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A Finite Mixture Model for Gene Expression and Methylation Pro les in a Bayesian Framewor

  • Received : 20110300
  • Accepted : 20110600
  • Published : 2011.08.31

Abstract

The pattern of methylation draws significant attention from cancer researchers because it is believed that DNA methylation and gene expression have a causal relationship. As the interest in the role of methylation patterns in cancer studies (especially drug resistant cancers) increases, many studies have been done investigating the association between gene expression and methylation. However, a model-based approach is still in urgent need. We developed a finite mixture model in the Bayesian framework to find a possible relationship between gene expression and methylation. For inference, we employ Expectation-Maximization(EM) algorithm to deal with latent (unobserved) variable, producing estimates of parameters in the model. Then we validated our model through simulation study and then applied the method to real data: wild type and hydroxytamoxifen(OHT) resistant MCF7 breast cancer cell lines.

Keywords

References

  1. Ahuja, N., Mohan, A. L., Li, Q., Stolker, J. M., Herman, J. G., Hamilton, S. R., Baylin, S. B. and Issa, J. J. (1997). Association between CpG island methylation and microsatellite instability in colorectal cancer, Cancer Research, 57, 3370.
  2. Baylin, S. B. and Herman, J. G. (2000). DNA hypermethylation in tumorigenesis: Epigenetics joins genetics, Trends Genetics, 16, 168-174. https://doi.org/10.1016/S0168-9525(99)01971-X
  3. Bird, A. (2002). DNA methylation patterns and epigenetic memory, Gene Development, 16, 6-21. https://doi.org/10.1101/gad.947102
  4. Day, N. E. (1969). Estimating the components of a mixture of two normal distributions, Biometrika, 56, 463-474. https://doi.org/10.1093/biomet/56.3.463
  5. Dempster, A. P., Laird, N. M. and Rubin, D. B. (1977). Maximum likelihood from incomplete data via the EM algorithm, Journal of Royal Statistical Society B, 39, 1-38.
  6. Dwivedi, R. S., Qiu, Y. Y., Devine, J. and Mirkin, B. L. (2003). Role of DNA methylation in acquired drug resistance in neuroblastoma tumors, Proceedings of Indian National Science Academy, 69, 111-120.
  7. Esteller, M., Hamilton, S. R., Burger, P. C., Baylin, S. B. and Herman, J. B. (1999). Inactivation of the DNA repair gene O6-Methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia, Cancer Research, 59, 793.
  8. Fan, M., Yan, P. S., Hartman, F. C., Chen, L., Paik, H., Oyer, S. L., Salisbury, J. D., Cheng, A. S., Li, L., Abbosh, P. H., Huang, T. H. and Nephew, K. P. (2006). Diverse gene expression and DNA methylation pro thisfiles correlate with differential adaptation of breast cancer cells to the antiestrogens Tamoxifen and Fulvestrant, Cancer Research, 66, 11954-11966. https://doi.org/10.1158/0008-5472.CAN-06-1666
  9. Figueiredo, A. T. M. and Jain, A. K. (2002). Unsupervised learning of finite mixture models, IEEE Trans- actions on Pattern Analysis and Machine Intelligence, 24, 381-396. https://doi.org/10.1109/34.990138
  10. George, C. (1985). An introduction to empirical bayes data analysis, American Statistician, 39, 83-87. https://doi.org/10.2307/2682801
  11. Herman, J. G. (1999). Hypermethylation of tumor suppressor genes in cancer, Seminars of Cancer Biology,9, 359-367. https://doi.org/10.1006/scbi.1999.0138
  12. Herman, J. G. and Baylin, S. B. (2003). Gene silencing in cancer in association with promoter hypermethylation, New England Journal of Medicine, 349, 2042-2054. https://doi.org/10.1056/NEJMra023075
  13. Hinshelwood, R. A. and Clark, S. J. (2008). Breast cancer epigenetics: normal human mammary epithelial cells as a model system, Journal of Molecular Medicine, 86, 1315-1328. https://doi.org/10.1007/s00109-008-0386-3
  14. Hui, R., Macmillan, R. D., Kenny, F. S., Musgrove, E. A., Blamey, R. W., Nicholson, R. I., Robertson, J. F. and Sutherland, R. L. (2000). INK4a gene expression and methylation in primary breast cancer: Overexpression of p16INK4a messenger RNA is a marker of poor prognosis, Clinical Cancer Research,6, 2777.
  15. Jeong, J., Li, L., Liu, Y., Nephew, K. P., Huang, T. H. and Shen, C. (2010). An empirical Bayes model for gene expression and methylation profiles in antiestrogen resistant breast cancer, BMC Medical Genomics, 3, 55. https://doi.org/10.1186/1755-8794-3-55
  16. Jones, P. A. and Baylin, S. B. (2007). The epigenomics of cancer, Cell, 128, 683-692. https://doi.org/10.1016/j.cell.2007.01.029
  17. Jones, P. A. and Laird, P. W. (1999). Cancer-epigenetics comes of age, Nature Genetics, 21, 163-167. https://doi.org/10.1038/5947
  18. McLachlan, G. J. and Krishnan, T. (2007). The EM Algorithm and Extensions, John Wiley & Sons, NewJersey.
  19. Muller, S., Fong, K. M., Maitra, A., Lam, S., Geradts, J., Ashfaq, R., Virmani, A. K., Milchgrub, S., Gazdar,A. F. and Minna, J. D. (2001). 5' CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer, Caner Research, 61, 3581.
  20. Sundberg, R. (1974). Maximum likelihood theory for incomplete data from an exponential family, Scandinavian Journal of Statistics, 1, 49-58.
  21. Sundberg, R. (1976). An iterative method for solution of the likelihood equations for incomplete data from exponential families, Communications in Statistics-Simulation and Computation, 5, 55-64. https://doi.org/10.1080/03610917608812007
  22. Wang, X., Chao, L., Jin, G., Ma, G., Zang, Y. and Sun, J. (2009). Association between CpG island methylation of the WWOX gene and its expression in breast cancers, Tumor Biology, 30, 8-14. https://doi.org/10.1159/000197911
  23. Wu, C. F. J. (1983). On the convergence properties of the EM algorithm, Annals of Statistics, 11, 95-103. https://doi.org/10.1214/aos/1176346060
  24. Xu, L. and Jordan, M. I. (1996). On convergence properties of the EM algorithm for Gaussian mixtures, Neural Computation, 8, 129-151. https://doi.org/10.1162/neco.1996.8.1.129