Viruses are established, causal factors in 15%-20% of human cancers and are widely suspected to be involved in more. The long-range goals of this project are to develop methods to simultaneously screen tumor and other tissue samples for the genomes or partial genomes of many viruses, to use these methods to test for novel virus-cancer associations, and to determine their statistical and clinical significance. In particular, this highly collaborative proposal describes how a new, uniquely flexible, maskless photolithography technology will be used to produce and refine high density oligonucleotide microarrays able to sensitively detect all genes or transcripts of all known human tumor viruses. For comparison, arrays of PCR-amplified viral probes spotted on glass slides will also be tested. Additional experiments will systematically optimize extraction and amplification methods for specific, sensitive, and robust detection of viral RNA and DNA sequences at low copy number in clinical tissue samples. The resulting tools and methodology will be applied to relevant clinical samples to test and resolve the emerging connections of two well- characterized human tumor viruses, human papilloamavirus (HPV) and Epstein- Barr virus (EBV), with oral cancers and breast cancers, respectively, and to compare the microarray results with other state-of-the-art virus detection methods applied to the same tissue samples. These studies will provide proof- of-principle tests of microarray use in detecting and characterizing viral contributions to cancer and address significant, current issues in the viral etiology of specific tumors. Simultaneous microarray screening for many viruses o viral genotypes amplifies the power of etiologic and diagnostic studies on precious tissue samples, offers the potential to discover unsuspected virus-cancer links, and allows profiling expression of viral and selected cell genes to provide the molecular signatures of a tumor and to evaluate the potential contribution of the virus to that tumor. The methods developed also will be applicable to probe for virus involvement in other chronic or acute disorders.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097944-03
Application #
6745626
Study Section
Special Emphasis Panel (ZAI1-GLM-M (J1))
Program Officer
Wong, May
Project Start
2002-05-01
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
3
Fiscal Year
2004
Total Cost
$354,195
Indirect Cost
Name
University of Wisconsin Madison
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Sengupta, Srikumar; den Boon, Johan A; Chen, I-How et al. (2008) MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci U S A 105:5874-8
Pyeon, Dohun; Newton, Michael A; Lambert, Paul F et al. (2007) Fundamental differences in cell cycle deregulation in human papillomavirus-positive and human papillomavirus-negative head/neck and cervical cancers. Cancer Res 67:4605-19
Dodd, Lori E; Sengupta, Srikumar; Chen, I-How et al. (2006) Genes involved in DNA repair and nitrosamine metabolism and those located on chromosome 14q32 are dysregulated in nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 15:2216-25
Sengupta, Srikumar; den Boon, Johan A; Chen, I-How et al. (2006) Genome-wide expression profiling reveals EBV-associated inhibition of MHC class I expression in nasopharyngeal carcinoma. Cancer Res 66:7999-8006
Perrigoue, Jacqueline G; den Boon, Johan A; Friedl, Andreas et al. (2005) Lack of association between EBV and breast carcinoma. Cancer Epidemiol Biomarkers Prev 14:809-14
Newton, Michael A; Noueiry, Amine; Sarkar, Deepayan et al. (2004) Detecting differential gene expression with a semiparametric hierarchical mixture method. Biostatistics 5:155-76