Special Reports and ReviewsEmerging concepts in colorectal neoplasia☆
Section snippets
Similar-appearing adenomas may be biologically different
In FAP, only a small proportion of the many thousands of adenomas will transform into cancers, and the transition may take decades.52 Additionally, a unique mode of adenomatous growth involving the fusion of microadenomas into a polyclonal mass has been documented in this condition.53 In HNPCC, the ratio of adenoma to carcinoma is close to unity, and evolution to cancer appears to be rapid as well as frequent.54, 55 An intermediate position is observed in common forms of colorectal cancer.
How common is APC mutation in initiation and progression of colorectal adenoma?
Is APC mutation the invariable first genetic alteration in colorectal neoplasms? The gene clearly has a major role in directing epithelial growth and differentiation. As a component of the WNT or wingless cell-signalling pathway, a normal function of APC protein is to bind the key effector molecule β-catenin. When APC is inactivated, β-catenin translocates from the lateral cell membrane to the nucleus, where it drives the transcription of multiple genes implicated in tumor growth and invasion.56
MSI and methylation: A basis for tumor classification?
In the introduction, a case was made for classifying colorectal cancer into 2 groups based on the presence or absence of DNA MSI. It was also noted that cancers may be distinguished according to the presence or absence of DNA methylation. Because MSI usually arises in sporadic colorectal neoplasia as a consequence of methylation and inactivation of the DNA mismatch repair gene hMLH1, there will be an association between DNA MSI and methylation, but the overlap of “mutator” and “methylator”
ACF
The term ACF was initially applied to the microscopic epithelial lesions observed in experimental animals exposed to carcinogens.81, 82 Similar lesions have been identified in the mucosal surface of human colon after methylene blue staining.83, 84 ACF in humans have been classified as dysplastic and nondysplastic.84, 85 Dysplastic ACF are equivalent to microadenomas and probably account for about 5% of all ACF.85 Most nondysplastic ACF often show the histologic finding of crypt serration in
Serrated polyps of the colorectum
The preceding data imply that neither K-ras nor APC mutation is necessarily implicated in the initiation of colorectal cancer. If this is the correct interpretation, then the gap must be filled by an alternative mechanism. Two serrated pathways of sporadic colorectal neoplasia have been proposed, one culminating as MSI-H cancers90 and the second as MSI-L cancers.29, 91 Below it will be argued that a similar, two-step mechanism initiates both serrated pathways: first, the inhibition of apoptosis
Serrated route to MSI-H cancer
A key pathogenic mechanism in the pathogenesis of sporadic MSI-H colorectal cancer is methylation and loss of expression of the DNA mismatch repair gene hMLH1. This loss of expression is observed in MSI-H admixed polyps and serrated adenomas as well as in MSI-H cancers.90, 94, 99 Loss of hMLH1 protein is occasionally observed in nondysplastic crypts within hyperplastic polyps,94 and methylation of hMLH1 has been described within nondysplastic ACF.97 The silencing of hMLH1 is an early event, and
Serrated route to MSI-L colorectal cancer
The evidence supporting a serrated MSI-L pathway does not add up to the strong case for a serrated MSI-H pathway, but a careful appraisal of the underlying mechanisms fortifies the argument in favor of the existence of a serrated MSI-L pathway. Features shared by serrated polyps and MSI-L cancers include MSI-L,91 alterations at chromosome 1p,109, 110, 111 a high frequency of K-ras mutation,29, 33, 111 and a serrated architecture29 (but in only a subset of MSI-L cancers). The MSI-L pathway is
Top-down and bottom-up models
Based on microreconstruction studies in the colorectal mucosa of subjects with FAP, the earliest morphologic evidence of adenomatous neoplasia has been identified as a bud arising from the side of a parent crypt.132 The bud migrates (in concert with the normal epithelium of the parent crypt) while elongating to form a short tubule composed of an immature and proliferating epithelium. The unicryptal adenoma so formed assumes a superficial position in the mucosa where it “drops” from the surface
Hyperplastic polyposis: A model for sporadic colorectal cancer?
If FAP is not an appropriate model for explaining all pathways to sporadic colorectal cancer, is there an alternative familial condition that could serve such a role? Hyperplastic polyposis presents a plausible model for the following reasons: (1) Polyps in this condition may show MSI and silencing of relevant DNA repair genes including hMLH1.90, 98, 99 (2) CpG island methylation is demonstrated in DNA extracted from hyperplastic polyps in a subset of subjects with hyperplastic polyposis.97 The
Conclusion and clinical implications
A significant proportion of colorectal cancer may not be initiated by mutation of APC, as is generally supposed, but through the epigenetic silencing of alternative genes implicated in apoptosis and DNA repair mechanisms. Epithelial hyperplasia and serration are early morphological changes within this alternative pathway. Although not initiating this pathway, APC mutation may occur early and generate subclones with an adenomatous morphology. However, APC mutation is not observed in most
Acknowledgements
The authors thank Dr. Richard Fishel, Kimmel Cancer Center, Philadelphia, Pennsylvania, and Dr. Asif Rashid and Dr. Jean-Pierre Issa, M. D. Anderson Cancer Center, Houston, Texas, for reading this review and providing helpful criticism and information.
References (146)
- et al.
Identification and characterization of the familial adenomatous polyposis gene
Cell
(1991) - et al.
Lessons from hereditary colorectal cancer
Cell
(1996) - et al.
The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer
Cell
(1993) - et al.
Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer
Cell
(1993) - et al.
Late onset and high incidence of colon cancer of the mutator phenotype with hypermethylated hMLH1 gene in women
Gastroenterology
(2000) - et al.
Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences
Am J Pathol
(1998) - et al.
Inverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer
Am J Pathol
(2001) - et al.
Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer
Gastroenterology
(1996) - et al.
Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer
Gastroenterology
(2000) - et al.
Interval cancers in hereditary non-polyposis colorectal cancer (Lynch syndrome)
Lancet
(1995)
Analysis of K-ras, APC, and β-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis
Gastroenterology
The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas
Am J Hum Genet
Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings
Cancer Lett
Identification and quantification of aberrant crypt foci and microadenomas in the human colon
Hum Pathol
CpG island methylation in aberrant crypt foci of the colorectum
Am J Pathol
Phenotypic and molecular characteristics of hyperplastic polyposis
Gastroenterology
Localization of the gene for familial adenomatous polyposis on chromosome 5
Nature
The gene for familial polyposis maps to the long arm of chromosome 5
Science
Identification of FAP locus genes from chromosome 5q21
Science
Chromosome 5 allele loss in human colorectal carcinomas
Nature
Genetic alterations during colorectal-tumor development
N Engl J Med
Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary nonpolyposis colon cancer
Nature
Mutation of a mutL homolog in hereditary colon cancer
Science
Mutations of GTBP in genetically unstable cells
Science
Hereditary nonpolyposis colorectal cancer and colonic adenomas: aggressive adenomas?
Semin Surg Oncol
Mutations in the APC tumor suppressor gene cause chromosomal instability
Nat Cell Biol
Mismatch repair, molecular switches, and signal transduction
Genes Dev
The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: revising the mutator hypothesis
Cancer Res
Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis
Nature
Clues to the pathogenesis of familial colorectal cancer
Science
Microsatellite instability in cancer of the proximal colon
Science
Microsatellite instability in colorectal cancer: different mutator phenotypes and the principle involvement of hMLH1
Cancer Res
Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines
Cancer Res
Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma
Proc Natl Acad Sci U S A
Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability
Cancer Res
The prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer
Br J Surg
Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences
Am J Pathol
Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics
Am J Pathol
Morphology of sporadic colorectal cancer with DNA replication errors
Gut
Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways
J Clin Pathol
Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history
Cancer Res
Colorectal cancer with and without microsatellite instability involves different genes
Genes Chromosom Cancer
Alternative genetic pathways in colorectal carcinogenesis
Proc Natl Acad Sci U S A
Reciprocal relationship between the tumor suppressors p53 and BAX in primary colorectal cancers
Oncogene
Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability
Science
The insulin-like growth factor II receptor gene is a target of microsatellite instability in human gastrointestinal tumours
Nat Genet
Somatic frameshift mutations in DNA mismatch repair and proapoptosis genes in hereditary nonpolyposis colorectal cancer
Cancer Res
Association between cPG island methylation and microsatellite instability in colorectal cancer
Cancer Res
Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon
Nat Genet
CpG island methylator phenotype in colorectal cancer
Proc Natl Acad Sci U S A
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Address requests for reprints to: Prof. J. R. Jass, Department of Pathology, McGill University, Lyman Duff Medical Sciences Building, 3775 University Street, Montreal, Quebec, Canada H3A 2B4. e-mail: [email protected]; fax: (514) 398 7446.