Sessile serrated adenoma shares similar genetic and epigenetic features with microsatellite unstable colon cancer in a location-dependent manner

Maeda,Takafumi; Suzuki,Koichi; Togashi,Kazutomo; Nokubi,Mitsuhiro; Saito,Masaaki; Tsujinaka,Shingo; Kamiyama,Hidenori; Konishi,Fumio

doi:10.3892/etm.2011.249

Sessile serrated adenoma shares similar genetic and epigenetic features with microsatellite unstable colon cancer in a location-dependent manner

Authors:
- Takafumi Maeda
- Koichi Suzuki
- Kazutomo Togashi
- Mitsuhiro Nokubi
- Masaaki Saito
- Shingo Tsujinaka
- Hidenori Kamiyama
- Fumio Konishi
View Affiliations

Affiliations: Department of Surgery, Jichi Medical University Saitama Medical Center, Saitama 330-8503, Japan, Department of Endoscopy, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan, Department of Pathology, Jichi Medical University Saitama Medical Center, Saitama 330-8503, Japan
Published online on: April 5, 2011 https://doi.org/10.3892/etm.2011.249
Pages: 695-700

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Genetic and epigenetic features of sessile serrated adenoma (SSA), a precursor lesion to colon cancer with microsatellite instability (MSI), were investigated. The aim of this study was to clarify whether there are location-dependent genetic and epigenetic features in SSA. Twenty-two patients with proximal SSAs and 8 with distal SSAs were recruited. Twenty-two patients with tubular adenoma (TA) and 66 with proximal colon cancer were studied for comparison. Genetic and epigenetic features were evaluated as BRAF and KRAS mutations, MSI, hMLH1 methylation and CpG island methylator phenotype (CIMP). BRAF mutation (p=0.007) and CIMP (p=0.012) were more frequently found in proximal than in distal SSAs. Furthermore, the KRAS mutation was found only in distal SSAs. In TAs, no location-related molecular features were observed. All SSAs, TAs and 42 colon cancer lesions were microsatellite stable (MSS). Twenty-four colon cancer lesions exhibited MSI and had more frequent BRAF mutations (p<0.001), hMLH1 methylation (p<0.001) and CIMP (p<0.001). BRAF mutation occurred in only 9.5% of MSS cancers (p=0.01). In MSI cancers with the BRAF mutation, a higher correlation with CIMP (p=0.032) was observed. We demonstrated the distinct genetic and epigenetic features between proximal and distal SSAs. Similar genetic and epigenetic features were shared between proximal SSAs and proximal MSI cancers harboring the BRAF mutation. By contrast, our results allow the possibility of carcinogenesis in SSAs leading to MSS cancer with the BRAF mutation.

View Figures

View References

1.	Longacre TA and Fenoglio-Preiser CM: Mixed hyperplastic adenomatous polyps/serrated adenomas. A distinct form of colorectal neoplasia. Am J Surg Pathol. 14:524–537. 1990. View Article : Google Scholar : PubMed/NCBI
2.	Torlakovic E, Skovlund E, Snover DC, Torlakovic G and Nesland JM: Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol. 27:65–81. 2003. View Article : Google Scholar : PubMed/NCBI
3.	Torlakovic EE, Gomez JD, Driman DK, et al: Sessile serrated adenoma (SSA) vs. traditional serrated adenoma (TSA). Am J Surg Pathol. 32:21–29. 2008. View Article : Google Scholar : PubMed/NCBI
4.	Torlakovic E and Snover DC: Serrated adenomatous polyposis in humans. Gastroenterology. 110:748–755. 1996. View Article : Google Scholar : PubMed/NCBI
5.	Lee SK, Chang HJ, Kim TI, et al: Clinicopathologic findings of colorectal traditional and sessile serrated adenomas in Korea: a multicenter study. Digestion. 77:178–183. 2008. View Article : Google Scholar : PubMed/NCBI
6.	Leggett B and Whitehall V: Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology. 138:2088–2100. 2010. View Article : Google Scholar : PubMed/NCBI
7.	Higuchi T and Jass JR: My approach to serrated polyps of the colorectum. J Clin Pathol. 57:682–686. 2004. View Article : Google Scholar : PubMed/NCBI
8.	Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH and Issa JP: A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res. 32:e382004. View Article : Google Scholar : PubMed/NCBI
9.	Sandmeier D, Benhattar J, Martin P and Bouzourene H: Serrated polyps of the large intestine: a molecular study comparing sessile serrated adenomas and hyperplastic polyps. Histopathology. 55:206–213. 2009. View Article : Google Scholar : PubMed/NCBI
10.	Carr NJ, Mahajan H, Tan KL, Hawkins NJ and Ward RL: Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma. J Clin Pathol. 62:516–518. 2009. View Article : Google Scholar : PubMed/NCBI
11.	Kambara T, Simms LA, Whitehall VL, et al: BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 53:1137–1144. 2004. View Article : Google Scholar : PubMed/NCBI
12.	Lash RH, Genta RM and Schuler CM: Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients. J Clin Pathol. 63:681–686. 2010. View Article : Google Scholar : PubMed/NCBI
13.	O’Brien MJ, Yang S, Mack C, et al: Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol. 30:1491–1501. 2006.
14.	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. 131:1400–1407. 2006. View Article : Google Scholar : PubMed/NCBI
15.	Farina-Sarasqueta A, van Lijnschoten G, Moerland E, et al: The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol. 21:2396–2402. 2010. View Article : Google Scholar : PubMed/NCBI
16.	Watanabe T, Kobunai T, Toda E, et al: Distal colorectal cancers with microsatellite instability (MSI) display distinct gene expression profiles that are different from proximal MSI cancers. Cancer Res. 66:9804–9808. 2006. View Article : Google Scholar : PubMed/NCBI
17.	Cho YK, Kim HC, Kim SH, et al: Location-related differences in sporadic microsatellite unstable colorectal cancer. Dig Liver Dis. 42:611–615. 2010. View Article : Google Scholar : PubMed/NCBI
18.	Davies H, Bignell GR, Cox C, et al: Mutations of the BRAF gene in human cancer. Nature. 417:949–954. 2002. View Article : Google Scholar : PubMed/NCBI
19.	Chan TL, Zhao W, Leung SY and Yuen ST: BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 63:4878–4881. 2003.PubMed/NCBI
20.	Takemoto N, Konishi F, Yamashita K, et al: The correlation of microsatellite instability and tumor-infiltrating lymphocytes in hereditary non-polyposis colorectal cancer (HNPCC) and sporadic colorectal cancers: the significance of different types of lymphocyte infiltration. Jpn J Clin Oncol. 34:90–98. 2004. View Article : Google Scholar
21.	Xiong Z and Laird PW: COBRA: a sensitive and quantitative DNA methylation assay. Nucleic Acids Res. 25:2532–2534. 1997. View Article : Google Scholar : PubMed/NCBI
22.	Toyota M, Ho C, Ahuja N, et al: Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res. 59:2307–2312. 1999.PubMed/NCBI
23.	Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB and Issa JP: CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA. 96:8681–8686. 1999. View Article : Google Scholar : PubMed/NCBI
24.	Kusano M, Toyota M, Suzuki H, et al: Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein-Barr virus. Cancer. 106:1467–1479. 2006. View Article : Google Scholar : PubMed/NCBI
25.	Kim YH, Kakar S, Cun L, Deng G and Kim YS: Distinct CpG island methylation profiles and BRAF mutation status in serrated and adenomatous colorectal polyps. Int J Cancer. 123:2587–2593. 2008. View Article : Google Scholar : PubMed/NCBI
26.	Vaughn CP, Wilson AR and Samowitz WS: Quantitative evaluation of CpG island methylation in hyperplastic polyps. Mod Pathol. 23:151–156. 2010. View Article : Google Scholar : PubMed/NCBI
27.	Miyakura Y, Sugano K, Konishi F, et al: Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability. Gastroenterology. 121:1300–1309. 2001. View Article : Google Scholar : PubMed/NCBI
28.	Deng G, Chen A, Hong J, Chae HS and Kim YS: Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res. 59:2029–2033. 1999.PubMed/NCBI
29.	Ogino S, Nosho K, Kirkner GJ, et al: CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 58:90–96. 2009. View Article : Google Scholar : PubMed/NCBI
30.	Zlobec I, Kovac M, Erzberger P, et al: Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer. Int J Cancer. 127:2569–2575. 2010. View Article : Google Scholar
31.	Lubomierski N, Plotz G, Wormek M, et al: BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors. Cancer. 104:952–961. 2005. View Article : Google Scholar : PubMed/NCBI
32.	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. 49:121–131. 2006.PubMed/NCBI