JC virus T-antigen in colorectal cancer is associated with p53 expression and chromosomal instability, independent of CpG island methylator phenotype.
JC virus has a transforming gene encoding JC virus T-antigen (JCVT). JCVT may inactivate wild-type p53, cause chromosomal instability (CIN), and stabilize beta-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 beta-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, beta-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.
Nosho
Katsuhiko
K
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Shima
Kaori
K
Kure
Shoko
S
Irahara
Natsumi
N
Baba
Yoshifumi
Y
Chen
Li
L
Kirkner
Gregory J
GJ
Fuchs
Charles S
CS
Ogino
Shuji
S
D000328:Adult; D000368:Aged; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000502:physiology*; D002277:Carcinoma / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics / Q000502:physiology*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000502:physiology; D015257:DNA-Cytosine Methylases / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D008040:Genetic Linkage; D006801:Humans; D007577:JC Virus / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D000957:Antigens, Viral, Tumor; C081573:DNA modification methylase SssI; D015257:DNA-Cytosine Methylases