General Research Interest

• Cancer susceptibility
• Mouse model of human cancers
• Chemical induced skin carcinogenesis
• Complex genetic traits Epigenetics
• Epistatics

Current Program

The current focus of our program is to develop mouse models for the major forms of human cancer, which will enable us to identify genes that confer susceptibility or resistance to tumors induced by environmental mutagens and tumor promoters. The goal is to understand all stages of multi-step carcinogenesis in the mouse, in particular the relationships between germ line predisposition and somatic genetic changes in tumors. The identification of human homologues of these predisposition genes and the discovery of their roles in carcinogenesis will ultimately be important for the development of methods for prediction of risk, diagnosis, prevention and treatment therapy for human cancers.

Laboratory Personnel

Makoto Kimura, PhD
Kyoko Fujiwara, PhD
Srimoyee Ghosh, PhD
Natsumi Irahara, PhD
Debra Tabaczynski, BS (part-time)                           

Description of Research

Genetic background plays a very important role in determining the probability of tumor development in both humans and mice. Many genes can confer a strong predisposition to tumor development when inherited in mutant form through the human or mouse germ-line. Such mutations are normally highly penetrant and give rise to familial cancer syndromes such as Li-Fraumeni Syndrome (p53), bilateral retinoblastoma (Rb) or familial adenomatous polyposis (APC). However, it is likely that a large number of low-penetrance genetic components contribute to the development of sporadic cancers, which constitute the major human tumor burden. Identification of these genetic factors will provide invaluable information not only on the biological pathways controlling tumor development but also on potential mechanisms of tumor prevention or treatment. Mapping and cloning of these low-penetrance genes are likely to be much easier using mouse models, where the etiology of tumor development and the genetic background of the host can be controlled. Studies on mice have revealed that tumor predisposition in different strains is controlled by multiple loci which probably control fundamental processes such as tumor growth rate, apoptosis, ability to stimulate angiogenesis, or invasive properties.  Mouse tumor systems in which the etiology can be carefully controlled and the stages of carcinogenesis can be easily monitored have shown that the early and late steps of tumorigenesis are under separate genetic control.

Identification of genetic factors involved in cancer susceptibility
We have demonstrated that “low penetrance type” cancer susceptibility genes have been able to be identified though mouse model of human cancers. For instance, the difference of AURKA variants due to codon 57 V/I and codon 31 F/I polymorphisms, diplotype combinations of AURKA are important to express different phenotypes in each individual. Particular diplotype combinations associated with significant increase of the esophageal cancer risk. A subset of AURKA variants may induce increasing chromosomal instability in somatic cells due to their functional differences. This demonsrates that AURKA is a cancer susceptibility gene in humans and has been implicated in our approach and we will be able to identify unknown human cancer susceptibility genes and the mechanisms behind their susceptibility.

Epigenetic factors involved in cancer susceptibility
The primary reason for establishing the global methylation screening method is to establish that epigenetic modifications, most importantly DNA methylation events, are involved in the mouse skin carcinogenesis model.  Subsequently analysis of the epigenetic DNA modification will facilitate identification of new fundamental areas of future research, including the somatic or germ-line DNA modifications which result in cancer initiation or progression. With the addition of epigenetic information, the ability to test the cumulative role of several cancer susceptibility genes will likely provide a greater power for definition of the susceptible component of the population, and it may provide an opportunity for more effective screening for susceptibility to non-familial cancers.  Composite information of epigenetic and genetic variants in various cell environments will accumulate evidence for how epigenetic methylation and genetic variation controls cancer development as well as many other biologically important phenomena in the mouse and possibly in humans.

Target therapy using designable chemical compounds
We are testing a new class of designable anticancer molecules that down-regulate a combination of target genes and induce cancer cell growth inhibition, therefore establishing a new target therapeutic approach and emerging technology for functional analysis of cancer development.  This approach may also develop potential therapeutic molecules or identify target pathways for cancer treatment and/or prevention.

Key Publications

• Smith JF, Mahmood S, Song F, Morrow A, Smiraglia D, Zhang Z, Rajput A, Higgins MJ, Krumm A, Petrelli N, Costello JF, Nagase H, Plass C, Held WA.  Identification of DNA methylation in 3' genomic regions that are associated with up regulation of gene expression in colorectal cancer.  Epigenetics 2007; 3:161-172.
• Fujiwara K, Kgarashi J, Irahara N, Kimura MT, Nagase H.  New chemically induced skin tumour susceptibility loci identified in a mouse backcross between FVB and dominant resistant PWK.  BMC Genet 2007; 8(1) 39.
• de Koning JP, Wakabayashi Y, Nagase H, Mao J-H, Balmain A. Convergence of congenic mapping and allele-specific alterations in tumors for the resolution of the Skts1 skin tumor susceptibility locus. Oncogene 2007; 26(28)4171-4178.
• Kitamura E, Igarashi J, Morohashi A, Hida N, Oinuma T, Nemoto N, Song F, Ghosh S, Held WA, Yoshida-Noro C, Nagase H.  Analysis of tissue-specific differentially methylated regions (TDMs) in humans.  Genomics 2007; 89:326-337.
• Kimura　MT, Mori T, Conroy J, Nowak NJ, Satomi S, Tamai K, Nagase H. Two functional coding single nucleotide polymorphisms in STK15 (Aurora-A) coordinately increase esophageal cancer risk. Cancer Res 2005; 65:3548-3554.
• Song F, Smith JF, Kimura MT, Morrow AD, Matsuyama T, Nagase H, Held WA. Association of tissue specific-differentially methylated regions (TS-DMRs) with differential gene expression. Proc Natl Acad Sci USA 2005; 102:3336-3341.
• Ewart-Toland A, Dai Q, Gao Y-T, Nagase H, et al. Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis 2005; 26:1368-1373.
• Members of the Complex Trait Consortium (CTC) Flaherty L, Abiola O, Angel JM, Avner P, Bachmanov AA, Belknap JK, Bennett B, Nagase H, et al. The collaborative cross: A community resource for the genetic analysis of complex traits. Nat Genet 36:1133-1137, 2004.
• Egan MK, Newcomb PA, Ambrosone CB, Trentham-Dietz A, Titus-Ernstoff L, Hampton JM, Kimura MT, Nagase H. STK15 polymorphism and breast cancer risk in a population-based study. Carcinogenesis 2004; 25:2149-2153.
• Members of the Complex Trait Consortium (CTC) Flaherty L, Abiola O, Angel JM, Avner P, Bachmanov AA, Belknap JK, Bennett B, Blankenhorn EP, Blizard DA, Bolivar V, Brockmann GA, Buck KJ, Bureau J-F, Casley WL, Chesler EJ, Cheverud JM, Churchill GA, Cook M, Crabbe JC, Crusio WE, Darvasi A, de Haan G, Demant P, Doerge RW, Elliott RW, Farber CR, Flint J, Gershenfeld H, Gibson JP, Gu W, Himmelbauer H, Hitzemann R, Hsu H, Hunter K, Iraqi F, Jansen RC, Johnson TE, Jones BC, Kempermann G, Lammert F, Lu L, Manly KF, Matthews DB, Medrano JF, Mehrabian M, Mittleman G, Mock BA, Mogil JS, Montagutelli X, Morahan G, Mountz JD, Nagase H, Nowakowski RS, O'Hara BF, Osadchuk AV, Palmer AA, Peirce JL, Pomp D, Rosemann M., Rosen, G.D., Schalkwyk, P.B., Leonard C., Seltzer, Z., Settle, S., Shimomura, K., Shou, S, Sikela JM, Siracusa LD, Spearow JL, Teuscher C, Threadgill DW, Toth LA, Toye AA, Vadasz C, Van Zant G, Wakeland E, Williams RW, Zhang H-G, Zou F. The nature and identification of quantitative trait loci: a community's view. Nat Genet Rev 2003; 4:911-916.
• Nagase H, Mao JH, Balmain A. Allele-specific H-ras mutation and genetic alterations at tumor susceptibility loci in skin carcinomas from interspecific hybrid mice. Cancer Res 2003; 63:4849-4853.
• Matsuyama T, Kimura MT, Koike K, Abe T, Nakao T, Asami T, Ebisuzaki T, Held WA, Yoshida S, Nagase H. Global methylation screening at NotI sites in the Arabidopsis thaliana and Mus musculus genome. Nuclei Acid Res 2003; 31(15):4490-4496.
• Nagase H, Mao JH, deKoning JP, Minami T, Balmain A. Epistatic interactions between skin tumor modifier loci in interspecific (spetus/musculus) backcross mice. Cancer Res 2001; 61:1305-1308.
• Nagase H, Mao JH, Balmain A. A subset of skin tumour modifier loci determines survival time of tumour bearing mice. Proc Natl Acad Sci USA 1999; 96:15032-15037.
• Balmain A, and Nagase H. Cancer resistance genes in mice: models for the study of tumour modifiers. Trends Genet 1998; 14(4):139-144.
• Nagase H. and Nakamura Y.  Cleavage using RNase to detect mutations.  Mutation Detection - A Practical Approach.  Eds: R.G.H. Cotton, E. Edkins and S. Forrest.  IRL Press, Oxford-New York, Toyko, Chapter 4 1998; pp. 63-80.
• Nagase H, Bryson S, Cordell H, Kemp CJ, Fee F, Balmain A. Cancer predisposition in mice. Distinct genetic loci control development of benign and malignant skin tumours. Nat Genet 1995; 10:424-429.
• Nagase H, and Nakamura Y. Mutations of the APC (Adenomatous polyposis coli) gene. Human Mutat 1993; 2:425-434.
• Nagase H, Miyyoshi Y, Horji S, Aoki T, Ogawa M, Utsunomiya J, Baba S, Sasazuki T, Nakamura Y. Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res 1992; 52:4055-4057.