M. Eileen Dolan, Ph.D.

Pharmacogenomics of Anticancer Agents

Research Summary

    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 reactions to chemotherapeutic agents.

Selected Papers

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 PMID17701890   PMCID: PMC1950832

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.  PMID17545624

Zhang, W., Duan, S., Kistner, E. O., Bleibel, W. K., Huang, R. S., Clark, T. A., Chen, T. X., Schweitzer, A.C., Blume, J. E., Cox, N. J. and Dolan, M. E.  Evaluation of Genetic Variation Contributing to Differences in Gene Expression Between Populations. Amer. J. Human Genetics, 82: 631-640, 2008.  PMID18313023  PMCID: PMC2427223

Duan, S., Huang, R.S., Zhang, W., Bleibel, W.K., Roe, C.A., Clark, T.A., Chen, T.X., Schweitzer, A.C., Blume, J.E., Cox, N.J., and Dolan, M.E. Genetic Architecture of Transcript-Level Variation in Humans, Amer. J. Human Genetics, 82:1101-1113, 2008. PMID18439551   PMCID: PMC2651622

Huang, R.S., Duan. S, Kistner, E.O., Hartford, C.M., Dolan, M.E. Genetic variants associated with carboplatin-induced cytotoxicity in cell lines derived from Africans, Molec Cancer Ther., 7(9): 3038-3046, 2008.  PMID18765826

Hartford CM, Duan S, Delaney SM, Mi S, Kistner EO, Lamba JK, Huang RS, Dolan ME. Population specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity. Blood 10:2145-2153, 2009. PMID19109566   PMCID: PMC2652364

O’Donnell, P.H. and Dolan, M.E.  Cancer Pharmacoethnicity:  Ethnic Differences in Susceptibility to the Effects of Chemotherapy.  Clin Cancer Res, 15:4806-14, 2009 PMID: 19622575  PMCID: PMC2774468

Welsh M., Mangravite L., Medina M., Tantisira K., Zhang, W., Huang R. S., McLeod H., Dolan M. E. Pharmacogenomic Discovery Using Cell-Based Models. Pharmacological Reviews. 61:413-429, 2009. PMID: 20038569  PMCID: PMC2802425

Gamazon E.R., Huang R.S., Cox N.J., Dolan, M.E. Chemotherapeutic Drug Susceptibility Associated SNPs are Enriched in Expression Quantitative Trait Loci, PNAS, 107, 9287-9292, 2010. PMID: 20442332 PMCID: PMC2889115