Abstract
Genetic variations among individuals account for a large portion of variability in drug response. The underlying mechanism of the variability is still not known, but it is expected to comprise of a wide range of genetic factors that interact and communicate with each other. Here, we present an integrated genome-wide approach to uncover the interactions among genetic factors that can explain some of the inter-individual variation in drug response. The International HapMap consortium generated genotyping data on human lymphoblastoid cell lines of (Center d’Etude du Polymorphisme Humain population - CEU) European descent and (Yoruba population - YRI) African descent. Using genome-wide analysis, Huang et al. identified SNPs that are associated with etoposide, a chemotherapeutic drug, response on the cell lines. Using the same lymphoblastoid cell lines, Fraser et al. generated genome-wide methylation profiles for gene promoter regions. We evaluated associations between candidate SNPs generated by Huang et al and genome-wide methylation sites. The analysis identified a set of methylation sites that are associated with etoposide related SNPs. Using the set of methylation sites and the candidate SNPs, we built an integrated model to explain etoposide response observed in CEU and YRI cell lines. This integrated method can be extended to combine any number of genomics data types to explain many phenotypes of interest.
Keywords
- Methylation Level
- Drug Response
- Methylation Site
- Interactive Relationship
- Candidate SNPs
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, access via your institution.
Buying options
Preview
Unable to display preview. Download preview PDF.
References
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. Mol. Cancer Ther. 7, 3038–3046 (2008)
Huang, R.S., et al.: Genetic variants contributing to daunorubicin-induced cytotoxicity. Cancer Res. 68, 3161–3168 (2008)
Huang, R.S., et al.: Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. Am. J. Hum. Genet. 81, 427–437 (2007)
Gamazon, E.R., Huang, R.S., Cox, N.J., Dolan, M.E.: Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci. Proc. Natl. Acad. Sci. U. S. A. 107, 9287–9292 (2010)
Huang, R.S., et al.: A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity. Proc. Natl. Acad. Sci. U. S. A. 104, 9758–9763 (2007)
The International HapMap Consortium: A haplotype map of the human genome. Nature 437, 1299–13320 (2005)
Fraser, H.B., Lam, L.L., Neumann, S.M., Kobor, M.S.: Population-specificity of human DNA methylation. Genome Biol. 13, R8 (2012)
Sinha, B.K., Haim, N., Dusre, L., Kerrigan, D., Pommier, Y.: DNA strand breaks produced by etoposide (VP-16,213) in sensitive and resistant human breast tumor cells: implications for the mechanism of action. Cancer Res. 48, 5096–5100 (1988)
Mistry, A.R., et al.: DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N. Engl. J. Med. 352, 1529–1538 (2005)
Ratain, M.J., et al.: Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung. Blood 70, 1412–1417 (1987)
Thomson.Micromedex. Drug Inf. Heal. Care Prof. 24th edn. vol. 1, p. 1326 (2004)
Holzinger, E., Buchanan, C.: Initialization Parameter Sweep in ATHENA: Optimizing Neural Networks for Detecting Gene-Gene Interactions in the Presence of Small Main Effects. In: Proc. 12th …, pp. 203–210 (2010). doi:10.1145/1830483.1830519.Initialization
Holzinger, E.R., Dudek, S.M., Torstenson, E.C., Ritchie, M.D.: ATHENA Optimization : The Effect of Initial Parameter Settings across Different Genetic Models, pp. 48–58 (2011)
Turner, S.D., Dudek, S.M., Ritchie, M.D.: ATHENA: A knowledge-based hybrid backpropagation-grammatical evolution neural network algorithm for discovering epistasis among quantitative trait Loci. BioData Min. 3, 5 (2010)
Holzinger, E.R., et al:. Comparison of Methods for Meta-dimensional Data Analysis Using in Silico and Biological Data Sets, pp. 134–143
Holzinger, E.R., et al.: ATHENA: a tool for meta-dimensional analysis applied to genotypes and gene expression data to predict HDL cholesterol levels. In: Pac. Symp. Biocomput., pp. 385–96 (2013). http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3587764&tool=pmcentrez&rendertype=abstract
Skapura, D.M.: Building neural networks (1995). http://dl.acm.org/citation.cfm?id=217718
Koza, J.R., Rice, J.P.: Genetic generation of both the weights and architecture for a neural network. In: IJCNN 1991, Seattle Int. Jt. Conf. Neural Networks ii, pp. 397–404. IEEE (1991)
Dunham, I., et al.: An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012)
Westra, H.-J., et al.: Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238–1243 (2013)
Liu, X., et al.: Fine-mapping of prostate cancer aggressiveness loci on chromosome 7q22-35. Prostate 71, 682–689 (2011)
Rouget-Quermalet, V., et al.: Protocadherin 15 (PCDH15): a new secreted isoform and a potential marker for NK/T cell lymphomas. Oncogene 25, 2807–2811 (2006)
Salih, M.A., et al.: A newly recognized autosomal recessive syndrome affecting neurologic function and vision. Am. J. Med. Genet. A 161, 1207–1213 (2013)
Akizu, N., et al.: Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia. Am. J. Hum. Genet. 92, 392–400 (2013)
Jiang, Y., et al.: Germline PTPRD Mutations in Ewing Sarcoma: Biologic and Clinical Implications. Oncotarget 4, 884–889 (2013)
Shah, S.P., et al.: Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461, 809–813 (2009)
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Li, R., Kim, D., Dudek, S.M., Ritchie, M.D. (2014). An integrated analysis of genome-wide DNA methylation and genetic variants underlying etoposide-induced cytotoxicity in European and African populations. In: Esparcia-Alcázar, A., Mora, A. (eds) Applications of Evolutionary Computation. EvoApplications 2014. Lecture Notes in Computer Science(), vol 8602. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-45523-4_75
Download citation
DOI: https://doi.org/10.1007/978-3-662-45523-4_75
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-45522-7
Online ISBN: 978-3-662-45523-4
eBook Packages: Computer ScienceComputer Science (R0)