Field Cancerization in Sporadic Colon Cancer
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Background/Aims: Aberrant DNA methylation has a specific role in field cancerization. Certain molecular markers, including secreted frizzled-related protein 2 (SFRP2), tissue factor pathway inhibitor 2 (TFPI2 ), N-Myc downstream-regulated gene 4 (NDRG4) and bone morphogenic protein 3 (BMP3), have previously been shown to be hypermethylated in colorectal cancer (CRC). We aim to examine field cancerization in CRC based on the presence of aberrant DNA methylation in normal-appearing tissue from CRC patients. Methods: We investigated promoter methylation in 34 CRC patients and five individuals with normal colonoscopy results. CRC patients were divided into three tissue groups: tumor tissue, adjacent and nonadjacent normal-appearing tissue. The methylation status (positive: methylation level >20%) of SFRP2 , TFPI2 , NDRG4 , and BMP3 promoters was investigated using methylation-specific PCR. Results: The methylation frequencies of the SFRP2 , TFPI2 , NDRG4 and BMP3 promoters in tumor/adjacent/nonadjacent normal-appearing tissue were 79.4%/63.0%/70.4%, 82.4%/53.6%/60.7%, 76.5%/61.5%/69.2%, 41.2%/35.7%/50.0%, respectively. The methylation levels of the SFRP, TFPI2, NDRG4 and BMP3 promoters in tumor tissues were significantly higher than those in normal-appearing tissue (SFRP2, p=0.013; TFPI2, p<0.001; NDRG4, p=0.003; BMP3, p=0.001). No significant correlation was observed between the methylation levels of the promoters and the clinicopathological variables. Conclusions: The field effect is present in CRC and affects both the adjacent and nonadjacent normal-appearing mucosa.
Abstract
Background/Aims: Aberrant DNA methylation has a specific role in field cancerization. Certain molecular markers, including secreted frizzled-related protein 2 (SFRP2), tissue factor pathway inhibitor 2 (TFPI2 ), N-Myc downstream-regulated gene 4 (NDRG4) and bone morphogenic protein 3 (BMP3), have previously been shown to be hypermethylated in colorectal cancer (CRC). We aim to examine field cancerization in CRC based on the presence of aberrant DNA methylation in normal-appearing tissue from CRC patients. Methods: We investigated promoter methylation in 34 CRC patients and five individuals with normal colonoscopy results. CRC patients were divided into three tissue groups: tumor tissue, adjacent and nonadjacent normal-appearing tissue. The methylation status (positive: methylation level >20%) of SFRP2 , TFPI2 , NDRG4 , and BMP3 promoters was investigated using methylation-specific PCR. Results: The methylation frequencies of the SFRP2 , TFPI2 , NDRG4 and BMP3 promoters in tumor/adjacent/nonadjacent normal-appearing tissue were 79.4%/63.0%/70.4%, 82.4%/53.6%/60.7%, 76.5%/61.5%/69.2%, 41.2%/35.7%/50.0%, respectively. The methylation levels of the SFRP, TFPI2, NDRG4 and BMP3 promoters in tumor tissues were significantly higher than those in normal-appearing tissue (SFRP2, p=0.013; TFPI2, p<0.001; NDRG4, p=0.003; BMP3, p=0.001). No significant correlation was observed between the methylation levels of the promoters and the clinicopathological variables. Conclusions: The field effect is present in CRC and affects both the adjacent and nonadjacent normal-appearing mucosa.
참고문헌 (31)
- Markowitz SD, "Molecular origins of cancer: molecular basis of colorectal cancer", N Engl J Med, 361, pp.2449~2460 (2009)
- 김은란, "Clinical Application of Genetics in Management of Colorectal Cancer", Intestinal research, 12(3), pp.184~193 (2014), 대한장연구학회
- Baylin SB, "Epigenetic gene silencing in cancer: a mechanism for early oncogenic pathway addiction?", Nat Rev Cancer, 6, pp.107~116 (2006)
- Goel A, "Epigenetics of colorectal cancer", Gastroenterology, 143(e1), pp.1442~1460 (2012)
- Kim MS, "DNA methylation markers in colorectal cancer", Cancer Metastasis Rev, 29, pp.181~206 (2010)
- Kondo Y, "Epigenetic changes in colorectal cancer", Cancer Metastasis Rev, 23, pp.29~39 (2004)
- Zou H, "Highly methylated genes in colorectal neoplasia: implications for screening", Cancer Epidemiol Biomarkers Prev, 16, pp.2686~2696 (2007)
- Slaughter DP, "Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin", Cancer, 6, pp.963~968 (1953)
- Luo Y, "Field cancerization in the colon: a role for aberrant DNA methylation?", Gastroenterol Rep, 2, pp.16~20 (2014)
- Bernstein C, "Field defects in progression to gastrointestinal tract cancers", Cancer Lett, 260, pp.1~10 (2008)
- Turenne CY, "Necessity of qualitycontrolled 16S rRNA gene sequence databases: identifying nontuberculous Mycobacterium species", J Clin Microbiol, 39, pp.3637~3648 (2001)
- Shen L, "MGMT promoter methylation and field defect in sporadic colorectal cancer", J Natl Cancer Inst, 97, pp.1330~1338 (2005)
- Van Assche G, "Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations", J Crohns Colitis, 7, pp.1~33 (2013)
- Levi F, "High constant incidence of second primary colorectal cancer", Int J Cancer, 132, pp.1679~1682 (2013)
- Vogelstein B, "Cancer genes and the pathways they control", Nat Med, 10, pp.789~799 (2004)
- Worthley DL, "DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer", Oncogene, 29, pp.1653~1662 (2010)
- Grady WM, "Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer", Oncogene, 27, pp.3880~3888 (2008)
- Suzuki H, "A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer", Nat Genet, 31, pp.141~149 (2002)
- Suzuki H, "Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer", Nat Genet, 36, pp.417~422 (2004)
- Sui C, "Variation risks of SFRP2 hypermethylation between precancerous disease and colorectal cancer", Tumour Biol, 35, pp.10457~10465 (2014)
- Hibi K, "Methylation of TFPI2 gene is frequently detected in advanced well-differentiated colorectal cancer", Anticancer Res, 30, pp.1205~1207 (2010)
- Melotte V, "N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer", J Natl Cancer Inst, 101, pp.916~927 (2009)
- Loh K, "Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development", Genes Chromosomes Cancer, 47, pp.449~460 (2008)
- Ahlquist DA, "Next-generation stool DNA test accurately detects colorectal cancer and large adenomas", Gastroenterology, 142, pp.248~256 (2012)
- Imperiale TF, "Multitarget stool DNA testing for colorectal-cancer screening", N Engl J Med, 370, pp.1287~1297 (2014)
- Fodde R, "APC, signal transduction and genetic instability in colorectal cancer", Nat Rev Cancer, 1, pp.55~67 (2001)
- Xu Q, "Functional and biochemical interactions of Wnts with FrzA, a secreted Wnt antagonist", Development, 125, pp.4767~4776 (1998)
- Wong CM, "Tissue factor pathway inhibitor-2as a frequently silenced tumor suppressor gene in hepatocellular carcinoma", Hepatology, 45, pp.1129~1138 (2007)
- Sato N, "Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma", Oncogene, 24, pp.850~858 (2005)
- Zhou RH, "Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart", Genomics, 73, pp.86~97 (2001)
- Koinuma K, "Screening for genomic fragments that are methylated specifically in colorectal carcinoma with a methylated MLH1 promoter", Carcinogenesis, 26, pp.2078~2085 (2005)