Predicting
Drug Resistance in Cancer Genomes by DNA Methylation Profiling
Ovarian cancer is the most lethal of all gynecological neoplasms. Although ovarian tumor resistance to chemotherapeutic drugs is a common problem, the underlying mechanisms of this multifactorial phenomenon remain poorly understood. While CpG island methylation likely plays a prominent role in the complexity of drug resistance in cancer, this has not been widely addressed in ovarian cancer, nor has the emerging phenomenon of acquired DNA methylation induced by cisplatin.
Our previous genome-wide interrogation of CpG island loci in drug-resistant ovarian cancer identified a subset of CpG islands that were differentially hypermethylated in drug-resistant cell lines and relapse tumors and also were strongly correlated with shorter survival of ovarian cancer patients. Furthermore, within these loci, we identified conserved DNA sequences, characteristic of methylation-prone CpG islands. We hypothesize that CpG island methylation is associated with cisplatin resistance, and we will test this hypothesis by using mathematical- and computer-generated models to predict susceptibility of CpGi sequences to cisplatin-induced methylation in ovarian cancer. Models of ovarian cancer drug resistance and patient tumor samples will be used. We will conduct computational modeling, using the drug-resistant, hypermethylated CpG island loci as our machine training set. An unsupervised learning scheme, specifically, a sequence clustering algorithm, will be used to classify CpG island sequences into groups of similar sequences. Patterns or subsequences in CpG island sequences will be used to further select methylation-prone CpGi sequences associated with drug-induced DNA methylation in ovarian cancer.
The experimental approaches we will use to test models and generate new models of CpG island methylation in ovarian cancer include 1) methylation-specific oligonucleotide (MSO) microarray method to determine detailed methylation patterns of the CpG island loci; 2) a time-course experimental system we have designed to determine CpG island loci susceptible to drug-induced de novo methylation and also to directly associate CpG islands with the development of cisplatin resistance in ovarian cancer; 3) small interfering RNA technology to knock down specific genes in drug sensitive cell lines and examine the subsequent effects on drug sensitivity. The computational analysis of experimental data will guide the reformulation of hypotheses. The entire procedure will be iterated to generate and refine mathematical models that predict drug-induced CpGi methylation and perhaps identify epigenetic relapse biomarkers in ovarian cancer.
Please click images to enlarge.
Overview of model building from experimental data
Supervised learning process
hybridization
Indiana University:
Kenneth Nephew, Principle Investigator
Sun Kim, Co-Investigator
Daniela Matei, Co-Investigator
Robert Bigsby, Co-Investigator
Curt Balch, Research Assistant Professor
Henry Hyun-il Paik, Research Associate
Bernadette Allison, Research Analyst
Mike Mand, Research Analyst
The Ohio State University:
Tim Huang, Co-Investigator
Relevant Publications:
- Phillip H. Abbosh, John S. Montgomery, Jason A. Starkey, Milos Novotny, Eleanor G. Zuhowski, Merrill J. Egorin, Annie P. Moseman, Adam Golas, Kate M. Brannon, Curtis Balch, Tim H.M. Huang, and Kenneth P. Nephew
Dominant-Negative Histone H3 Lysine 27 Mutant Derepresses Silenced Tumor Suppressor Genes and Reverses the Drug-Resistant Phenotype in Cancer Cells
Cancer Research. 2006 June 1, 66(11):5582-5591
- Susan H.Wei, Curtis Balch, Henry H. Paik, Yoo-Sung Kim, Rae Lynn Baldwin, Sandya Liyanarachchi, Lang Li, Zailong Wang, Joseph C.Wan, Ramana V. Davuluri, Beth Y. Karlan, Gillian Gifford, Robert Brown, Sun Kim, Tim H-M. Huang, and Kenneth P. Nephew
Prognostic DNA Methylation Biomarkers in Ovarian Cancer
Clinical Cancer Research. 2006 May 1, 12(9):2788-2794
- Curtis Balch, Pearlly Yan, Teresa Craft, Suzanne Young, David G. Skalnik, Tim H-M. Huang, and Kenneth P. Nephew1,
Antimitogenic and chemosensitizing effects of the methylation inhibitor zebularine in ovarian cancer
Molecular Cancer Therapeutics. 2005 October, 4(10):1505-1514
- Curtis Balch, PhD, Tim H-M. Huang, PhD, Robert Brown, PhD, Kenneth P. Nephew, PhD
The epigenetics of ovarian cancer drug resistance and resensitization
American Journal of Obstetrics and Gynecology. 2004 November, 191:1552-1572
- Wei SH, Chen CM, Shi S, Yan PS, Harnsomburana J, Shyu CR,
Nephew KP, Brown R, Huang T H-M.
Methylation microarray analysis of late stage ovarian carcinomas distinguishes disease-free survival in patients and identifies candidate epigenetic markers.
Clinical Cancer Research,2002, 8: 2246-2252
- Shi H, Wei SH, Leu Y-W, Rahmatpanah F, Liu JC, Yan PS,
Nephew KP, Huang T H-M.
Triple analysis of the cancer epigenome: an integrated microarray system for assessing gene expression, DNA methylation and histone acetylation.
Cancer Res 2003, 63:2164-2171 (cover article)
- Nephew KP, Huang TH-M
Epigenetic gene silencing in cancer initiation and progression.
Cancer Letters 2003,190:125-33
- Leu YW, Yan PS, Fan W, Jin VX, Liu CJ, Curran EM, Welshons WV, Wei HS, Davuluri RV, Plass C, Nephew KP, Huang TH-M.
Loss of estrogen signaling triggers epigenetic silencing of downstream targets
Cancer Res 2004, 64:8184-8192
- Balch C, Montgomery JS, Paik H-I, Kim SH, Huang T H-M, Nephew KP.
New anti-cancer strategies
Epigenetic therapies and biomarkers Front Biosci 2005, 10:1897-931
- Li, L, Shi H, Yiannoutsos C, Huang TH, Nephew KP.
An empirical bayesian model for a DNA methylation-acetylation triple-microarray experiment
J Computational Biol (in press)
- Huang T H-M, Nephew KP, Bast R, Brenton, J, Yan PS, Brown R.
International workshop on biomarkers and DNA methylation in ovarian cancer.
(under review)
- Wei SH, Paik HH, Balch C, Kim YS, Baldwin RL, Liyanarachchi S, Li L, Wang Z, Wan JC, Davuluri RV, Karlan BY, Brown R, Kim S, Huang T H-M, Nephew KP.
Building discriminative models to classify methylation-prone sequences in cancer.
(under review)
- Susan H. Wei, Curtis Balch, Henry H. Paik, Yoo-Sung Kim,Rae Lynn Baldwin, Sandya Liyanarachchi, Lang Li, Zailong Wang, Joseph C. Wan, Ramana V. Davuluri, Beth Y. Karlan, Gillian Gifford, Robert Brown, Sun Kim, Tim H.-M. Huang, Kenneth P. Nephew
DNA Biomarkers Possessing Methylation-Predictive SequencePatterns in Ovarian Cancer
(under review)
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