Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1994 Jul;145(1):148–156.

Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences.

H Kim 1, J Jen 1, B Vogelstein 1, S R Hamilton 1
PMCID: PMC1887287  PMID: 8030745

Abstract

DNA replication errors (RERs) in repeated nucleotide sequences due to defective mismatch repair genes have been reported in a subset of sporadic colorectal carcinomas and in the majority of tumors from patients with hereditary nonpolyposis colorectal cancer syndrome (HNPCC). We detected RER in 18 cases (13%) in a prospective series of 137 sporadic stage II and III (Dukes' B and C) colorectal carcinomas. The clinical and pathological features of the RER-positive cases differed from those without RER. The patients with RER-positive cancers tended to be somewhat younger (60 +/- 5 years, range 22-83, versus 66 +/- 1, range 27-90, P = 0.2 with unequal variances) and had a marked preponderance of tumors proximal to the splenic flexure (17/18, 94%, versus 41/119, 34%, P < 0.0001). Only two RER-positive patients (11%) had a family history of colorectal cancer. In comparison to the 41 RER-negative proximal colonic cancers, RER-positive cancers had more frequent exophytic growth (P = 0.04), large size (P = 0.03), poor differentiation (P = 0.0004), extracellular mucin production (P = 0.003) and Crohn's-like lymphoid reaction (P = 0.003), and a trend toward less frequent p53 gene product overexpression by immunohistochemistry (3/17, 18%, versus 18/41, 44%, P = 0.06). We conclude that a subset of sporadic colorectal carcinomas has unique biological features that may indicate inherited germline mutation, de novo germline mutation, or somatic mutations of the mismatch repair genes involved in HNPCC.

Full text

PDF
153

Images in this article

150Figure 1
on p.150
152Figure 2
on p.152
153Figure 3
on p.153

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., Leach F. S., Sistonen P., Pylkkänen L., Mecklin J. P., Järvinen H., Powell S. M., Jen J., Hamilton S. R. Clues to the pathogenesis of familial colorectal cancer. Science. 1993 May 7;260(5109):812–816. doi: 10.1126/science.8484121. [DOI] [PubMed] [Google Scholar]
  2. Alexander R. J., Buxbaum J. N., Raicht R. F. Oncogene alterations in primary human colon tumors. Gastroenterology. 1986 Dec;91(6):1503–1510. doi: 10.1016/0016-5085(86)90208-8. [DOI] [PubMed] [Google Scholar]
  3. Baas I. O., Mulder J. W., Offerhaus G. J., Vogelstein B., Hamilton S. R. An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms. J Pathol. 1994 Jan;172(1):5–12. doi: 10.1002/path.1711720104. [DOI] [PubMed] [Google Scholar]
  4. Baker S. J., Fearon E. R., Nigro J. M., Hamilton S. R., Preisinger A. C., Jessup J. M., vanTuinen P., Ledbetter D. H., Barker D. F., Nakamura Y. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. doi: 10.1126/science.2649981. [DOI] [PubMed] [Google Scholar]
  5. Bos J. L., Fearon E. R., Hamilton S. R., Verlaan-de Vries M., van Boom J. H., van der Eb A. J., Vogelstein B. Prevalence of ras gene mutations in human colorectal cancers. 1987 May 28-Jun 3Nature. 327(6120):293–297. doi: 10.1038/327293a0. [DOI] [PubMed] [Google Scholar]
  6. Bufill J. A. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med. 1990 Nov 15;113(10):779–788. doi: 10.7326/0003-4819-113-10-779. [DOI] [PubMed] [Google Scholar]
  7. Cartwright C. A., Kamps M. P., Meisler A. I., Pipas J. M., Eckhart W. pp60c-src activation in human colon carcinoma. J Clin Invest. 1989 Jun;83(6):2025–2033. doi: 10.1172/JCI114113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fearon E. R., Cho K. R., Nigro J. M., Kern S. E., Simons J. W., Ruppert J. M., Hamilton S. R., Preisinger A. C., Thomas G., Kinzler K. W. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. doi: 10.1126/science.2294591. [DOI] [PubMed] [Google Scholar]
  9. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  10. Finlay C. A., Hinds P. W., Tan T. H., Eliyahu D., Oren M., Levine A. J. Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life. Mol Cell Biol. 1988 Feb;8(2):531–539. doi: 10.1128/mcb.8.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Graham D. M., Appelman H. D. Crohn's-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Mod Pathol. 1990 May;3(3):332–335. [PubMed] [Google Scholar]
  13. Ionov Y., Peinado M. A., Malkhosyan S., Shibata D., Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993 Jun 10;363(6429):558–561. doi: 10.1038/363558a0. [DOI] [PubMed] [Google Scholar]
  14. Jass J. R., Love S. B., Northover J. M. A new prognostic classification of rectal cancer. Lancet. 1987 Jun 6;1(8545):1303–1306. doi: 10.1016/s0140-6736(87)90552-6. [DOI] [PubMed] [Google Scholar]
  15. Kinzler K. W., Nilbert M. C., Vogelstein B., Bryan T. M., Levy D. B., Smith K. J., Preisinger A. C., Hamilton S. R., Hedge P., Markham A. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science. 1991 Mar 15;251(4999):1366–1370. doi: 10.1126/science.1848370. [DOI] [PubMed] [Google Scholar]
  16. Kunkel T. A. Nucleotide repeats. Slippery DNA and diseases. Nature. 1993 Sep 16;365(6443):207–208. doi: 10.1038/365207a0. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Levine A. J. The p53 tumor-suppressor gene. N Engl J Med. 1992 May 14;326(20):1350–1352. doi: 10.1056/NEJM199205143262008. [DOI] [PubMed] [Google Scholar]
  19. Lindblom A., Tannergård P., Werelius B., Nordenskjöld M. Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nat Genet. 1993 Nov;5(3):279–282. doi: 10.1038/ng1193-279. [DOI] [PubMed] [Google Scholar]
  20. Lothe R. A., Peltomäki P., Meling G. I., Aaltonen L. A., Nyström-Lahti M., Pylkkänen L., Heimdal K., Andersen T. I., Møller P., Rognum T. O. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res. 1993 Dec 15;53(24):5849–5852. [PubMed] [Google Scholar]
  21. Lynch H. T., Smyrk T. C., Watson P., Lanspa S. J., Lynch J. F., Lynch P. M., Cavalieri R. J., Boland C. R. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology. 1993 May;104(5):1535–1549. doi: 10.1016/0016-5085(93)90368-m. [DOI] [PubMed] [Google Scholar]
  22. Mecklin J. P., Sipponen P., Järvinen H. J. Histopathology of colorectal carcinomas and adenomas in cancer family syndrome. Dis Colon Rectum. 1986 Dec;29(12):849–853. doi: 10.1007/BF02555362. [DOI] [PubMed] [Google Scholar]
  23. Meltzer S. J., Ahnen D. J., Battifora H., Yokota J., Cline M. J. Protooncogene abnormalities in colon cancers and adenomatous polyps. Gastroenterology. 1987 May;92(5 Pt 1):1174–1180. doi: 10.1016/s0016-5085(87)91074-2. [DOI] [PubMed] [Google Scholar]
  24. Oren M. p53: the ultimate tumor suppressor gene? FASEB J. 1992 Oct;6(13):3169–3176. doi: 10.1096/fasebj.6.13.1397838. [DOI] [PubMed] [Google Scholar]
  25. Parsons R., Li G. M., Longley M. J., Fang W. H., Papadopoulos N., Jen J., de la Chapelle A., Kinzler K. W., Vogelstein B., Modrich P. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell. 1993 Dec 17;75(6):1227–1236. doi: 10.1016/0092-8674(93)90331-j. [DOI] [PubMed] [Google Scholar]
  26. Peinado M. A., Malkhosyan S., Velazquez A., Perucho M. Isolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10065–10069. doi: 10.1073/pnas.89.21.10065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Peltomäki P., Aaltonen L. A., Sistonen P., Pylkkänen L., Mecklin J. P., Järvinen H., Green J. S., Jass J. R., Weber J. L., Leach F. S. Genetic mapping of a locus predisposing to human colorectal cancer. Science. 1993 May 7;260(5109):810–812. doi: 10.1126/science.8484120. [DOI] [PubMed] [Google Scholar]
  28. Powell S. M., Zilz N., Beazer-Barclay Y., Bryan T. M., Hamilton S. R., Thibodeau S. N., Vogelstein B., Kinzler K. W. APC mutations occur early during colorectal tumorigenesis. Nature. 1992 Sep 17;359(6392):235–237. doi: 10.1038/359235a0. [DOI] [PubMed] [Google Scholar]
  29. Rodrigues N. R., Rowan A., Smith M. E., Kerr I. B., Bodmer W. F., Gannon J. V., Lane D. P. p53 mutations in colorectal cancer. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7555–7559. doi: 10.1073/pnas.87.19.7555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Strand M., Prolla T. A., Liskay R. M., Petes T. D. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature. 1993 Sep 16;365(6443):274–276. doi: 10.1038/365274a0. [DOI] [PubMed] [Google Scholar]
  31. Thibodeau S. N., Bren G., Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993 May 7;260(5109):816–819. doi: 10.1126/science.8484122. [DOI] [PubMed] [Google Scholar]
  32. Vogelstein B., Kinzler K. W. p53 function and dysfunction. Cell. 1992 Aug 21;70(4):523–526. doi: 10.1016/0092-8674(92)90421-8. [DOI] [PubMed] [Google Scholar]
  33. Wiggers T., Arends J. W., Schutte B., Volovics L., Bosman F. T. A multivariate analysis of pathologic prognostic indicators in large bowel cancer. Cancer. 1988 Jan 15;61(2):386–395. doi: 10.1002/1097-0142(19880115)61:2<386::aid-cncr2820610231>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  34. van den Berg F. M., Baas I. O., Polak M. M., Offerhaus G. J. Detection of p53 overexpression in routinely paraffin-embedded tissue of human carcinomas using a novel target unmasking fluid. Am J Pathol. 1993 Feb;142(2):381–385. [PMC free article] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES