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. 2001 Jan;84(2):232–236. doi: 10.1054/bjoc.2000.1554

Microsatellite-stable diploid carcinoma: a biologically distinct and aggressive subset of sporadic colorectal cancer

N J Hawkins 1, I Tomlinson 2, A Meagher 3, R L Ward 4,5
PMCID: PMC2363701  PMID: 11161382

Abstract

Chromosomal instability and microsatellite instability represent the major pathways for colorectal cancer (CRC) progression. However, a significant percentage of CRC shows neither pattern of instability, and thus represents a potentially distinctive form of the disease. Flow cytometry was used to determine the degree of DNA aneuploidy in 46 consecutive sporadic colorectal cancers. Microsatellite status was determined by PCR amplification using standard markers, while immunostaining was used to examine the expression of p53. K- ras status was determined by restriction-mediated PCR assay. Twenty-five (54%) tumours were aneuploid, 14 (30%) were diploid and microsatellite-stable and seven (15%) were diploid and microsatellite-unstable. Tumours with microsatellite instability were more likely to be right sided, to occur in women and to be associated with an improved survival. Aneuploid tumours were significantly more common in men and were likely to be left sided. The diploid microsatellite-stable (MSS) tumours did not show a sex or site predilection, but were strongly associated with the presence of metastatic disease at the time of diagnosis. Our data suggests that diploid, MSS tumours represent a biologically and phenotypically distinct subset of colorectal carcinoma, and one that is associated with the early development of metastases. We suggest that the genetic stability that characterizes these tumours may favour the maintenance of an invasive phenotype, and thus facilitate disease progression. These findings may have important implications for treatment options in this disease subset. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: colorectal carcinoma, ploidy, survival, microsatellite instability

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Selected References

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  1. Bauer K. D., Bagwell C. B., Giaretti W., Melamed M., Zarbo R. J., Witzig T. E., Rabinovitch P. S. Consensus review of the clinical utility of DNA flow cytometry in colorectal cancer. Cytometry. 1993;14(5):486–491. doi: 10.1002/cyto.990140506. [DOI] [PubMed] [Google Scholar]
  2. Boland C. R., Thibodeau S. N., Hamilton S. R., Sidransky D., Eshleman J. R., Burt R. W., Meltzer S. J., Rodriguez-Bigas M. A., Fodde R., Ranzani G. N. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998 Nov 15;58(22):5248–5257. [PubMed] [Google Scholar]
  3. Cianchi F., Balzi M., Becciolini A., Giachè V., Messerini L., Palomba A., Tisti E., Faraoni P., Chellini F., Pucciani F. Correlation between DNA content and p53 deletion in colorectal cancer. Eur J Surg. 1999 Apr;165(4):363–368. doi: 10.1080/110241599750006910. [DOI] [PubMed] [Google Scholar]
  4. Cohn K. H., Ornstein D. L., Wang F., LaPaix F. D., Phipps K., Edelsberg C., Zuna R., Mott L. A., Dunn J. L. The significance of allelic deletions and aneuploidy in colorectal carcinoma. Results of a 5-year follow-up study. Cancer. 1997 Jan 15;79(2):233–244. [PubMed] [Google Scholar]
  5. Elsaleh H., Joseph D., Grieu F., Zeps N., Spry N., Iacopetta B. Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet. 2000 May 20;355(9217):1745–1750. doi: 10.1016/S0140-6736(00)02261-3. [DOI] [PubMed] [Google Scholar]
  6. Eshleman J. R., Casey G., Kochera M. E., Sedwick W. D., Swinler S. E., Veigl M. L., Willson J. K., Schwartz S., Markowitz S. D. Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53. Oncogene. 1998 Aug 13;17(6):719–725. doi: 10.1038/sj.onc.1201986. [DOI] [PubMed] [Google Scholar]
  7. Flyger H. L., Larsen J. K., Nielsen H. J., Christensen I. J. DNA ploidy in colorectal cancer, heterogeneity within and between tumors and relation to survival. Cytometry. 1999 Dec 15;38(6):293–300. doi: 10.1002/(sici)1097-0320(19991215)38:6<293::aid-cyto6>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  8. Forster S., Sattler H. P., Hack M., Romanakis K., Rohde V., Seitz G., Wullich B. Microsatellite instability in sporadic carcinomas of the proximal colon: association with diploid DNA content, negative protein expression of p53, and distinct histomorphologic features. Surgery. 1998 Jan;123(1):13–18. [PubMed] [Google Scholar]
  9. Fujiwara T., Stolker J. M., Watanabe T., Rashid A., Longo P., Eshleman J. R., Booker S., Lynch H. T., Jass J. R., Green J. S. Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences. Am J Pathol. 1998 Oct;153(4):1063–1078. doi: 10.1016/S0002-9440(10)65651-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Georgiades I. B., Curtis L. J., Morris R. M., Bird C. C., Wyllie A. H. Heterogeneity studies identify a subset of sporadic colorectal cancers without evidence for chromosomal or microsatellite instability. Oncogene. 1999 Dec 23;18(56):7933–7940. doi: 10.1038/sj.onc.1203368. [DOI] [PubMed] [Google Scholar]
  11. Halling K. C., French A. J., McDonnell S. K., Burgart L. J., Schaid D. J., Peterson B. J., Moon-Tasson L., Mahoney M. R., Sargent D. J., O'Connell M. J. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst. 1999 Aug 4;91(15):1295–1303. doi: 10.1093/jnci/91.15.1295. [DOI] [PubMed] [Google Scholar]
  12. Herman J. G., Umar A., Polyak K., Graff J. R., Ahuja N., Issa J. P., Markowitz S., Willson J. K., Hamilton S. R., Kinzler K. W. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6870–6875. doi: 10.1073/pnas.95.12.6870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hiddemann W., Schumann J., Andreef M., Barlogie B., Herman C. J., Leif R. C., Mayall B. H., Murphy R. F., Sandberg A. A. Convention on nomenclature for DNA cytometry. Committee on Nomenclature, Society for Analytical Cytology. Cancer Genet Cytogenet. 1984 Oct;13(2):181–183. doi: 10.1016/0165-4608(84)90059-1. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Jass J. R., Ajioka Y., Allen J. P., Chan Y. F., Cohen R. J., Nixon J. M., Radojkovic M., Restall A. P., Stables S. R., Zwi L. J. Assessment of invasive growth pattern and lymphocytic infiltration in colorectal cancer. Histopathology. 1996 Jun;28(6):543–548. doi: 10.1046/j.1365-2559.1996.d01-467.x. [DOI] [PubMed] [Google Scholar]
  16. Jass J. R., Do K. A., Simms L. A., Iino H., Wynter C., Pillay S. P., Searle J., Radford-Smith G., Young J., Leggett B. Morphology of sporadic colorectal cancer with DNA replication errors. Gut. 1998 May;42(5):673–679. doi: 10.1136/gut.42.5.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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. 1994 Jul;145(1):148–156. [PMC free article] [PubMed] [Google Scholar]
  18. Lanza G., Gafà R., Matteuzzi M., Santini A. Medullary-type poorly differentiated adenocarcinoma of the large bowel: a distinct clinicopathologic entity characterized by microsatellite instability and improved survival. J Clin Oncol. 1999 Aug;17(8):2429–2438. doi: 10.1200/JCO.1999.17.8.2429. [DOI] [PubMed] [Google Scholar]
  19. Lanza G., Gafà R., Santini A., Maestri I., Dubini A., Gilli G., Cavazzini L. Prognostic significance of DNA ploidy in patients with stage II and stage III colon carcinoma: a prospective flow cytometric study. Cancer. 1998 Jan 1;82(1):49–59. doi: 10.1002/(sici)1097-0142(19980101)82:1<49::aid-cncr6>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  20. Martin L., Assem M., Piard F. Are there several types of colorectal carcinomas? Correlations with genetic data. Eur J Cancer Prev. 1999 Dec;8 (Suppl 1):S13–S20. [PubMed] [Google Scholar]
  21. 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]
  22. Pietra N., Sarli L., Thenasseril B. J., Costi R., Sansebastiano G., Peracchia A. Risk factors of local recurrence of colorectal cancer: a multivariate study. Hepatogastroenterology. 1998 Sep-Oct;45(23):1573–1578. [PubMed] [Google Scholar]
  23. Rüschoff J., Dietmaier W., Lüttges J., Seitz G., Bocker T., Zirngibl H., Schlegel J., Schackert H. K., Jauch K. W., Hofstaedter F. Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics. Am J Pathol. 1997 May;150(5):1815–1825. [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Thibodeau S. N., French A. J., Cunningham J. M., Tester D., Burgart L. J., Roche P. C., McDonnell S. K., Schaid D. J., Vockley C. W., Michels V. V. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998 Apr 15;58(8):1713–1718. [PubMed] [Google Scholar]
  26. Tonouchi H., Matsumoto K., Kinoshita T., Itoh H., Suzuki H. Prognostic value of DNA ploidy patterns of colorectal adenocarcinoma: univariate and multivariate analysis. Dig Surg. 1998;15(6):687–692. doi: 10.1159/000018679. [DOI] [PubMed] [Google Scholar]
  27. Tsuchiya A., Ando Y., Ishii Y., Yoshida T., Abe R. Flow cytometric DNA analysis in Japanese colorectal cancer. A multivariate analysis. Eur J Surg Oncol. 1992 Dec;18(6):585–590. [PubMed] [Google Scholar]
  28. Veigl M. L., Kasturi L., Olechnowicz J., Ma A. H., Lutterbaugh J. D., Periyasamy S., Li G. M., Drummond J., Modrich P. L., Sedwick W. D. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8698–8702. doi: 10.1073/pnas.95.15.8698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Visscher D. W., Zarbo R. J., Ma C. K., Sakr W. A., Crissman J. D. Flow cytometric DNA and clinicopathologic analysis of Dukes' A&B colonic adenocarcinomas: a retrospective study. Mod Pathol. 1990 Nov;3(6):709–712. [PubMed] [Google Scholar]
  30. Ward R. L., Todd A. V., Santiago F., O'Connor T., Hawkins N. J. Activation of the K-ras oncogene in colorectal neoplasms is associated with decreased apoptosis. Cancer. 1997 Mar 15;79(6):1106–1113. [PubMed] [Google Scholar]
  31. Ward R., Hawkins N., O'Grady R., Sheehan C., O'Connor T., Impey H., Roberts N., Fuery C., Todd A. Restriction endonuclease-mediated selective polymerase chain reaction: a novel assay for the detection of K-ras mutations in clinical samples. Am J Pathol. 1998 Aug;153(2):373–379. doi: 10.1016/S0002-9440(10)65581-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Witzig T. E., Loprinzi C. L., Gonchoroff N. J., Reiman H. M., Cha S. S., Wieand H. S., Katzmann J. A., Paulsen J. K., Moertel C. G. DNA ploidy and cell kinetic measurements as predictors of recurrence and survival in stages B2 and C colorectal adenocarcinoma. Cancer. 1991 Aug 15;68(4):879–888. doi: 10.1002/1097-0142(19910815)68:4<879::aid-cncr2820680434>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]

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