Less than 5% of all cancers result from the action of a single tumor suppressor gene or dominantly acting oncogenes. Instead, for all of the common cancers, it is the cumulative effect of many 'low penetrance' genetic mutations which confer the majority of the risk. Identifying these low penetrance genes has been a challenge which has been greatly assisted by the development of mouse cancer models between resistant and susceptible strains. In these inter-specific crosses the resistant phenotype is dominant and backcrossing to the sensitive strain has been used to perform linkage analyses to identify the chromosomal location of the tumor susceptibility genes. Over the past several years we have used a skin carcinogenesis model to identify 13 susceptibility loci and, in one case, have identified a gene, AURORA2, which confers increased risk in mice and human populations. At present the remaining 12 susceptibility loci are too large for positional cloning strategies. In this proposal, therefore, we will use a combination of strategies to define the positions of the susceptibility genes more precisely as a prelude to identifying the critical gene. In the first aim we use heavy ion beam irradiation to create microdeletions in the testes of resistant mice, which if they affect susceptibility genes, will make the F1 animals susceptible and simultaneously define the critical locus. In the second aim we will use inbred and outbred backcrosses together with linkage disequilibrium haplotype analysis to define the susceptibility loci.
The third aim will exploit our previous observation that tumor-specific genetic changes (deletions and amplifications), when they occur in regions known to contain susceptibility genes, can be used to define their location more accurately. These genetic changes will be identified with high-resolution custom BAC arrays available at RPCI. It is anticipated that this combination of approaches will identify candidate suppressor genes which can then be analyzed in more detail for their involvement in cancer risk in mice and human populations. In the long term, understanding the genetic load which leads to cancer susceptibility in the human population will provide rational alternatives to cancer prevention, screening and risk assessment. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012249-02
Application #
6891567
Study Section
Special Emphasis Panel (ZRG1-CG (01))
Program Officer
Humble, Michael C
Project Start
2004-05-03
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$404,460
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Fujiwara, Kyoko; Ghosh, Srimoyee; Liang, Ping et al. (2015) Genome-wide screening of aberrant DNA methylation which associated with gene expression in mouse skin cancers. Mol Carcinog 54:178-88
Liang, Ping; Song, Fei; Ghosh, Srimoyee et al. (2011) Genome-wide survey reveals dynamic widespread tissue-specific changes in DNA methylation during development. BMC Genomics 12:231
Fujiwara, Kyoko; Wie, Benjamin; Elliott, Rosemary et al. (2010) New outbred colony derived from Mus musculus castaneus to identify skin tumor susceptibility loci. Mol Carcinog 49:653-61
Shinojima, Yui; Terui, Tadashi; Hara, Hiroyuki et al. (2010) Identification and analysis of an early diagnostic marker for malignant melanoma: ZAR1 intra-genic differential methylation. J Dermatol Sci 59:98-106
Wang, Xiaofei; Nagase, Hiroki; Watanabe, Takayoshi et al. (2010) Inhibition of MMP-9 transcription and suppression of tumor metastasis by pyrrole-imidazole polyamide. Cancer Sci 101:759-66
Chen, Min; Matsuda, Hiroyuki; Wang, Linghua et al. (2010) Pretranscriptional regulation of Tgf-beta1 by PI polyamide prevents scarring and accelerates wound healing of the cornea after exposure to alkali. Mol Ther 18:519-27
Suzuki, Tsukasa; Asami, Yukihiro; Takahashi, Teruyuki et al. (2009) Development of a molecule-recognized promoter DNA sequence for inhibition of HER2 expression. J Antibiot (Tokyo) 62:339-41
Igarashi, Jun; Muroi, Satomi; Kawashima, Hiroyuki et al. (2008) Quantitative analysis of human tissue-specific differences in methylation. Biochem Biophys Res Commun 376:658-64
Traber, Maret G; Atkinson, Jeffrey (2007) Vitamin E, antioxidant and nothing more. Free Radic Biol Med 43:4-15
Ailawadhi, Sikander; Nagase, Hiroki; Khoury, Thaer et al. (2007) Intestinal trefoil factor (TFF-3) and extracellular signal-regulated kinase (ERK) in cholangiocarcinoma. Hepatogastroenterology 54:1339-44

Showing the most recent 10 out of 14 publications