Sequential activation of oncogenes and inactivation of tumor suppressor and DNA repair genes causes human cancers. The activation and inactivation of these cancer genes can be mutations or epigenetic modification such as methylation of CpG islands and chromatin modification. My researches center on integrating biological knowledge, genome sequences, and high-throughput experiments to identify genes and genetics elements that are important for the cancer development. Bioinformatics approach to cancer epigenetics. 1) Data mining--We developed a computational method to study the allele-specific gene expression by mining the EST database. Bayesian statistics was used to estimate the genotype of each SNP in the library. Significant reduction in the frequency of the cDNA libraries expressing both alleles could identify SNPs located in the imprinted genes. Among the top 1% of SNPs with the small p values, 4 of 194 were in the known imprinted genes. We are experimentally determining if any of 190 candidate SNPs is located in novel imprinted genes. 2) Genetic elements--We performed comparative genome sequence analysis for each of the 46 imprinted genes to identify the regions conserved between human and mouse. We searched for motifs in the conserved non-coding sequences that can serve as genetic regulatory elements for imprinting. We also identified the transcription factor binding sites for each of imprinted genes. We found that five motifs and two transcription factor binding sites, AP1 and SOX5, occurred more frequently in the imprinted genes locus than rest of the genome. Genome-wide identification of tumor-associated alternative RNA splicing. We performed a genome-wide computational analysis of the EST database to identify alternative RNA splicing isoforms that are associated with human cancers. We found 26,258 alternative splicing isoforms and analysis of ESTs and their library sources suggested that 845 alternative splicing isoforms were significantly associated with human cancers. We also found considerably more GC dinucleotides at the splicing donor sites in tumors than in normal samples. Experimental validation demonstrated that 45 of 76 alternative splicing isoforms were present in some of the tumors but not in the matched normal samples.

Agency
National Institute of Health (NIH)
Institute
Division of Cancer Epidemiology And Genetics (NCI)
Type
Intramural Research (Z01)
Project #
1Z01CP010155-03
Application #
6755610
Study Section
(HGP)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Cancer Epidemiology and Genetics
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lee, Maxwell P; Dunn, Barbara K (2008) Influence of genetic inheritance on global epigenetic states and cancer risk prediction with DNA methylation signature: challenges in technology and data analysis. Nutr Rev 66 Suppl 1:S69-72
Riss, Joseph; Khanna, Chand; Koo, Seongjoon et al. (2006) Cancers as wounds that do not heal: differences and similarities between renal regeneration/repair and renal cell carcinoma. Cancer Res 66:7216-24
Hu, Nan; Wang, Chaoyu; Hu, Ying et al. (2005) Genome-wide association study in esophageal cancer using GeneChip mapping 10K array. Cancer Res 65:2542-6
Lin, Wei; Yang, Howard H; Lee, Maxwell P (2005) Allelic variation in gene expression identified through computational analysis of the dbEST database. Genomics 86:518-27
Lee, Maxwell P; Howcroft, Kevin; Kotekar, Aparna et al. (2005) ATG deserts define a novel core promoter subclass. Genome Res 15:1189-97
Lee, Maxwell P (2005) Genome-wide analysis of allele-specific gene expression using oligo microarrays. Methods Mol Biol 311:39-47
Yang, Howard H; Lee, Maxwell P (2004) Application of bioinformatics in cancer epigenetics. Ann N Y Acad Sci 1020:67-76
Wang, Zhining; Fan, Hongtao; Yang, Howard H et al. (2004) Comparative sequence analysis of imprinted genes between human and mouse to reveal imprinting signatures. Genomics 83:395-401
Yang, Howard H; Hu, Ying; Buetow, Kenneth H et al. (2004) A computational approach to measuring coherence of gene expression in pathways. Genomics 84:211-7
Wang, Zhining; Lo, H Shuen; Yang, Howard et al. (2003) Computational analysis and experimental validation of tumor-associated alternative RNA splicing in human cancer. Cancer Res 63:655-7

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