Molecular pathogenesis of sporadic colorectal cancers

Abstract

Colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic mucosa to adenocarcinoma. Approximately 75% of CRCs are sporadic and occur in people without genetic predisposition or family history of CRC. During the past two decades, sporadic CRCs were classified into three major groups according to frequently altered/mutated genes. These genes have been identified by linkage analyses of cancer-prone families and by individual mutation analyses of candidate genes selected on the basis of functional data. In the first half of this review, we describe the genetic pathways of sporadic CRCs and their clinicopathologic features. Recently, large-scale genome analyses have detected many infrequently mutated genes as well as a small number of frequently mutated genes. These infrequently mutated genes are likely described in a limited number of pathways. Gene-oriented models of CRC progression are being replaced by pathway-oriented models. In the second half of this review, we summarize the present knowledge of this research field and discuss its prospects.

Fig. 1

Evolutional pathways for colorectal morphogenesis. The traditional pathway is the most homogenous pathway, originating from tubular adenoma (via adenomatous polyposis coli (APC) and subsequently Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation) and leading to adenocarcinoma [via tumor protein 53 (TP53) mutation]. This pathway is characterized by chromosomal instability (CIN), negative CpG island methylator phenotype (CIMP), and average outcome. The serrated pathway is also the most homogenous pathway, originating from sessile serrated adenoma/polyps (SSA/P) via B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation and CIMP-high (CIMP-H) and leading to adenocarcinoma via MutL homolog 1 (MLH1) promoter methylation and microsatellite instability-high (MSI-H). This pathway is characterized by good prognosis. The alternative pathway is more heterogeneous and may arise mostly from villous adenoma and perhaps also from SSA/P and traditional serrated adenoma (TSA) via CIMP-low (CIMP-L) and predominant KRAS but occasional BRAF mutations. This pathway lacks CIN and has the worse prognosis with low responsiveness to chemotherapy. The de novo cancers usually lack KRAS mutation but are significantly associated with TP53 and APC mutations and also loss of heterozygosity (LOH) at chromosome 3p (chr 3p). EMT epithelial-mesenchymal transition, TGF-β transforming growth factor-β, MSI-L MSI-low. A part of this figure was reproduced from figure 1 in Patholog Res Int 2012;2012:509348 authored by Pancione et al. [42], with permission

Fig. 2

Representative histological figures of polyps, adenoma, and carcinoma of the colon and rectum (hematoxylin and eosin stain). a hyperplastic polyp. b sessile serrated adenoma/polyp. c tubular adenoma. d villous adenoma. e traditional serrated adenoma. f adenocarcinoma