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 β-catenin. A link between JCVT and CpG island methylator phenotype (CIMP) has been suggested. However, no large-scale study has examined the rela...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2009-01-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558609800924 |
| _version_ | 1811329012037844992 |
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| author | Katsuhiko Nosho Kaori Shima Shoko Kure Natsumi Irahara Yoshifumi Baba Li Chen Gregory J. Kirkner Charles S. Fuchs Shuji Ogino |
| author_facet | Katsuhiko Nosho Kaori Shima Shoko Kure Natsumi Irahara Yoshifumi Baba Li Chen Gregory J. Kirkner Charles S. Fuchs Shuji Ogino |
| author_sort | Katsuhiko Nosho |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T15:36:15Z |
| format | Article |
| id | doaj.art-1a79ce1524844c7fa133be6f64c3502a |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-13T15:36:15Z |
| publishDate | 2009-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-1a79ce1524844c7fa133be6f64c3502a2022-12-22T02:41:15ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022009-01-01111879510.1593/neo.81188JC Virus T-Antigen in Colorectal Cancer Is Associated with p53 Expression and Chromosomal Instability, Independent of CpG Island Methylator PhenotypeKatsuhiko Nosho0Kaori Shima1Shoko Kure2Natsumi Irahara3Yoshifumi Baba4Li Chen5Gregory J. Kirkner6Charles S. Fuchs7Shuji Ogino8Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USADepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USADepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USADepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USADepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USADepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USAChanning Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USADepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USADepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USAJC 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.http://www.sciencedirect.com/science/article/pii/S1476558609800924 |
| spellingShingle | Katsuhiko Nosho Kaori Shima Shoko Kure Natsumi Irahara Yoshifumi Baba Li Chen Gregory J. Kirkner Charles S. Fuchs Shuji Ogino JC Virus T-Antigen in Colorectal Cancer Is Associated with p53 Expression and Chromosomal Instability, Independent of CpG Island Methylator Phenotype Neoplasia: An International Journal for Oncology Research |
| title | JC Virus T-Antigen in Colorectal Cancer Is Associated with p53 Expression and Chromosomal Instability, Independent of CpG Island Methylator Phenotype |
| title_full | JC Virus T-Antigen in Colorectal Cancer Is Associated with p53 Expression and Chromosomal Instability, Independent of CpG Island Methylator Phenotype |
| title_fullStr | JC Virus T-Antigen in Colorectal Cancer Is Associated with p53 Expression and Chromosomal Instability, Independent of CpG Island Methylator Phenotype |
| title_full_unstemmed | JC Virus T-Antigen in Colorectal Cancer Is Associated with p53 Expression and Chromosomal Instability, Independent of CpG Island Methylator Phenotype |
| title_short | JC Virus T-Antigen in Colorectal Cancer Is Associated with p53 Expression and Chromosomal Instability, Independent of CpG Island Methylator Phenotype |
| title_sort | jc virus t antigen in colorectal cancer is associated with p53 expression and chromosomal instability independent of cpg island methylator phenotype |
| url | http://www.sciencedirect.com/science/article/pii/S1476558609800924 |
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