The laboratory has contributed a significant body of research on DNA methylation, microRNA expression, and somatic genetic variation, their etiology, and their clinical significance in bladder, head and neck, and lung tumors. For example, we have specifically examined how demographics and exposure histories of patients contribute to variation in the status of DNA methylation of tumor suppressor genes, including identification of specific patterns of DNA methylation related to early life smoking initiation in human lung cancers, the relationship between arsenic, tobacco, and other exposures and DNA methylation in human bladder tumors or describing the concept of CpG-island methylator phenotype-like profiles of DNA methylation across a number of tobacco related tumors. We also determine the potential clinical utility of these somatic alterations, for example, demonstrating that the combined profiles of hypermethylation of the SFRP family of genes with inactive TP53 was a strong predictor of patient survival in bladder cancer. We are leaders in the application of array-based technologies, in examining DNA methylation and microRNA expression in human cancers. Bioinformatically inclined researchers in the group, such as former student, Jeff Thompson, now at the University of Kansas Medical Center, have also pioneered truly innovative integrated analyses of multi-lmic datasets, providing opportunities to define novel biomarkers of renal cell and breast cancer, as well as understanding of the biology underlying genes and genomic regions targeted for epigenetic and genetic perturbations in cancer.
As a logical and independent extension of the work on human tumor molecular profiles, we now are considered a leader in the field in examining how variation in DNA methylation in peripheral blood can be a risk factor for cancers and other health conditions. This developed from initial work which focused on the association between markers of global methylation and human bladder cancer risk and then genome-scale studies identifying a panel specific sites of DNA methylation that can be used as a predictor of bladder cancer risk. A fundamental question which developed from this work was a better understanding of mechanistically how this variation could contribute to risk, and so we undertook a series of studies that demonstrated that due to DNA methylation’s critical role in cell differentiation, this variation is actually a marker of the distribution of cell types within a given sample and that much of the risk associated with methylation variation is really as a marker of variation in immune cell subpopulations that themselves likely contribute to risk. We have continued to pursue this this line of research, with the recent award of a large pilot grant from the Geisel School of Medicine as a mPI with collaborator Dr. Jennifer Doherty now at the Huntsman Cancer Institute in Salt Lake City, Utah, and Dr. Devin Koestler at the University of Kansas Medical Center, to examine DNA methylation and telomere length as prospective biomarkers in order to improve existing screening protocols in lung cancer. We hope that this pilot research will allow for submission of a competitive R01 proposal to expand these studies in various prospective cohorts.
As a logical and independent extension of the work on human tumor molecular profiles, we now are considered a leader in the field in examining how variation in DNA methylation in peripheral blood can be a risk factor for cancers and other health conditions. This developed from initial work which focused on the association between markers of global methylation and human bladder cancer risk and then genome-scale studies identifying a panel specific sites of DNA methylation that can be used as a predictor of bladder cancer risk. A fundamental question which developed from this work was a better understanding of mechanistically how this variation could contribute to risk, and so we undertook a series of studies that demonstrated that due to DNA methylation’s critical role in cell differentiation, this variation is actually a marker of the distribution of cell types within a given sample and that much of the risk associated with methylation variation is really as a marker of variation in immune cell subpopulations that themselves likely contribute to risk. We have continued to pursue this this line of research, with the recent award of a large pilot grant from the Geisel School of Medicine as a mPI with collaborator Dr. Jennifer Doherty now at the Huntsman Cancer Institute in Salt Lake City, Utah, and Dr. Devin Koestler at the University of Kansas Medical Center, to examine DNA methylation and telomere length as prospective biomarkers in order to improve existing screening protocols in lung cancer. We hope that this pilot research will allow for submission of a competitive R01 proposal to expand these studies in various prospective cohorts.
