Gastroenterology

Gastroenterology

Volume 123, Issue 3, September 2002, Pages 862-876
Gastroenterology

Special Reports and Reviews
Emerging concepts in colorectal neoplasia

https://doi.org/10.1053/gast.2002.35392Get rights and content

Abstract

An understanding of the mechanisms that explain the initiation and early evolution of colorectal cancer should facilitate the development of new approaches to effective prevention and intervention. This review highlights deficiencies in the current model for colorectal neoplasia in which APC mutation is placed at the point of initiation. Other genes implicated in the regulation of apoptosis and DNA repair may underlie the early development of colorectal cancer. Inactivation of these genes may occur not by mutation or loss but through silencing mediated by methylation of the gene's promoter region. hMLH1 and MGMT are examples of DNA repair genes that are silenced by methylation. Loss of expression of hMLH1 and MGMT protein has been demonstrated immunohistochemically in serrated polyps. Multiple lines of evidence point to a “serrated” pathway of neoplasia that is driven by inhibition of apoptosis and the subsequent inactivation of DNA repair genes by promoter methylation. The earliest lesions in this pathway are aberrant crypt foci (ACF). These may develop into hyperplastic polyps or transform while still of microscopic size into admixed polyps, serrated adenomas, or traditional adenomas. Cancers developing from these lesions may show high- or low-level microsatellite instability (MSI-H and MSI-L, respectively) or may be microsatellite stable (MSS). The suggested clinical model for this alternative pathway is the condition hyperplastic polyposis. If colorectal cancer is a heterogeneous disease comprising discrete subsets that evolve through different pathways, it is evident that these subsets will need to be studied individually in the future.

GASTROENTEROLOGY 2002;123:862-876

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.

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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.

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