Article | Published:

Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability


Microsatellite instability has been observed in both sporadic and hereditary forms of colorectal cancer. In the hereditary form, this instability is generally due to germline mutations in mismatch repair (MMR) genes. However, only one in ten patients with sporadic tumours exhibiting microsatellite instability had a detectable germline mutation. Moreover, only three of seven sporadic tumour cell lines with microsatellite instability had mutations in a MMR gene, and these mutations could occur somatically. These results demonstrate that tumours can acquire somatic mutations that presumably do not directly affect cell growth but result only in genetic instability. They also suggest that many sporadic tumours with microsatellite instability have alterations in genes other than the four now known to participate in MMR.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

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

  2. 2

    Thibodeau, S.N., Bren, G. & Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260, 816–819 (1993).

  3. 3

    Aaltonen, L.A. et al. Clues to the pathogenesis of familial colorectal cancer. Science 260, 812–816 (1993).

  4. 4

    Han, H.-J., Yanagisawa, A., Kato, Y., Park, J.-G. & Nakamura, Y. Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res. 53, 5087–5089 (1993).

  5. 5

    Peltomaki, P. et al. Microsatellite instability is associated with tumours that characterize the hereditary non-polyposis colorectal carcinoma. Cancer Res. 53, 5853–5855 (1993).

  6. 6

    Risinger, I. et al. Genetic instability of microsatellites in endometrial carcinoma. Cancer Res. 53, 5100–5103 (1993).

  7. 7

    Burks, R.T., Kessis, T.D., Cho, K.R. & Hedrick, L. Microsatellite instability in endometrlal carcinoma. Oncogene 9, 1163–1166 (1994).

  8. 8

    Wooster, R. et al. Instability of short tandem repeats (microsatellites) in human cancers. Nature Genet. 6, 152–156 (1994).

  9. 9

    Merlo, A. et al. Frequent microsatellite instability in primary small cell lung cancer. Cancer Res. 54, 2098–2101 (1994).

  10. 10

    Orth, K. et al. Genetic instability In human ovarian cancer cell lines. Prac. natn. Acad. Sci. U.S.A. 91, 9495–9499 (1994).

  11. 11

    Glebov, O.K., McKenzie, K.E., White, C.A. & Sukumar, S. Frequent p53 gene mutations and novel alleles in familial breast cancer. Cancer Res. 54, 3703–3709 (1994).

  12. 12

    Parsons, R. et al. Hypermutability and mismatch repair deficiency in RER+ tumour cells. Cell 75, 1227–1236 (1993).

  13. 13

    Shibata, D., Peinado, M.A., lonov, Y., Malkhosyan, S. & Perucho, M. Genomic instability in repeated sequences is an early somatic event In colorectal tumourigenesis that persists after transformation. Nature Genet. 6, 273–281 (1994).

  14. 14

    Umar, A. et al. Defective mismatch repair In extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J. biol. Chem. 269, 14367–14370 (1994).

  15. 15

    Modrich, P. Mechanisms and biological effects of mismatch repair. A. Rev. Genet. 25, 229–253 (1991).

  16. 16

    Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposls colon cancer. Cell 75, 1027–1038 (1993).

  17. 17

    Leach, F.S. et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993).

  18. 18

    Bronner, C.E. et al. Mutation in the DNA mismatch repair gene homologue hMLHl is associated with hereditary non-polyposis colon cancer. Nature 368, 258–261 (1994).

  19. 19

    Papadopoulos, N. et al. Mutation of a mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).

  20. 20

    Nicolaides, N.C. et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371, 75–80 (1994).

  21. 21

    Palombo, F., Hughes, M., Jlricny, J., Truong, O. & Hsuan, J. Mismatch repair and cancer. Nature 367, 417–418 (1994).

  22. 22

    Lothe, R.A. et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res. 53, 5849–5852 (1993).

  23. 23

    Kim, H., Jen, J., Vogelstein, B. & Hamilton, S.R. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am. J. Pathol. 145, 1–8 (1994).

  24. 24

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

  25. 25

    Aaltonen, L.A. et al. Replication errors in benign and malignant tumours from hereditary nonpolyposis colorectal cancer patients Cancer Res. 54, 1645–1648 (1994).

  26. 26

    Lynch, H.T. et al. Genetics, natural history, tumour spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gasfroenferotogy 104, 1535–1549 (1993).

  27. 27

    Vasen, H.F., Mecklin, J.P., Meera Khan, P. & Lynch, H.T. The international collaborative group on hereditary nonpolyposis colorectal cancer (ICG-HNPCC). Dis. Colon. Rectum. 34, 424–425 (1991).

  28. 28

    Liu, B. et al. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 54, 4590–4594 (1994).

  29. 29

    Powell, S.M. et al. Molecular diagnosis of familial adenomatous polyposis. New Engl. J. Med. 329, 1982–1987 (1993).

  30. 30

    Van der Luijit, R. et al. Rapid detection of translation-terminating mutations at the adenomatous polyposis coli (APC) gene by direct protein truncation test. Genomics 20, 1–4 (1994).

  31. 31

    Tuddenham, E.G.D. et al. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. Nucl. Acids Res. 22, 3511–3533 (1994).

  32. 32

    Giannelli, F. et al. Haemophilia B: data of point mutations and short additions and deletions. 5th edn Nucl. Acids Res. 22, 3534–3546 (1994).

  33. 33

    Knudson, A.G. Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 46, 1437–1443 (1985).

  34. 34

    Hemminki, A. et al. Loss of the wild type hMLH1 gene is a feature of hereditary non-polyposis colorectal cancer. Nature Genet. 8, 405–410 (1994).

  35. 35

    Willson, J. et al. Cell culture of human colon adenomas and carcinomas. Cancer Res. 47, 2704–2713 (1987).

  36. 36

    Jen, J. et al. Alleic loss of chromosome 18q and prognosis in colorectal cancer. New Engl. J. Med. 331, 213–221 (1994).

  37. 37

    Sidransky, D. et al. Identification of p53 gene mutations In bladder cancers and urine samples. Science 252, 706–709 (1991).

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Further reading