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• W2095587247 abstract "Background & Aims: Laterally spreading tumors (LST), characterized by superficial extension along the colonic lumen, have recently been detected by colonoscopy. However, genetic and epigenetic characteristics of these tumors were scarcely reported. Methods: A total of 205 sporadic colorectal adenoma tissues (157 protruded-type, 23 granular-type LST (G-LST), 12 flat-type LST (F-LST), and 13 flat-type smaller than 1 cm) were collected. CpG island methylator phenotype (CIMP) was determined by examination of methylation status at p16, methylated in tumor (MINT) 1, 2, 12, and 31 loci. K-ras codon 12 and 13 point mutations were also examined. The relationship between macroscopic appearance and CIMP status or K-ras mutations was analyzed. Results: Among adenomas larger than 1 cm, CpG island methylation involving 2 or more loci (CIMP-high) was more likely to be observed in G-LST (14/23, 61%) than in protruded-type adenomas (18/73, 25%) (P = .002). The prevalence of K-ras mutations in G-LST (18/23, 78%) was significantly higher than that in protruded-type adenomas (18/73, 25%) (P < .0001). Moreover, the prevalence of CIMP-high and K-ras mutations in G-LST located in the proximal colon was much higher (11/13, 85%; and 12/13, 92%, respectively). In contrast, F-LST exhibited low prevalence of CIMP-high (1/12, 8%) and K-ras mutations (2/12, 16%). Conclusions: High prevalence of CIMP-high and K-ras mutations in G-LST, especially in the proximal colon, could strongly suggest that G-LST appearance is associated with a unique carcinogenic pathway. Background & Aims: Laterally spreading tumors (LST), characterized by superficial extension along the colonic lumen, have recently been detected by colonoscopy. However, genetic and epigenetic characteristics of these tumors were scarcely reported. Methods: A total of 205 sporadic colorectal adenoma tissues (157 protruded-type, 23 granular-type LST (G-LST), 12 flat-type LST (F-LST), and 13 flat-type smaller than 1 cm) were collected. CpG island methylator phenotype (CIMP) was determined by examination of methylation status at p16, methylated in tumor (MINT) 1, 2, 12, and 31 loci. K-ras codon 12 and 13 point mutations were also examined. The relationship between macroscopic appearance and CIMP status or K-ras mutations was analyzed. Results: Among adenomas larger than 1 cm, CpG island methylation involving 2 or more loci (CIMP-high) was more likely to be observed in G-LST (14/23, 61%) than in protruded-type adenomas (18/73, 25%) (P = .002). The prevalence of K-ras mutations in G-LST (18/23, 78%) was significantly higher than that in protruded-type adenomas (18/73, 25%) (P < .0001). Moreover, the prevalence of CIMP-high and K-ras mutations in G-LST located in the proximal colon was much higher (11/13, 85%; and 12/13, 92%, respectively). In contrast, F-LST exhibited low prevalence of CIMP-high (1/12, 8%) and K-ras mutations (2/12, 16%). Conclusions: High prevalence of CIMP-high and K-ras mutations in G-LST, especially in the proximal colon, could strongly suggest that G-LST appearance is associated with a unique carcinogenic pathway. A part of colorectal adenomas is known to be precancerous lesions of most colorectal cancers (CRC). Although the macroscopic appearance of adenomas varies, only protruded-type polyps, with or without stalks, have mainly been recognized and discussed. Recently, however, adenomas with other morphologies, including flat-type, depressed-type, and laterally spreading-type tumors, have been identified along with the progress of colonoscopy.1Kudo S. Kashida H. Nakajima T. Tamura S. Nakajo K. Endoscopic diagnosis and treatment of early colorectal cancer.World J Surg. 1997; 21: 694-701Google Scholar Although these types of tumors were initially recognized only in Japan, they have also been detected and accepted in Western countries in recent years.2Saitoh Y. Waxman I. West A.B. Popnikolov N.K. Gatalica Z. Watari J. Obara T. Kohgo Y. Pasricha P.J. Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population.Gastroenterology. 2001; 120: 1657-1665Google Scholar, 3Hurlstone D.P. Sanders D.S. Cross S.S. Adam I. Shorthouse A.J. Brown S. Drew K. Lobo A.J. Colonoscopic resection of lateral spreading tumours a prospective analysis of endoscopic mucosal resection.Gut. 2004; 53: 1334-1339Google Scholar Laterally spreading tumors (LST), which are characterized by lateral extension along the luminal wall with a low vertical axis, were initially reported by Kudo et al.1Kudo S. Kashida H. Nakajima T. Tamura S. Nakajo K. Endoscopic diagnosis and treatment of early colorectal cancer.World J Surg. 1997; 21: 694-701Google Scholar A previous report indicated that LST were found in approximately 6% of early stage CRC.4Kudo S. Endoscopic mucosal resection of flat and depressed type of early colorectal cancer.Endoscopy. 1993; 25: 455-461Google Scholar In addition, LST have usually been categorized into 2 types: granular-type (G-LST) and flat- or nongranular-type (F-LST). G-LST were reported as composed of superficially spreading aggregates of nodules, forming a flat, broad-based lesion with a granulonodular and uneven surface.3Hurlstone D.P. Sanders D.S. Cross S.S. Adam I. Shorthouse A.J. Brown S. Drew K. Lobo A.J. Colonoscopic resection of lateral spreading tumours a prospective analysis of endoscopic mucosal resection.Gut. 2004; 53: 1334-1339Google Scholar In contrast, F-LST were defined as lesions with a flat smooth surface and the absence of granulonodular formation.3Hurlstone D.P. Sanders D.S. Cross S.S. Adam I. Shorthouse A.J. Brown S. Drew K. Lobo A.J. Colonoscopic resection of lateral spreading tumours a prospective analysis of endoscopic mucosal resection.Gut. 2004; 53: 1334-1339Google Scholar F-LST were therefore also designated as flat-type adenomas.5Sawada T. Hojo K. Moriya Y. Colonoscopic management of focal and early colorectal carcinoma.Baillieres Clin Gastroenterol. 1989; 3: 627-645Google Scholar, 6Ajioka Y. Watanabe H. Kazama S. Hashidate H. Yokoyama J. Yamada S. Takaku H. Nishikura K. Early colorectal cancer with special reference to the superficial nonpolypoid type from a histopathologic point of view.World J Surg. 2000; 24: 1075-1080Google Scholar LST were considered to be less invasive because neoplastic cells tended to spread along the surface of the lumen and because these tumors were likely to be found in the stage of adenoma or early stage cancer. However, few studies have been reported regarding the clinical or biologic characteristics and molecular background of these tumors. Moreover, the relationship between the macroscopic appearance of adenomas and the genetic or epigenetic changes that occur in tumors have also been scarcely reported. Recently, epigenetic changes, including DNA methylation, have been recognized to play an important role in carcinogenesis in addition to genetic changes. DNA methylation is a covalent chemical modification, resulting in the addition of a methyl (CH3) group at the C5-position of cytosine in the sequence context 5′-CG-3′. This epigenetic effect is particularly striking when DNA methylation affects promoter CpG islands. Methylation of cytosines within CpG islands is associated with the loss of protein expression by repression of transcription. Therefore, gene hypermethylation is associated with the silencing of tumor suppressor genes in cancer.7Baylin S.B. Herman J.G. Graff J.R. Vertino P.M. Issa J.P. Alterations in DNA methylation a fundamental aspect of neoplasia.Adv Cancer Res. 1998; 72: 141-196Google Scholar On the other hand, it has also been reported that global hypomethylation of genes is linked to genomic instability and increased mutation rates.8Feinberg A.P. Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts.Nature. 1983; 301: 89-92Google Scholar Therefore, gene hypomethylation is considered to be related with other types of carcinogenesis. In this context, the idea of CpG island methylator phenotype (CIMP) has been proposed in colon carcinogenesis.9Toyota M. Ahuja N. Ohe-Toyota M. Herman J.G. Baylin S.B. Issa J.P. CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci U S A. 1999; 96: 8681-8686Google Scholar Toyota et al9Toyota M. Ahuja N. Ohe-Toyota M. Herman J.G. Baylin S.B. Issa J.P. CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci U S A. 1999; 96: 8681-8686Google Scholar classified CRCs according to the frequency of CpG island methylation into CIMP-high and CIMP-low. CIMP-high CRC, which is characterized by a high frequency of CpG island methylation, were more likely to be observed in elderly patients,10Hawkins N. Norrie M. Cheong K. Mokany E. Ku S.L. Meagher A. O’Connor T. Ward R. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Google Scholar, 11Samowitz W.S. Albertsen H. Herrick J. Levin T.R. Sweeney C. Murtaugh M.A. Wolff R.K. Slattery M.L. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer.Gastroenterology. 2005; 129: 837-845Abstract Full Text Full Text PDF Scopus (485) Google Scholar women,10Hawkins N. Norrie M. Cheong K. Mokany E. Ku S.L. Meagher A. O’Connor T. Ward R. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Google Scholar and proximal colon9Toyota M. Ahuja N. Ohe-Toyota M. Herman J.G. Baylin S.B. Issa J.P. CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci U S A. 1999; 96: 8681-8686Google Scholar, 10Hawkins N. Norrie M. Cheong K. Mokany E. Ku S.L. Meagher A. O’Connor T. Ward R. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Google Scholar, 11Samowitz W.S. Albertsen H. Herrick J. Levin T.R. Sweeney C. Murtaugh M.A. Wolff R.K. Slattery M.L. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer.Gastroenterology. 2005; 129: 837-845Abstract Full Text Full Text PDF Scopus (485) Google Scholar compared with CIMP-low CRC. In cases of adenoma, most serrated adenomas exhibit CIMP-high.12Park S.J. Rashid A. Lee J.H. Kim S.G. Hamilton S.R. Wu T.T. Frequent CpG island methylation in serrated adenomas of the colorectum.Am J Pathol. 2003; 162: 815-822Google Scholar, 13Kambara T. Simms L.A. Whitehall V.L. Spring K.J. Wynter C.V. Walsh M.D. Barker M.A. Arnold S. McGivern A. Matsubara N. Tanaka N. Higuchi T. Young J. Jass J.R. Laggett B.A. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.Gut. 2004; 53: 1137-1144Google Scholar, 14Konishi K. Yamochi T. Makino R. Kaneko K. Yamamoto T. Nozawa H. Katagiri A. Ito H. Nakayama K. Ota H. Mitamura K. Imawari M. Molecular differences between sporadic serrated and conventional colorectal adenomas.Clin Cancer Res. 2004; 10: 3082-3090Google Scholar In addition, a previous report indicated that the CIMP-high phenotype in conventional adenomas (except serrated adenomas) was associated with large size15Toyota M. Ohe-Toyota M. Ahuja N. Issa J.P. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype.Proc Natl Acad Sci U S A. 2000; 97: 710-715Google Scholar, 16Rashid A. Shen L. Morris J.S. Issa J.P. Hamilton S.R. CpG island methylation in colorectal adenomas.Am J Pathol. 2001; 159: 1129-1135Google Scholar and a villous component.16Rashid A. Shen L. Morris J.S. Issa J.P. Hamilton S.R. CpG island methylation in colorectal adenomas.Am J Pathol. 2001; 159: 1129-1135Google Scholar However, no report has appeared regarding the relationship between CIMP and the detailed macroscopic appearance of adenomas. Accordingly, in this study, the CIMP status of a large number of adenomas was determined. We focused on the differences in CIMP status observed with variations in macroscopic appearance, especially between LST and conventional protruded adenomas. Moreover, K-ras mutations, both in LST and conventional adenomas, were examined and analyzed in conjunction with the methylation phenotypes. Colorectal adenoma tissues were collected from individuals who underwent endoscopic or surgical resection of colorectal polyps at Okayama University Hospital and affiliated hospitals in the period from June 2003 to November 2004. A total of 205 adenomas from 134 patients were collected and examined. Adenomas with each macroscopic appearance (protruded, G-LST, F-LST, and small flat-type) were collected consecutively. Tissues from patients with inflammatory bowel disease or a known history of familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer were excluded from this analysis. Clinical information of patients including age, gender, smoking habits, and alcohol consumption was obtained. Smokers were defined as those with a lifetime exposure of approximately 100 cigarettes or more.17Toyooka S. Maruyama R. Toyooka K.O. McLerran D. Feng Z. Fukuyama Y. Virmani A.K. Zochbauer-Muller S. Tsukuda K. Sugio K. Shimizu N. Shimizu K. Lee H. Chen C.Y. Fong K.M. Gilcrease M. Roth J.A. Minna J.D. Gazdar A.F. Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer.Int J Cancer. 2003; 103: 153-160Google Scholar Alcohol drinkers were defined as those with an alcohol consumption in excess of approximately 20 g per day. At the time of resection, the location, size, and macroscopic appearance of the adenomas were determined. Adenoma locations were classified into 2 groups: proximal, defined as the cecum, ascending, and transverse colon; and distal, defined as the descending, sigmoid colon, and rectum. Adenoma size was recorded as the maximum diameter of the extirpated specimen. In addition to the adenoma samples, normal colorectal mucosa samples from 50 patients with adenomas and 30 sporadic CRC tissue samples from patients who underwent surgical treatment at Okayama University were also collected and analyzed. Normal colon mucosa and peripheral blood from healthy volunteers (20–30-year-old individuals without cancer and adenomas) were obtained and used as an unmethylated control in the methylation analyses. A small tissue fragment was excised from resected neoplasia for DNA extraction, and the remaining portion was submitted for histologic diagnosis. Samples were stored at −80°C prior to beginning the analysis. This study protocol was approved by the institutional review board of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, and informed consent was obtained from each patient. Histologic studies were performed on all removed adenomas. The resected adenomas were fixed and embedded in paraffin. Serial sections were obtained and stained with H&E. All cases were reviewed by 2 board-certificated pathologists and were classified as tubular, tubulovillous, or villous adenomas. Hyperplastic polyps and serrated adenomas were not included in this analysis. We classified the macroscopic appearance of adenomas, based on colonoscopy observations, into conventional protruded-type, G-LST, F-LST, and small flat-type. G-LST and F-LST were defined based on the description of Hurlstone et al.3Hurlstone D.P. Sanders D.S. Cross S.S. Adam I. Shorthouse A.J. Brown S. Drew K. Lobo A.J. Colonoscopic resection of lateral spreading tumours a prospective analysis of endoscopic mucosal resection.Gut. 2004; 53: 1334-1339Google Scholar In brief, both G-LST and F-LST were characterized by a size in excess of 10 mm in diameter, a low vertical axis, and lateral extension along the luminal wall. G-LST was composed of superficially spreading aggregates of nodules forming a flat-based lesion with a granulonodular and uneven surface (Figure 1A). F-LST has a flat smooth surface, with an absence of granulonodular formation (Figure 1B). The small flat-type was defined as a flat adenoma, based on the description of Kudo et al,1Kudo S. Kashida H. Nakajima T. Tamura S. Nakajo K. Endoscopic diagnosis and treatment of early colorectal cancer.World J Surg. 1997; 21: 694-701Google Scholar with a size less than 10 mm. In general, the dysplastic mucosal thickness of F-LST and small flat-type adenomas do not exceed twice the thickness of adjacent nonneoplastic mucosa, and this definition is consistent with the description of flat-type adenoma in previous studies.18Yashiro M. Carethers J.M. Laghi L. Saito K. Slezak P. Jaramillo E. Rubio C. Koizumi K. Hirakawa K. Boland C.R. Genetic pathways in the evolution of morphologically distinct colorectal neoplasms.Cancer Res. 2001; 61: 2676-2683Google Scholar, 19Sakamoto N. Terai T. Ajioka Y. Abe S. Kobayasi O. Hirai S. Hino O. Watanabe H. Sato N. Shimoda T. Fujii H. Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors.Oncogene. 2004; 23: 8900-8907Google Scholar Meanwhile, the height of a part of the nodules of G-LST can be more than twice the thickness of adjacent nonneoplastic mucosa. Adenomas forming protruded morphologies, other than LST or small flat-type, were designated as conventional protruded-type adenomas. Genomic DNA was extracted from neoplastic and nonneoplastic tissues using a QIAmp DNA mini kit (Qiagen, Hilden, Germany). Bisulfite modification of DNA was performed using an EZ DNA Methylation Kit (ZYMO Research, Orange, CA), according to the manufacturer’s instructions. The methylation status of p16 and MINT1 (methylated in tumor 1), MINT2, MINT12, MINT31, and hMLH1 mismatch repair gene was determined by methylation-specific polymerase chain reaction (PCR) as described previously.10Hawkins N. Norrie M. Cheong K. Mokany E. Ku S.L. Meagher A. O’Connor T. Ward R. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Google Scholar, 12Park S.J. Rashid A. Lee J.H. Kim S.G. Hamilton S.R. Wu T.T. Frequent CpG island methylation in serrated adenomas of the colorectum.Am J Pathol. 2003; 162: 815-822Google Scholar, 15Toyota M. Ohe-Toyota M. Ahuja N. Issa J.P. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype.Proc Natl Acad Sci U S A. 2000; 97: 710-715Google Scholar, 20Lee S. Kim W.H. Jung H.Y. Yang M.H. Kang G.H. Aberrant CpG island methylation of multiple genes in intrahepatic cholangiocarcinoma.Am J Pathol. 2002; 161: 1015-1022Google Scholar, 21Herman J.G. Graff J.R. Myohanen S. Nelkin B.D. Baylin S.B. Methylation-specific PCR a novel PCR assay for methylation status of CpG islands.Proc Natl Acad Sci U S A. 1996; 93: 9821-9826Google Scholar In brief, approximately 50 ng of bisulfite-treated DNA was used as a template for PCR, using primers specific for methylated and unmethylated alleles. Analysis of p16 was performed as previously described with primers using touchdown PCR for 35 cycles.10Hawkins N. Norrie M. Cheong K. Mokany E. Ku S.L. Meagher A. O’Connor T. Ward R. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Google Scholar For MINT 1, 2, 12, and 31 and hMLH1, the primers used in this study were described in previous studies,12Park S.J. Rashid A. Lee J.H. Kim S.G. Hamilton S.R. Wu T.T. Frequent CpG island methylation in serrated adenomas of the colorectum.Am J Pathol. 2003; 162: 815-822Google Scholar, 20Lee S. Kim W.H. Jung H.Y. Yang M.H. Kang G.H. Aberrant CpG island methylation of multiple genes in intrahepatic cholangiocarcinoma.Am J Pathol. 2002; 161: 1015-1022Google Scholar and PCR reactions with annealing temperature of 53°C–65°C were performed for 35 cycles. These MINT loci (MINT 1, 2, 12, 31) have been reported to be the sites preferentially methylated within the genome of CRC.9Toyota M. Ahuja N. Ohe-Toyota M. Herman J.G. Baylin S.B. Issa J.P. CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci U S A. 1999; 96: 8681-8686Google Scholar, 15Toyota M. Ohe-Toyota M. Ahuja N. Issa J.P. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype.Proc Natl Acad Sci U S A. 2000; 97: 710-715Google Scholar The primers toward hMLH1 were designed for the sequences from −268 to −200 (relative to the transcription start site) of the promoter region,11Samowitz W.S. Albertsen H. Herrick J. Levin T.R. Sweeney C. Murtaugh M.A. Wolff R.K. Slattery M.L. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer.Gastroenterology. 2005; 129: 837-845Abstract Full Text Full Text PDF Scopus (485) Google Scholar, 12Park S.J. Rashid A. Lee J.H. Kim S.G. Hamilton S.R. Wu T.T. Frequent CpG island methylation in serrated adenomas of the colorectum.Am J Pathol. 2003; 162: 815-822Google Scholar methylation of which could induce the loss of hMLH1 protein expression.22Miyakura Y. Sugano K. Konishi F. Ichikawa A. Maekawa M. Shitoh K. Igarashi S. Kotake K. Koyama Y. Nagai H. Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability.Gastroenterology. 2001; 121: 1300-1309Abstract Full Text Full Text PDF Scopus (167) Google Scholar Each PCR run included separate reactions with template from a colorectal cancer cell line RKO (American Type Culture Collection, Manassas, VA) as the methylated control and from normal colon mucosa and peripheral blood lymphocytes of healthy individuals as the unmethylated control, as well as controls with no template. After amplification, PCR products were electrophoresed on 3% agarose gels and visualized under ultraviolet light by staining with ethidium bromide. The loci were classified as unmethylated if the intensity of methylated band was <5% of the unmethylated band or methylated if the intensity of the methylated band was ≥5% of the unmethylated band.15Toyota M. Ohe-Toyota M. Ahuja N. Issa J.P. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype.Proc Natl Acad Sci U S A. 2000; 97: 710-715Google Scholar The CIMP status of adenomas was determined based on results from 5 or more evaluated loci. Adenomas were classified as CIMP-low if 1 or none of the evaluated loci were methylated and as CIMP-high if 2 or more loci were methylated out of 5 sites excluding hMLH1 in accordance with the previous reports.10Hawkins N. Norrie M. Cheong K. Mokany E. Ku S.L. Meagher A. O’Connor T. Ward R. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Google Scholar, 11Samowitz W.S. Albertsen H. Herrick J. Levin T.R. Sweeney C. Murtaugh M.A. Wolff R.K. Slattery M.L. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer.Gastroenterology. 2005; 129: 837-845Abstract Full Text Full Text PDF Scopus (485) Google Scholar For another evaluation of CIMP, 46 adenomas determined to be CIMP-high with methylation-specific PCR (MSP) were also analyzed using combined bisulfite restriction analysis (COBRA). The COBRA of p16 and MINT1, 2, 12, and 31 were determined using primers, restriction enzymes, and conditions as previously described.10Hawkins N. Norrie M. Cheong K. Mokany E. Ku S.L. Meagher A. O’Connor T. Ward R. CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Google Scholar, 16Rashid A. Shen L. Morris J.S. Issa J.P. Hamilton S.R. CpG island methylation in colorectal adenomas.Am J Pathol. 2001; 159: 1129-1135Google Scholar In brief, bisulfite-treated DNA was amplified by PCR, and the PCR products were incubated with restriction enzymes that digest only methylated alleles. Digested samples were electrophoresed on 6% polyacrylamide gels and visualized under ultraviolet light by staining with ethidium bromide. Any sample showing ≥5% methylation was considered positive.15Toyota M. Ohe-Toyota M. Ahuja N. Issa J.P. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype.Proc Natl Acad Sci U S A. 2000; 97: 710-715Google Scholar Positive and negative controls were determined with the same samples of MSP. Also in this analysis, we classified tumors as CIMP-high if 2 or more loci were methylated out of 5 sites. K-ras codons 12 and 13 point mutations were detected by direct sequencing. The following primers were used for the sequencing reactions: 5′-GCCTGCTGAAAATGACTGAAT-3′ (forward) and 5′-GACCATTCTTTGATACAGATAA-3′ (reverse). DNA sequencing was performed on an ABI Genetic Analyzer 3100, using the BigDye 3.1 cycle sequencing technology (ABI, Foster City, CA). Categorical variables were compared using the χ2 test or the Fisher exact test as appropriate. For analysis of concordance in methylation between the different loci, the method of Pearson correlation coefficient was performed. To identify factors contributing to CIMP-high, multivariate analysis was performed using a logistic regression model with corresponding calculation of odds ratios (ORs) and 95% confidence intervals (CIs). These analyses were performed using the SAS program (version 9.1 SAS Institute, Cary, NC). All P values were 2-sided and considered significant when less than .05. We evaluated 205 colorectal adenomas derived from 134 patients. Clinicopathologic characteristics of patients and adenomas are depicted in Table 1. Patients consisted of 43 (32%) women and 91 (68%) men, with a median age of 66 years (range, 31–88 years). Of these patients, 71 (53%) were alcohol drinkers, and 68 (51%) were smokers. In 36 (27%) patients, 2 or more polyps were simultaneously resected and analyzed.Table 1Clinicopathologic Characteristics of Patients and AdenomasCharacteristicsNo. (%) of patients (N = 134)No. (%) of adenomas (N = 205)Gender Female43 (32)56 (27) Male91 (68)149 (73)Age, median (range)66 (31–88)66 (31–88)Alcohol use Occasionally or none63 (47)82 (40) Drinker71 (53)123 (60)Tobacco exposure None66 (49)100 (49) Smoker68 (51)105 (51)Number of adenomas analyzed from each patient (range, 1–9; median, 2) 198 (73)98 (48) 221 (16)42 (20) 37 (5)21 (10) >48 (6)44 (21)LocationaTotal percentage for patients exceeds 100% because of multiple adenomas. Proximal73 (54)99 (48) Distal79 (59)106 (52)SizeaTotal percentage for patients exceeds 100% because of multiple adenomas. <1 cm68 (51)97 (47) 1–2 cm60 (45)71 (35) ≥2 cm35 (26)37 (18)Macroscopic appearanceaTotal percentage for patients exceeds 100% because of multiple adenomas. Protruded-type98 (73)157 (77) G-LST22 (16)23 (11) F-LST12 (9)12 (6) Small flat-type11 (8)13 (6)HistopathologyaTotal percentage for patients exceeds 100% because of multiple adenomas. Tubular106 (79)161 (79) Tubulovillous35 (26)44 (21)G-LST, granular-type laterally spreading tumors; F-LST, flat-type laterally spreading tumors.a Total percentage for patients exceeds 100% because of multiple adenomas. Open table in a new tab G-LST, granular-type laterally spreading tumors; F-LST, flat-type laterally spreading tumors. Of these 205 adenomas, 149 (73%) were derived from men, 123 (60%) were from alcohol drinkers, and 105 (51%) were from smokers. Ninety-nine (48%) adenomas were located in the proximal colon, whereas 106 (52%) were in the distal colon. More than half (108, 53%) of the adenomas were larger than 1 cm in diameter, including 37 (18%) adenomas with a size in excess of 2 cm. Regarding macroscopic appearance, 157 (77%) were categorized as protruded-type, 23 (11%) as G-LST, 12 (6%) as F-LST, and 13 (6%) as small flat-type adenomas. Histologic examinations revealed that 161 (79%) were tubular adenomas, and 44 (21%) were tubulovillous adenomas. The methylation status of 6 CpG islands, including p16, MINT1, 2, 12, and 31, and hMLH1, was examined by MSP. Typical results of PCR analysis of bisulfite-treated DNA for methylation are shown in Figure 2. The frequency of methylation for each locus in 205 adenomas, 30 cancers, and 50 normal mucosa from patients with adenomas is shown (Table 2). Methylation was detected in 12% to 16% of the adenomas and in 30% to 40% of the cancers at the p16 and MINT1, 2, and 31 loci. The proportions of neoplasia methylated at the MINT12 locus were relatively high (28% of adenomas and 57% of cancers). In contrast, neoplasia methylated at the hMLH1 promoter region was found in only 2 cases of cancer (7%) and 1 case of adenomas (.5%). Methylation was not observed at any locus examined in normal mucosal samples, except for 1 sample at MINT12 and 2 samples at MINT31. When we analyzed the statistical concordance in methylation correlations between the different loci using Pearson correlation coefficient, positive correlations were observed between most combinations of loci. However, highly significant correlations did not exist among any combination (maximum, r = .29, between p16 and MINT31).Table 2Frequency of Methylation in Colorectal Adenomas, Cancers, and Normal Colonic MucosaGene lociNumber (%) of methylated samplesAdenoma (n = 205)Cancer (n = 30)Normal mucosa of patients with adenoma (n = 50)p1633 (16)10 (33)0 (0)MINT125 (12)9 (30)0 (0)MINT233 (16)10 (33)0 (0)MINT1257 (28)17 (57)1 (2)MINT3132 (16)12 (40)2 (4)hMLH11 (.5)2 (7)0 (0) Open table in a new tab The distribution of adenomas according to the number of methylated CpG islands out of the 5 loci examined, excluding the hMLH1 promoter region, is presented because the frequency of methylation at the hMLH1 promoter region was extremely low compared with other loci. None of the evaluated loci were methylated in 104 (51%) adenomas. The number of adenomas decreased as the number of methylated loci increased (1 locus/55 ade" @default.
• W2095587247 created "2016-06-24" @default.
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• W2095587247 date "2006-08-01" @default.
• W2095587247 modified "2023-09-30" @default.
• W2095587247 title "Laterally Spreading Type of Colorectal Adenoma Exhibits a Unique Methylation Phenotype and K-ras Mutations" @default.
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