M. Eileen Dolan
Research Summary / Selected Publications
Recent advances in genome research have suggested strong associations between genetic factors and complex human traits, such as an individual s disease susceptibility, response to therapy, and gene expression levels. The objective of our work is to identify genetic determinants contributing to cellular susceptibility to chemotherapeutic agents. Most chemotherapeutic drugs exhibit serious toxicity; hence elucidating the genetic variants that alter their pharmacodynamic effects is an important but challenging project. Challenges include our inability to do family studies evaluating the effects of chemotherapy on individuals without cancer and the multigenic nature of drug response. Therefore, we have developed several cell based models to identify genetic variants important in chemotherapeutic-induced toxicity. The models employ EBV-transformed lymphoblastoid cell lines from related healthy Caucasians of European descent (CEPH) and Yorubans of African descent to evaluate chemotherapeutic-induced cytotoxicity and/or apoptosis. These family-based cell lines allow us to apply familial genetic strategies to determine the heritability and the genetic components contributing to complex phenotypes such as susceptibility to chemotherapy. The pedigrees have microsatellite and SNP data available for linkage mapping studies. Furthermore, the HapMap trios contained within these large pedigrees have over 3 million SNPs genotyped. We have performed expression array to allow for studies of population differences in gene expression and cellular susceptibility to chemotherapy. Our laboratory was the first to demonstrate susceptibility to chemotherapy-induced cytotoxicity is significantly heritable and that susceptibility to chemotherapeutic toxicity in Caucasians and Africans is significantly different for certain drugs. Our long-term goal is to identify genetic variants and gene expression, including those in an underserved population that predict risk for adverse drug reactions.
Recent advances in genome research have suggested strong associations between genetic factors and complex human traits, such as an individual s disease susceptibility, response to therapy, and gene expression levels. The objective of our work is to identify genetic determinants contributing to cellular susceptibility to chemotherapeutic agents. Most chemotherapeutic drugs exhibit serious toxicity; hence elucidating the genetic variants that alter their pharmacodynamic effects is an important but challenging project. Challenges include our inability to do family studies evaluating the effects of chemotherapy on individuals without cancer and the multigenic nature of drug response. Therefore, we have developed several cell based models to identify genetic variants important in chemotherapeutic-induced toxicity. The models employ EBV-transformed lymphoblastoid cell lines from related healthy Caucasians of European descent (CEPH) and Yorubans of African descent to evaluate chemotherapeutic-induced cytotoxicity and/or apoptosis. These family-based cell lines allow us to apply familial genetic strategies to determine the heritability and the genetic components contributing to complex phenotypes such as susceptibility to chemotherapy. The pedigrees have microsatellite and SNP data available for linkage mapping studies. Furthermore, the...
1. Zhang, W. and Dolan, M.E.. On the Challenges of the HapMap Resource. Bioinformation, 2, 338-339, 2008.
2. Huang, R.S., Duan, S., Shukla, S.J., Kistner, E.O., Clark, T.A., Chen, T.X., Schweitzer, A.C., Blume, J.E., Dolan, M.E. Identification of genetic variants contributing to Cisplatin-induced cytotoxicity using a genome-wide approach. Amer. J. Human Gen. 81(3):427-37. 2007.
3. Duan, S., Bleibel, W.K., Huang, S.R., Shukla, S.J., Wu, X., Badner, J.A., Dolan, M.E. Mapping genes that contribute to Daunorubicin-induced cytotoxicity. Cancer Res. 67(11):5425-5433, 2007.
4. Huang, R. S., Duan, S., Bleibel, W. K. Kistner, E. O., Zhang, W., Clark, T. A., Chen, T.X., Schweitzer, A.C., Blume, J. E., Cox, N. J. and Dolan, M. E. A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity, PNAS, 104: 9758-9763, 2007.
5. Huang, R.S., Kistner, E.O., Bleibel, W.K., Shukla, S.J., Dolan, M.E. Effect of population and Gender on Chemotherapeutic Agent-Induced Cytotoxicity. Molecular Cancer Therapeutics, 6(1); 31-36, 2007
6. Zhang, W., Bleibel, W.K., Roe, C.R., Cox, N.J., Dolan, M.E. Gender-specific Differences in Expression in Lymphoblastoid Cell Lines. Pharmacogenetics and Genomics. 17: 447-450, 2007.
7. Shukla, S.J. and Dolan, M.E. Use of CEPH and nonCEPH cells in pharmacogenetic studies. Pharmacogenomics, 6:303-310, 2005.
8. Dolan, M.E., Newbold, K.G., Nagasubramanian, R., Wu, X., Ratain, M.J., Cook, Jr., E.H., and Badner, J.A. Heritability and linkage analysis of sensitivity to cisplatin-induced cytotoxicity. Cancer Res, 64(12):4353-4346, 2004.
9. Wu, M.H., Chen, P., Wu, X., Liu, W., Strom, S., Das, S., Cook, Jr., E.H., and Dolan, M.E. Determination and analysis of single nucleotide polymorphisms and haplotype structure of the human carboxylesterase 2 gene. Pharmacogenetics 14(9):595-605, 2004.
1. Zhang, W. and Dolan, M.E.. On the Challenges of the HapMap Resource. Bioinformation, 2, 338-339, 2008.
2. Huang, R.S., Duan, S., Shukla, S.J., Kistner, E.O., Clark, T.A., Chen, T.X., Schweitzer, A.C., Blume, J.E., Dolan, M.E. Identification of genetic variants contributing to Cisplatin-induced cytotoxicity using a genome-wide approach. Amer. J. Human Gen. 81(3):427-37. 2007.
3. Duan, S., Bleibel, W.K., Huang, S.R., Shukla, S.J., Wu, X., Badner, J.A., Dolan, M.E. Mapping genes that contribute to Daunorubicin-induced cytotoxicity. Cancer Res. 67(11):5425-5433, 2007.
4. Huang, R. S., Duan, S., Bleibel, W. K. Kistner, E. O., Zhang, W., Clark, T. A., Chen, T.X., Schweitzer, A.C., Blume, J. E., Cox, N. J. and Dolan, M. E. A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity, PNAS, 104: 9758-9763, 2007.
5. Huang, R.S., Kistner, E.O., Bleibel, W.K., Shukla, S.J., Dolan, M.E. Effect of population and Gender on Chemotherapeutic Agent-Induced Cytotoxicity. Molecular Cancer Therapeutics, 6(1); 31-36, 2007
