Role of the Serrated Pathway in Colorectal Cancer Pathogenesis Barbara Leggett, Vicki Whitehall  Gastroenterology  Volume 138, Issue 6, Pages 2088-2100 (May 2010) DOI: 10.1053/j.gastro.2009.12.066 Copyright © 2010 AGA Institute Terms and Conditions

Figure 1 (A) Endoscopic appearance of sessile serrated adenomas (SSA) showing pale sessile appearance in the proximal colon (image supplied by Dr Mark Appleyard, Royal Brisbane and Women's Hospital). (B) Histological appearance of a polyp predominantly covered by SSA epithelium with abrupt transition (marked with arrow) to high-grade adenomatous dysplasia and invasive adenocarcinoma. The dysplastic area but not the SSA showed loss of MLH1 expression on immunohistochemistry (photomicrograph courtesy of A/Prof Andrew Clouston and A/Prof Neal Walker, Envoi Pathology). Gastroenterology 2010 138, 2088-2100DOI: (10.1053/j.gastro.2009.12.066) Copyright © 2010 AGA Institute Terms and Conditions

Figure 2 CpG island methylation leads to gene silencing. The gene promoter and coding regions of an active gene are indicated in red and blue, respectively (A). The aberrant addition of methyl groups (CH3) to CpG sites in the promoter region interferes with gene transcription, resulting in silencing (B). Gastroenterology 2010 138, 2088-2100DOI: (10.1053/j.gastro.2009.12.066) Copyright © 2010 AGA Institute Terms and Conditions

Figure 3 KRAS and BRAF mediate transduction of signals from extracellular stimuli via the mitogen-activated protein kinase (MAPK) signaling pathway. Activated extracellular signal-regulated kinase (ERK) can translocate to the nucleus, where it activates transcription factors to alter expression of genes that regulate cell growth and proliferation. Mutations in the oncogenes KRAS or BRAF result in constitutive activation of the pathway and uncontrolled cell proliferation. Gastroenterology 2010 138, 2088-2100DOI: (10.1053/j.gastro.2009.12.066) Copyright © 2010 AGA Institute Terms and Conditions

Figure 4 Mitogen-activated protein kinase (MAPK) pathway activation, which results from BRAF mutations, is accompanied by an initial proliferative burst, followed by up-regulation of p16INK4a and increased secretion of insulin-like growth factor binding protein 7 (IGFBP7), resulting in cellular senescence. Silencing of either p16INK4a or IGFBP7 via methylation in cells with CpG island methylator phenotype (CIMP) could facilitate escape from senescence and progression to sessile serrated adenomas (SSA). Gastroenterology 2010 138, 2088-2100DOI: (10.1053/j.gastro.2009.12.066) Copyright © 2010 AGA Institute Terms and Conditions

Figure 5 Model of colorectal tumorigenesis: mitogen-activated protein kinase (MAPK) pathway activation and CpG island methylation have synergisitic effects in subsets of tumors, especially those with serrated polyp precursors. Red shading indicates a predisposition to high levels of methylation that increase as the lesion progresses; blue shading represents a predisposition to low levels of methylation that are qualitatively different. This model represents the predominant pathways, but there is undoubtedly overlap between them. Not all the genetic changes are well-understood. Those pathways in bold type are the best understood, whereas italicized sections are hypothetical. CIMP, CpG Island methylator phenotype; CIN, chromosomal instability; GCHP, global cell type hyperplastic polyp; MSS, microsatellite stable; MVHP, microvesicular hyperplastic polyp; SSA, sessile serrated adenomas; TA, tubular adenoma; TSA, traditional serrated adenomas; TVA, tubulovillous adenoma. Gastroenterology 2010 138, 2088-2100DOI: (10.1053/j.gastro.2009.12.066) Copyright © 2010 AGA Institute Terms and Conditions

Barbara Leggett*,‡ Gastroenterology 2010 138, 2088-2100DOI: (10.1053/j.gastro.2009.12.066) Copyright © 2010 AGA Institute Terms and Conditions

Vicki Whitehall*,§ Gastroenterology 2010 138, 2088-2100DOI: (10.1053/j.gastro.2009.12.066) Copyright © 2010 AGA Institute Terms and Conditions