Abstract
JC virus has a transforming gene encoding JC virus T-antigen (JCVT). JCVT may inactivate wild-type p53, cause chromosomal instability (CIN), and stabilize β-catenin. A link between JCVT and CpG island methylator phenotype (CIMP) has been suggested. However, no large-scale study has examined the relations of JCVT with molecular alterations, clinical outcome, or prognosis in colon cancer. We detected JCVT expression (by immunohistochemistry) in 271 (35%) of 766 colorectal cancers. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other loci (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, WRN) by MethyLight. We examined loss of heterozygosity in 2p, 5q, 17q, and 18q. JCVT was significantly associated with p53 expression (P < .0001), p21 loss (P < .0001), CIN (≥2 chromosomal segments with LOH; P < .0001), nuclear β-catenin (P = .006), LINE-1 hypomethylation (P = .002), and inversely with CIMP-high (P = .0005) and microsatellite instability (MSI) (P < .0001), but not with PIK3CA mutation. In multivariate logistic regression analysis, the associations of JCVT with p53 [adjusted odds ratio (OR), 8.45; P < .0001], CIN (adjusted OR, 2.53; P = .003), cyclin D1 (adjusted OR, 1.57; P = .02), LINE-1 hypomethylation (adjusted OR, 1.97 for a 30% decline as a unit; P = .03), BRAF mutation (adjusted OR, 2.20; P = .04), and family history of colorectal cancer (adjusted OR, 0.64; P = .04) remained statistically significant. However, JCVT was no longer significantly associated with CIMP, MSI, β-catenin, or cyclooxygenase-2 expression in multivariate analysis. JCVT was unrelated with patient survival. In conclusion, JCVT expression in colorectal cancer is independently associated with p53 expression and CIN, which may lead to uncontrolled cell proliferation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 87-95 |
| Number of pages | 9 |
| Journal | Neoplasia |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2009 |
| Externally published | Yes |
Bibliographical note
Funding Information:Abbreviations: BMI, body mass index; CI, confidence interval; CIMP, CpG island methylator phenotype; CIN, chromosomal instability; COX-2, cyclooxygenase-2 (PTGS2); HR, hazard ratio; JCVT, JC virus T-antigen; LINE-1, long interspersed nucleotide element 1; LOH, loss of heterozygosity; MSI, microsatellite instability; MSS, microsatellite stable; OR, odds ratio Address all correspondence to: Shuji Ogino, MD, PhD, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, 44 Binney St, Room JF-215C, Boston, MA 02115. E-mail: shuji_ogino@dfci.harvard.edu 1This work was supported by US National Institutes of Health (NIH) grants P01 CA87969, P01 CA55075, P50 CA127003, and K07 CA122826 (to S.O.) and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. K.N. was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 2K.N., K.S., and S.K. contributed equally. Received 17 September 2008; Revised 16 October 2008; Accepted 16 October 2008 Copyright © 2009 Neoplasia Press, Inc. All rights reserved 1522-8002/09/$25.00 DOI 10.1593/neo.81188
