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J Clin Pathol. 1999 Jun; 52(6): 455–460.
PMCID: PMC501434

Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways.


BACKGROUND: 10% of sporadic colorectal cancers are characterised by a low level of microsatellite instability (MSI-L). These are not thought to differ substantially from microsatelite-stable (MSS) cancers, but MSI-L and MSS cancers are distinguished clinicopathologically and in their spectrum of genetic alterations from cancers showing high level microsatellite instability (MSI-H). AIMS: To study the distribution of molecular alterations in a series of colorectal cancers stratified by DNA microsatellite instability. METHODS: A subset of an unselected series of colorectal cancers was grouped by the finding of DNA MSI at 0 loci (MSS) (n = 51), 1-2 loci (MSI-L) (n = 38) and 3-6 loci (MSI-H) (n = 25). The frequency of K-ras mutation, loss of heterozygosity (LOH) at 5q, 17p and 18q, and patterns of p53 and beta catenin immunohistochemistry was determined in the three groups. RESULTS: MSI-H cancers had a low frequency of K-ras mutation (7%), LOH on chromosomes 5q (0%), 17p (0%) and 18q (12.5%), and a normal pattern of immunostaining for p53 and beta catenin. MSI-L cancers differed from MSS cancers in terms of a higher frequency of K-ras mutation (54% v 27%) (p = 0.01) and lower frequency of 5q LOH (23% v 48%) (p = 0.047). Whereas aberrant beta catenin expression and 5q LOH were concordant (both present or both absent) in 57% of MSS cancers, concordance was observed in only 20% of MSI-L cancers (p = 0.01). CONCLUSIONS: MSI-L colorectal cancers are distinct from both MSI-H and MSS cancers. This subset combines features of the suppressor and mutator pathways, may be more dependent on K-ras than on the APC gene in the early stages of neoplastic evolution, and a proportion may be related histogenetically to the serrated (hyperplastic) polyp.

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  • Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996 Oct 18;87(2):159–170. [PubMed]
  • Nowell PC. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. [PubMed]
  • Hartwell L. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell. 1992 Nov 13;71(4):543–546. [PubMed]
  • Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B. Mutations of mitotic checkpoint genes in human cancers. Nature. 1998 Mar 19;392(6673):300–303. [PubMed]
  • Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993 May 7;260(5109):816–819. [PubMed]
  • Ionov Y, Peinado MA, 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. [PubMed]
  • Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan RS, Zborowska E, Kinzler KW, Vogelstein B, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995 Jun 2;268(5215):1336–1338. [PubMed]
  • Souza RF, Appel R, Yin J, Wang S, Smolinski KN, Abraham JM, Zou TT, Shi YQ, Lei J, Cottrell J, et al. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Nat Genet. 1996 Nov;14(3):255–257. [PubMed]
  • Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, Perucho M. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997 Feb 14;275(5302):967–969. [PubMed]
  • Simms LA, Radford-Smith G, Biden KG, Buttenshaw R, Cummings M, Jass JR, Young J, Meltzer SJ, Leggett BA. Reciprocal relationship between the tumor suppressors p53 and BAX in primary colorectal cancers. Oncogene. 1998 Oct 15;17(15):2003–2008. [PubMed]
  • Wicking C, Simms LA, Evans T, Walsh M, Chawengsaksophak K, Beck F, Chenevix-Trench G, Young J, Jass J, Leggett B, et al. CDX2, a human homologue of Drosophila caudal, is mutated in both alleles in a replication error positive colorectal cancer. Oncogene. 1998 Aug 6;17(5):657–659. [PubMed]
  • Perucho M. Cancer of the microsatellite mutator phenotype. Biol Chem. 1996 Nov;377(11):675–684. [PubMed]
  • Lothe RA, Peltomäki P, Meling GI, Aaltonen LA, Nyström-Lahti M, Pylkkänen L, Heimdal K, Andersen TI, Møller P, Rognum TO, et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res. 1993 Dec 15;53(24):5849–5852. [PubMed]
  • Horii A, Han HJ, Shimada M, Yanagisawa A, Kato Y, Ohta H, Yasui W, Tahara E, Nakamura Y. Frequent replication errors at microsatellite loci in tumors of patients with multiple primary cancers. Cancer Res. 1994 Jul 1;54(13):3373–3375. [PubMed]
  • Carethers JM, Hawn MT, Chauhan DP, Luce MC, Marra G, Koi M, Boland CR. Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine. J Clin Invest. 1996 Jul 1;98(1):199–206. [PMC free article] [PubMed]
  • Ishimaru G, Adachi J, Shiseki M, Yamaguchi N, Muto T, Yokota J. Microsatellite instability in primary and metastatic colorectal cancers. Int J Cancer. 1995 Jun 22;64(3):153–157. [PubMed]
  • Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Onda A, Okumura Y, Kishi N, Iwama T, Mori T, Koike M, et al. Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology. 1996 Aug;111(2):307–317. [PubMed]
  • Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Rüschoff J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res. 1997 Nov 1;57(21):4749–4756. [PubMed]
  • Bocker T, Diermann J, Friedl W, Gebert J, Holinski-Feder E, Karner-Hanusch J, von Knebel-Doeberitz M, Koelble K, Moeslein G, Schackert HK, et al. Microsatellite instability analysis: a multicenter study for reliability and quality control. Cancer Res. 1997 Nov 1;57(21):4739–4743. [PubMed]
  • Jass JR, Do KA, Simms LA, Iino H, Wynter C, Pillay SP, 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. [PMC free article] [PubMed]
  • Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart LJ, Roche PC, McDonnell SK, Schaid DJ, Vockley CW, Michels VV, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998 Apr 15;58(8):1713–1718. [PubMed]
  • Percesepe A, Kristo P, Aaltonen LA, Ponz de Leon M, de la Chapelle A, Peltomäki P. Mismatch repair genes and mononucleotide tracts as mutation targets in colorectal tumors with different degrees of microsatellite instability. Oncogene. 1998 Jul 16;17(2):157–163. [PubMed]
  • Biden KG, Simms LA, Cummings M, Buttenshaw R, Schoch E, Searle J, Gobe G, Jass JR, Meltzer SJ, Leggett BA, et al. Expression of Bcl-2 protein is decreased in colorectal adenocarcinomas with microsatellite instability. Oncogene. 1999 Feb 4;18(5):1245–1249. [PubMed]
  • Iino H, Jass JR, Simms LA, Young J, Leggett B, Ajioka Y, Watanabe H. DNA microsatellite instability in hyperplastic polyps, serrated adenomas, and mixed polyps: a mild mutator pathway for colorectal cancer? J Clin Pathol. 1999 Jan;52(1):5–9. [PMC free article] [PubMed]
  • Bell SM, Kelly SA, Hoyle JA, Lewis FA, Taylor GR, Thompson H, Dixon MF, Quirke P. c-Ki-ras gene mutations in dysplasia and carcinomas complicating ulcerative colitis. Br J Cancer. 1991 Jul;64(1):174–178. [PMC free article] [PubMed]
  • Huang Y, Boynton RF, Blount PL, Silverstein RJ, Yin J, Tong Y, McDaniel TK, Newkirk C, Resau JH, Sridhara R, et al. Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers. Cancer Res. 1992 Dec 1;52(23):6525–6530. [PubMed]
  • Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res. 1998 Mar 15;58(6):1130–1134. [PubMed]
  • Grady WM, Myeroff LL, Swinler SE, Rajput A, Thiagalingam S, Lutterbaugh JD, Neumann A, Brattain MG, Chang J, Kim SJ, et al. Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res. 1999 Jan 15;59(2):320–324. [PubMed]
  • Heinen CD, Richardson D, White R, Groden J. Microsatellite instability in colorectal adenocarcinoma cell lines that have full-length adenomatous polyposis coli protein. Cancer Res. 1995 Nov 1;55(21):4797–4799. [PubMed]
  • Haseloff J, Siemering KR, Prasher DC, Hodge S. Removal of a cryptic intron and subcellular localization of green fluorescent protein are required to mark transgenic Arabidopsis plants brightly. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2122–2127. [PMC free article] [PubMed]
  • Iwao K, Nakamori S, Kameyama M, Imaoka S, Kinoshita M, Fukui T, Ishiguro S, Nakamura Y, Miyoshi Y. Activation of the beta-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Cancer Res. 1998 Mar 1;58(5):1021–1026. [PubMed]
  • Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destrée O, Clevers H. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell. 1996 Aug 9;86(3):391–399. [PubMed]
  • Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science. 1997 Mar 21;275(5307):1784–1787. [PubMed]
  • Jen J, Powell SM, Papadopoulos N, Smith KJ, Hamilton SR, Vogelstein B, Kinzler KW. Molecular determinants of dysplasia in colorectal lesions. Cancer Res. 1994 Nov 1;54(21):5523–5526. [PubMed]
  • Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. [PubMed]
  • Uchida H, Ando H, Maruyama K, Kobayashi H, Toda H, Ogawa H, Ozawa T, Matsuda Y, Sugimura H, Kanno T, et al. Genetic alterations of mixed hyperplastic adenomatous polyps in the colon and rectum. Jpn J Cancer Res. 1998 Mar;89(3):299–306. [PubMed]
  • Otori K, Oda Y, Sugiyama K, Hasebe T, Mukai K, Fujii T, Tajiri H, Yoshida S, Fukushima S, Esumi H. High frequency of K-ras mutations in human colorectal hyperplastic polyps. Gut. 1997 May;40(5):660–663. [PMC free article] [PubMed]
  • Hiyama T, Yokozaki H, Shimamoto F, Haruma K, Yasui W, Kajiyama G, Tahara E. Frequent p53 gene mutations in serrated adenomas of the colorectum. J Pathol. 1998 Oct;186(2):131–139. [PubMed]
  • Ajioka Y, Watanabe H, Jass JR, Yokota Y, Kobayashi M, Nishikura K. Infrequent K-ras codon 12 mutation in serrated adenomas of human colorectum. Gut. 1998 May;42(5):680–684. [PMC free article] [PubMed]
  • Jass JR, Smith M. Sialic acid and epithelial differentiation in colorectal polyps and cancer--a morphological, mucin and lectin histochemical study. Pathology. 1992 Oct;24(4):233–242. [PubMed]
  • Fujiwara T, Stolker JM, Watanabe T, Rashid A, Longo P, Eshleman JR, Booker S, Lynch HT, Jass JR, Green JS, et al. 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. [PMC free article] [PubMed]
  • Grady WM, Rajput A, Myeroff L, Liu DF, Kwon K, Willis J, Markowitz S. Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Res. 1998 Jul 15;58(14):3101–3104. [PubMed]
  • Jass JR, Stewart SM. Evolution of hereditary non-polyposis colorectal cancer. Gut. 1992 Jun;33(6):783–786. [PMC free article] [PubMed]
  • Benhattar J, Losi L, Chaubert P, Givel JC, Costa J. Prognostic significance of K-ras mutations in colorectal carcinoma. Gastroenterology. 1993 Apr;104(4):1044–1048. [PubMed]
  • Finkelstein SD, Sayegh R, Christensen S, Swalsky PA. Genotypic classification of colorectal adenocarcinoma. Biologic behavior correlates with K-ras-2 mutation type. Cancer. 1993 Jun 15;71(12):3827–3838. [PubMed]
  • Tanaka M, Omura K, Watanabe Y, Oda Y, Nakanishi I. Prognostic factors of colorectal cancer: K-ras mutation, overexpression of the p53 protein, and cell proliferative activity. J Surg Oncol. 1994 Sep;57(1):57–64. [PubMed]
  • Jeevaratnam P, Cottier DS, Browett PJ, Van De Water NS, Pokos V, Jass JR. Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. J Pathol. 1996 May;179(1):20–25. [PubMed]

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