BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP) is one of the mechanisms involved in colorectal carcinogenesis (CRC). Although CIMP is probably the cause of high-frequency microsatellite instability (MSI-H) sporadic CRCs, its role in microsatellite stable (MSS) tumors is debated. The majority of MSS CRCs demonstrate chromosomal instability (CIN) with frequent loss of heterozygosity (LOH) at key tumor suppressor genes. We hypothesized that the majority of sporadic CRCs without CIN would be associated with CIMP. METHODS: We tested 126 sporadic CRCs for MSI and LOH and categorized tumors into MSI, LOH, or MSI-/LOH- subgroups. Methylation status was evaluated using 6 CIMP-related markers (MINT1, MINT2, MINT31, p16(INK4alpha), p14(ARF), and hMLH1) and 6 tumor suppressor genes (PTEN, TIMP3, RUNX3, HIC1, APC, and RARbeta2). BRAF V600E mutation analysis was performed using allele-specific polymerase chain reaction and DNA sequencing. RESULTS: We observed frequent methylation at all 12 loci in all CRCs. BRAF V600E mutations correlated with the MSI (P < .0001) and MSI-/LOH- (P = .03) subgroups. MSI and MSI-/LOH- tumors exhibited more promoter methylation than CRCs with LOH (P < .0001). We also found an inverse correlation between the frequencies of methylation and LOH (rho = -0.36; P < .0001). CONCLUSIONS: The associations between methylation frequencies at CIMP-related markers and MSI or MSI-/LOH- sporadic CRCs suggest that the majority of these tumors evolve through CIMP. These findings suggest that CIN and CIMP represent 2 independent and inversely related mechanisms of genetic and epigenetic instability in sporadic CRCs and confirm that MSI cancers arise as a consequence of CIMP.
BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP) is one of the mechanisms involved in colorectal carcinogenesis (CRC). Although CIMP is probably the cause of high-frequency microsatellite instability (MSI-H) sporadic CRCs, its role in microsatellite stable (MSS) tumors is debated. The majority of MSS CRCs demonstrate chromosomal instability (CIN) with frequent loss of heterozygosity (LOH) at key tumor suppressor genes. We hypothesized that the majority of sporadic CRCs without CIN would be associated with CIMP. METHODS: We tested 126 sporadic CRCs for MSI and LOH and categorized tumors into MSI, LOH, or MSI-/LOH- subgroups. Methylation status was evaluated using 6 CIMP-related markers (MINT1, MINT2, MINT31, p16(INK4alpha), p14(ARF), and hMLH1) and 6 tumor suppressor genes (PTEN, TIMP3, RUNX3, HIC1, APC, and RARbeta2). BRAFV600E mutation analysis was performed using allele-specific polymerase chain reaction and DNA sequencing. RESULTS: We observed frequent methylation at all 12 loci in all CRCs. BRAFV600E mutations correlated with the MSI (P < .0001) and MSI-/LOH- (P = .03) subgroups. MSI and MSI-/LOH- tumors exhibited more promoter methylation than CRCs with LOH (P < .0001). We also found an inverse correlation between the frequencies of methylation and LOH (rho = -0.36; P < .0001). CONCLUSIONS: The associations between methylation frequencies at CIMP-related markers and MSI or MSI-/LOH- sporadic CRCs suggest that the majority of these tumors evolve through CIMP. These findings suggest that CIN and CIMP represent 2 independent and inversely related mechanisms of genetic and epigenetic instability in sporadic CRCs and confirm that MSI cancers arise as a consequence of CIMP.
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Authors: R Yahyapour; E Motevaseli; A Rezaeyan; H Abdollahi; B Farhood; M Cheki; S Rezapoor; D Shabeeb; A E Musa; M Najafi; V Villa Journal: Clin Transl Oncol Date: 2018-01-09 Impact factor: 3.405
Authors: Rodrigo Jover; Thuy-Phuong Nguyen; Lucía Pérez-Carbonell; Pedro Zapater; Artemio Payá; Cristina Alenda; Estefanía Rojas; Joaquín Cubiella; Francesc Balaguer; Juan D Morillas; Juan Clofent; Luis Bujanda; Josep M Reñé; Xavier Bessa; Rosa M Xicola; David Nicolás-Pérez; Antoni Castells; Montserrat Andreu; Xavier Llor; C Richard Boland; Ajay Goel Journal: Gastroenterology Date: 2010-12-24 Impact factor: 22.682
Authors: Noriko Tanaka; Curtis Huttenhower; Katsuhiko Nosho; Yoshifumi Baba; Kaori Shima; John Quackenbush; Kevin M Haigis; Edward Giovannucci; Charles S Fuchs; Shuji Ogino Journal: Am J Pathol Date: 2010-10-29 Impact factor: 4.307
Authors: Jinsheng Yu; Robert R Freimuth; Robert Culverhouse; Sharon Marsh; Mark A Watson; Howard L McLeod Journal: Oncol Rep Date: 2008-10 Impact factor: 3.906