Abstract
Introduction
Serrated polyps have been considered to be precursors of colorectal cancer with microsatellite instability. However, the biological and/or morphological changes which occur during the course of serrated polyp to cancer remain to be elucidated.
Methods
Twenty-eight colorectal serrated polyps including five mixed polyps (MP) from 20 patients were observed by chromoendoscopy with magnification, and subsequently resected endoscopically. The presence of mutations in two genes (K-ras and BRAF) and the methylation status of six genes (MLH1-A, MLH1-C, ESR1, P16, SOCS1, and IGFBP7) were examined.
Results
The 28 polyps included 32 histological serrated lesions (22 sessile serrated adenomas [SSA], six hyperplastic polyps [HP], and four traditional serrated adenoma [TSA]-like lesions). BRAF mutation was frequently observed in SSAs (19/22), while K-ras mutation was dominant in HPs (5/6). The externalization of saw-tooth architecture in serrated polyps was endoscopically observed more frequently in those with high levels of IGFBP7 methylation (P = 0.03). Moreover, the endoscopic finding was observed in five of six small serrated lesions (<10 mm) which contained both BRAF mutation and high levels of IGFBP7 methylation. TSA-like lesions in small MPs demonstrated the endoscopic finding with no or little MLH1 methylation, while the counterparts in the mixed polyps had high levels of MLH1 methylation with relatively low levels of IGFBP7 methylation.
Conclusions
Our data suggests two distinct pathways may be involved in the early stages of the serrated pathway: one where MLH1 is primarily methylated, and a second where methylated IGFBP7 is associated with an externalization of saw-tooth architecture.
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References
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–767.
Kambara T, Simms LA, Whitehall VL, et al. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004;53:1137–1144.
O’Brien MJ, Yang S, Mack C, et al. Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and K-ras status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol. 2006;30:1491–1501.
Longacre TA, Fenoglio-Preiser CM. Mixed hyperplastic adenomatous polyps/serrated adenomas. A distinct form of colorectal neoplasia. Am J Surg Pathol. 1990;14:524–537.
Snover DC, Jass JR, Fenoglio-Preiser C, Batts KP. Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol. 2005;124:380–391.
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA. 1999;96:8681–8686.
Kim KM, Lee EJ, Kim YH, Chang DK, Odze RD. KRAS mutations in traditional serrated adenomas from Korea Herald an aggressive phenotype. Am J Surg Pathol. 2010;34:667–675.
Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38:787–793.
Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 2008;132:363–374.
Burger AM, Zhang X, Li H, et al. Down-regulation of T1A12/MAC25, a novel insulin-like growth factor binding protein related gene, is associated with disease progression in breast carcinomas. Oncogene. 1998;16:2459–2467.
Landberg G, Ostlund H, Nielsen NH, et al. Downregulation of the potential suppressor gene IGFBP-rP1 in human breast cancer is associated with inactivation of the retinoblastoma protein, cyclin E overexpression and increased proliferation in estrogen receptor negative tumors. Oncogene. 2001;20:3497–3505.
Lin J, Lai M, Huang Q, Ma Y, Cui J, Ruan W. Methylation patterns of IGFBP7 in colon cancer cell lines are associated with levels of gene expression. J Pathol. 2007;212:83–90.
Yamashita S, Tsujino Y, Moriguchi K, Tatematsu M, Ushijima T. Chemical genomic screening for methylation silenced genes in gastric cancer cell lines using 5-aza-2′-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006;97:64–71.
Suzuki H, Igarashi S, Nojima M, et al. IGFBP7 is a p53 responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype. Carcinogenesis. 2010;31:342–349.
Kudo S, Rubio CA, Teixeira CR, Kashida H, Kogure E. Pit pattern in colorectal neoplasia: endoscopic magnifying view. Endoscopy. 2001;33:367–373.
Sandmeier D, Seelentag W, Bouzourene H. Serrated polyps of the colorectum: is sessile serrated adenoma distinguishable from hyperplastic polyp in a daily practice? Virchows Arch. 2007;450:613–618.
Eads CA, Danenberg KD, Kawakami K, et al. MethyLight: a high throughput assay to measure DNA methylation. Nucleic Acids Res. 2000;28:E32.
Eads CA, Lord RV, Wickramasinghe K, et al. Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res. 2001;61:3410–3418.
Trinh BN, Long TI, Laird PW. DNA methylation analysis by MethyLight technology. Methods. 2001;25:456–462.
Widschwendter M, Siegmund KD, Müller HM, et al. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen. Cancer Res. 2004;64:3807–3813.
Weisenberger DJ, Campan M, Long TI, et al. Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res. 2005;33:6823–6836.
Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 1998;95:6870–6875.
Deng G, Chen A, Hong J, Chae HS, Kim YS. Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res. 1999;59:2029–2033.
Hiraoka S, Kato J, Tatsukawa M, et al. Laterally spreading type of colorectal adenoma exhibits a unique methylation phenotype and K-ras mutations. Gastroenterology. 2006;131:379–389.
Harada K, Hiraoka S, Kato J, et al. Genetic and epigenetic alterations of Ras signalling pathway in colorectal neoplasia: analysis based on tumour clinicopathological features. Br J Cancer. 2007;97:1425–1431.
Miyakura Y, Sugano K, Konishi F, et al. Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability. Gastroenterology. 2001;121:1300–1309.
Nakagawa H, Nuovo GJ, Zervos EE, et al. Age-related hypermethylation of the 5′ region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development. Cancer Res. 2001;61:6991–6995.
Shen L, Toyota M, Kondo Y, et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci USA. 2007;104:18654–18659.
Kohonen-Corish MR, Sigglekow ND, Susanto J, et al. Promoter methylation of the mutated in colorectal cancer gene is a frequent early even in colorectal cancer. Oncogene. 2007;26:4435–4441.
Jass JR, Baker K, Zlobec I, et al. Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancer. Histopathology. 2006;49:121–131.
Rosenberg DW, Yang S, Pleau DC, et al. Mutations in BRAF and K-ras differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res. 2007;67:3551–3554.
Spring KJ, Zhao ZZ, Karamatic R, et al. High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology. 2006;131:1400–1407.
Yang S, Farraye FA, Mack C, Posnik O, O’Brien MJ. BRAF and K-ras mutations in hyperplastic polyps and serrated adenomas of the colorectum. Relationship to histology and CpG island methylation status. Am J Surg Pathol. 2004;28:1452–1459.
Mutaguchi K, Yasumoto H, Mita K, et al. Restoration of insulin-like growth factor binding protein-related protein 1 has a tumor-suppressive activity through induction of apoptosis in human prostate cancer. Cancer Res. 2003;63:7717–7723.
Sato Y, Chen Z, Miyazaki K. Strong suppression of tumor growth by insulin-like growth factor-binding protein-related protein 1/tumorderived cell adhesion factor/MAC25. Cancer Sci. 2007;98:1055–1063.
Lin J, Lai M, Huang Q, Ruan W, Ma Y, Cui J. Reactivation of IGFBP7 by DNA demethylation inhibits human colon cancer cell growth in vitro. Cancer Biol Ther. 2008;7:1896–1900.
Hurlstone DP, Cross SS, Adam I, et al. Efficacy of high magnification chromoscopic colonoscopy for the diagnosis of neoplasia in flat and depressed lesions of the colorectum: a prospective analysis. Gut. 2004;53:284–290.
Tamura S, Furuya Y, Tadokoro T, et al. Pit pattern and three-dimensional configuration of isolated crypts from the patients with colorectal neoplasm. J Gastroenterol. 2002;37:798–806.
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Kaji, E., Uraoka, T., Kato, J. et al. Externalization of Saw-Tooth Architecture in Small Serrated Polyps Implies the Presence of Methylation of IGFBP7 . Dig Dis Sci 57, 1261–1270 (2012). https://doi.org/10.1007/s10620-011-2008-0
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DOI: https://doi.org/10.1007/s10620-011-2008-0