JC Virus T-Antigen Is Associated with p53 Expression, Chromosomal Instability and LINE-1 Hypomethylation in Colorectal Cancer
K Nosho, K Shima, S Kure, N Irahara, Y Baba, L Chen, GJ Kirkner, CS Fuchs, S Ogino. Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; Brigham and Women's Hospital, Boston, MA; Harvard School of Public Health, Boston, MA
Background: JC virus has a gene encoding JC virus T-antigen (JCVT). JCVT may inactivate wild-type p53, cause chromosomal instability (CIN), and stabilize b-catenin. JCVT has been implicated in carcinogenesis in a number of human organs. A link between JCVT and the CpG island methylator phenotype (CIMP) has been suggested in colorectal cancer. However, no study has comprehensively examined the relations of JCVT with various molecular alterations and clinical outcome in a large number of colorectal cancers.
Design: We detected JCVT expression (by immunohistochemistry) in 271 (35%) of 766 colorectal cancers. Using MethyLight, we quantified DNA methylation in 8 CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, SOCS1) and 8 other CpG islands. We examined loss of heterozygosity (LOH) in 2p, 5q, 17q and 18q, and measured LINE-1 methylation by Pyrosequencing. Multivariate logistic regression analysis assessed independent association of each variable with JCVT. Cox regression models computed hazard ratio for cancer-specific and overall mortalities according to JCVT status, adjusted for patient and other molecular characteristics.
Results: In univariate analysis, JCVT was significantly associated with p53 expression (p<0.0001), p21 loss (p<0.0001), CIN (p<0.0001), nuclear b-catenin (p=0.006), LINE-1 hypomethylation (p=0.002), and inversely with CIMP (p=0.0005) and MSI (p<0.0001). In multivariate logistic regression analysis, p53+ [adjusted odds ratio (OR)=8.45; 95% confidence interval (CI), 5.72-12.5; p<0.0001] and CIN (adjusted OR=2.53; 95% CI, 1.38-4.62; p=0.003) remained highly significant. Cyclin D1 expression (adjusted OR=1.57; p=0.02), LINE-1 hypomethylation (adjusted OR=1.97 for a 30% decline as a unit; p=0.03), BRAF mutation (adjusted OR=2.20; p=0.04) and family history of colorectal cancer (adjusted OR=0.64; p=0.04) were also significantly associated with JCVT. In contrast, JCVT was not significantly associated with CIMP, MSI, -catenin or patient survival in multivariate analyses.
Conclusions: JCVT expression in colorectal cancer is associated with p53 expression (surrogate of p53 mutation), CIN and LINE-1 hypomethylation, all of which are key events in colorectal carcinogenesis.
Monday, March 9, 2009 1:00 PM
Poster Session II # 74, Monday Afternoon