meltzer PS, Yu JW, Kao FT, Chen DJ, Cerasoletti 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, Chapelle A de la, Kinzler KW, Vogelstein B (1993) Mutations of a MutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–25

    Google Scholar 

  22. Lindblom A, Tannergard P, Werelius B, Nordenskjold M (1993) Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nature Genet 5:279–282

    Google Scholar 

  23. Lips CJM, Landsvater RM, Höppener JWM, Geerdink RA, Blijham G, Jansen-Schillhorn van Veen JM, Gils APG van, Wit MJ de, Zewald RA, Berends MJH, Beemer FA, Brouwers-Smalbraak J, Jansen RPM, Ploos van Amstel HK, Vroonhoven TJMV van, Vroom TM (1994) Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 331:828–835

    Google Scholar 

  24. Liu B, Parsons RE, Hamilton SR, Petersen GM, Lynch HT, Watson P, Markowitz S, Willson JKV, Green J, Chapelle A de la, Kinzler KW, Vogelstein B (1994) hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res 54:4590–4594

    Google Scholar 

  25. Loeb LA (1994) Microsatellite instability: marker of amutator phenotype in cancer. Cancer Res 54:5059–5063

    Google Scholar 

  26. Lothe RA, Peltomaki P, Meling GI, Aaltonen LA, Nyström-Lahti M, Pylkkänen L, Heimdal K, Andersen TI, Moller P, Rognum TO, Fossa SD, Haldorsen T, Langmark F, Brogger A, Chapelle A de la, Borresen AL (1993) Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 53:5849–5852

    Google Scholar 

  27. Lynch HT, Watson P, Lanspa SJ, Marcus J, Smyrk T, Fitzgibbons RJ, Kriegler M, Lynch JF (1988) Natural history of colorectal carcinoma in hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). Dis Colon Rectum 31:439–444

    Google Scholar 

  28. 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

    Google Scholar 

  29. Mecklin JP, Jarvinen H (1993) Treatment and follow-up strategies in hereditary nonpolyposis colorectal carcinoma. Dis Colon Rectum 36:927–929

    Google Scholar 

  30. Merlo A, Mabry M, Gabrielson E, Vollmer R, Baylin SB, Sidransky D (1994) Frequent microsatellite instability in primary small cell lung cancer. Cancer Res 54:2098–2101

    Google Scholar 

  31. Mironov NM, Aguelon MA, Potapova GI, Omori Y, Gorbunov OV, Klimenkov AA, Yamasaki H (1994) Alterations of (CA)n DNA repeats and tumor suppressor genes in human gastric cancer. Cancer Res 54:41–44

    Google Scholar 

  32. Nicolaides 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, Peterson GM, Chapelle A de la, Vogelstein B, Kinzler KW (1994) Mutations of two PMS homologues in heredetary nonpolyposis colon cancer. Nature 371:75–80

    Google Scholar 

  33. Orlow I, Lianes P, Lacombe L, Dalbagni G, Reuter VE, Cordon-Cardo C (1994) Chromosome 9 allelic losses and microsatellite alterations in human bladder tumors. Cancer Res 54:2848–2851

    Google Scholar 

  34. Orr HT (1994) Unstable trinucleotide repeats and the diagnosis of neurodegenerative disease. Hum Pathol 25:598–601

    Google Scholar 

  35. Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Hamilton SR, Peterson GM, Watson P, Lynch HT, Peltomäki P, Mecklin JP, Chapelle A de la, Kinzler KW, Vogelstein B (1994) Mutation of a MutL homolog in hereditary colon cancer. Science 263:1625–1629

    Google Scholar 

  36. Parsons R, Li GM, Longley MJ, Fang W, Papadopoulos N, Jen J, Chapelle A de la, Kinzler KW, Vogelstein B, Modrich P (1993) Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75:1227–1236

    Google Scholar 

  37. Peinado MA, Malkhosyan S, Velazquez A, Perucho M (1992) Isolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction. Proc Natl Acad Sci USA 89:10065–10069

    Google Scholar 

  38. Peltomäki P, Sistonen P, Mecklin JP, Pylkkänen L, Aaltonen L, Nordling S, Kere J, Jarvinen H, Hamilton SR, Petersen G, Kinzler KW, Vogelstein B, Chapelle A de la (1992) Evidence that the MCC-APC gene region in 5q21 is not the site for susceptibility to hereditary nonpolyposis colorectal carcinoma. Cancer Res 52:4530–4533

    Google Scholar 

  39. Peltomäki P, Aaltonen LA, Sistonen P, Pylkkänen L, Mecklin JP, Järvinen H, Green JS, Jass JR, Weber JL, Leach FS, Petersen GM, Hamilton SR, Chapelle A de la, Vogelstein B (1993) Genetic mapping of a locus predisposing to human colorectal cancer. Science 260:810–812

    Google Scholar 

  40. Ponz de Leon M, Sassatelli R, Benatti P, Roncucci L (1993) Identification of hereditary nonpolyposis colorectal cancer in the general population. The 6-year experience of a population-based registry. Cancer 71:3493–3501

    Google Scholar 

  41. Richards RJ, Sutherland GR (1994) Simple repeat DNA is not repeated simply. Nature Genetics 6:114–116

    Google Scholar 

  42. Risinger JI, Berchuck A, Kohler MF, Watson P, Lynch HT, Boyd J (1993) Genetic instability of microsatellites in endometrial carcinoma. Cancer Res 53:5100–5103

    Google Scholar 

  43. Rüschoff J, Bocker T, Vogel P, Schlegel J (in press) Prognostic significance of molecular biological and immunohistological parameters in gastrointestinal carcinomas. Rec Results Cancer Res

  44. Schlegel J, Bocker T, Zirngibl H, Hofstädter F, Rüschoff J (1995) Detection of microsatellite instability in human colorectal carcinomas using a non-radioactive PCR-based screening method. Virchows Arch 426:223–227

    Google Scholar 

  45. Scott RJ, Müller HJ (1993) Familial and genetic aspects of colorectal carcinogenesis. Eur J Cancer 29A:2163–2167

    Google Scholar 

  46. Shibata D, Peinado MA, Ionov Y, Malkhosyan S, Perucho M (1994) Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation. Nature Genetics 6:273–281

    Google Scholar 

  47. Shridhar V, Siegfried J, Hunt J, Alonso M, Smith DI (1994) Genetic instability of microsatellite sequences in many non-small cell lung carcinomas. Cancer Res 54:2084–2087

    Google Scholar 

  48. Simon B, Weinel R, Höhne M, Watz J, Schmidt J, Körtner G, Arnold R (1994) Frequent alterations of the tumor suppressor genes p53 and DCC in human pancreatic carcinoma. Gastroenterology 106:1645–1651

    Google Scholar 

  49. Smith SA, Ponder BA (1993) Predisposing genes in breast and ovarian cancer: an overview. Tumori 79:291–296

    Google Scholar 

  50. Smyrk TC (1994) Colon cancer connections — cancer syndrome meets molecular biology meets histopathology. Am J Pathol 145:1–6

    Google Scholar 

  51. Strand M, Prolla TA, Liskay RM, Petes TD (1993) Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 365:274–276

    Google Scholar 

  52. Strickler JG, Zheng J, Shu Q, Burgart LJ, Alberts SR, Shibata D (1994) p53 mutations and microsatellite instability in sporadic gastric cancer: when guardians fail. Cancer Res 54:4750–4755

    Google Scholar 

  53. Suzuki H, Harpaz N, Tarmin L, Yin J, Jiang HY, Bell JD, Hontanosas M, Groisman GM, Abraham JM, Meltzer ST (1994) Microsatellite instability in ulcerative colitis-associated colorectal dysplasias and cancers. Cancer Res 54:4841–4844

    Google Scholar 

  54. Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819

    Google Scholar 

  55. Uchida T, Wada C, Wang C, Egawa S, Ohtani H, Koshiba K (1994) Genomic instability of microsatellite repeats and mutations of h-, k-, and n-ras, and p53 genes in renal cell carcinoma. Cancer Res 54:3682–3685

    Google Scholar 

  56. Vasen HF (1994) Periodic examination of families with hereditary nonpolyposis colonic carcinoma in the Netherlands: a study of 41 families. Ned Tijdschr Geneeskd 138:77–81

    Google Scholar 

  57. Vasen HFA, Mecklin JP, Meera Khan P, Lynch HT (1991) Hereditary non-polyposis colorectal cancer. Lancet 338:877

    Google Scholar 

  58. Vasen HF, Mecklin JP, Watson P, Utsunomiya J, Bertario L, Lynch P, Svendsen LB, Cristofaro G, Müller -H, Khan PM, Lynch HT, the International Collaborative Group on HNPCC (1993) Surveillance in hereditary nonpolyposis colorectal cancer: an international cooperative study of 165 families. Dis Colon Rectum 36:1–4

    Google Scholar 

  59. Warthin AS (1913) Heredity with reference to carcinoma: as shown by a study of the cases examined in the pathological laboratory of the University of Michigan, 1895–1913. Arch Intern Med 12:546–555

    Google Scholar 

  60. Watson P, Vasen HF, Mecklin JP, Jarvinen H, Lynch HT (1994) The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 96:516–20

    Google Scholar 

  61. Wooster R, Cleton-Jansen AM, Collins N, Mangion J, Cornelis RS, Cooper CS, Gusterson BA, Ponder BA, Deimling A von, Wiestler OD, Cornelisse CJ, Devilee P, Stratton MR (1994) Instability of short tandem repeats (microsatellites) in human cancers. Nature Genetics 6:152–156

    Google Scholar 

  62. Wu C, Akiyama Y, Imai K, Miyake S, Nagasaki H, Oto M, Okabe S, Iwama T, Mitamura K, Masumitsu H, et al (1994) DNA alterations in cells from hereditary non-polyposis colorectal cancer patients. Oncogene 9:991–994

    Google Scholar 

  63. Yee JC, Roodi N, Verrier C, Parl FF (1994) Microsatellite instability and loss of heterozygozyity in breast cancer. Cancer Res 54:1641–1644

    Google Scholar 

  64. Young J, Leggett B, Gustafson C, Ward M, Searle J, Thomas L, Buttenshaw R, Chenevix-Trench G (1993) Genomic instability occurs in colorectal carcinomas but not in adenomas. Hum Mutat 2:351–354

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042, Regensburg, Germany

    J. Rüschoff, T. Bocker, J. Schlegel, G. Stumm & F. Hofstaedter

Authors
  1. J. Rüschoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Bocker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Schlegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Stumm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Hofstaedter
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rüschoff, J., Bocker, T., Schlegel, J. et al. Microsatellite instability: new aspects in the carcinogenesis of colorectal carcinoma. Vichows Archiv A Pathol Anat 426, 215–222 (1995). https://doi.org/10.1007/BF00191357

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00191357

Key words

Search

Navigation