Molecular Epidemiology and Epigenetics

Group Leader: Professor Karl T. Kelsey

Laboratory Director: Dr. Rondi Butler

Research in the lab has long focused upon numerous aspects of chronic disease and cancer, specifically with a recent interest in further understanding the immunological contributors to this diverse spectrum of diseases. This work has evolved from our early studies of environmental disease and the mechanisms responsible for gene-environment interaction and genetic susceptibility to chronic occupational and environmental disease. As a result of our recent work in epigenetics, the lab has collaboratively developed methods to interrogate the immune profile in peripheral blood. This work, in addition to allowing for eliminating potential confounding by differing numbers of normal blood cells, has set the stage for further enumerating less common, but perhaps even more important, clonal immune  cells.  This application takes this concept and formalizes it by applying DNA methylation analysis to interrogate specific immune components of the leukocyte mixture, allowing us to study the association of particular immune profiles with different cancers in both case-control and prospective study design settings. We are currently funded to discover immune-related biomarkers that signal an immune response early in the cancer disease process.

We use genetic techniques in both case-control and prospective studies to assess effect modification and directly study genetic susceptibility to environmental and occupational disease. We collaborated broadly with the Nurses Health Study and with both national and international groups to test candidate gene variants for their ability to modify the effect of numerous known carcinogens and toxicants. This work has continued into the present day, as we conducted one of the largest population-based case-control studies of head and neck cancer over a more than 15 year period.

  • Wiencke, JK, Kelsey, KT, Varkonyi, A, Semey, K, Wain, JC, Mark, E, and Christiani, DC. Correlation of DNA adducts in blood monouclear cells with tobacco carcinogen-induced damage in human lung. Cancer Res 55:4910-14, 1995.
  • Hunter, DJ, Hankinson, SE, Hough, H, Gertig, DM, García-Closas, M, Spiegelman, Manson, JE, Colditz, GA, Willett, WC, Speizer, FE, and Kelsey, K. A prospective study of NAT2 acetylation genotype, cigarette smoking, and risk of breast cancer. Carcinogenesis 18:2127-32, 1997.
  • Applebaum KM, Furniss CS, Zeka A, Posner MR, Smith JF, Bryan J, Eisen EA, Peters ES, McClean MD, Kelsey KT. Lack of Association of Alcohol and Tobacco with HPV16-associated head and neck cancer. J Natl Cancer Inst. (23):1801-10, 2007.

As it became clear that the spectrum of somatic alterations in cancers included epigenetic changes, the lab expanded, initially to include study of DNA methylation silencing of tumor suppressor genes. We discovered that carcinogen exposure was associated with dose-dependent changes in DNA methylation profiles, stimulating increased interest in the potential for environmental exposures to alter the epigenome.

  • Christensen BC, Kelsey KT, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, Nelson HH, Karagas MR, Kushi LH, Kwan ML. Wiencke JK. Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake. PLoS Genet. 6(7):e1001043 2010. PMCID: PMC2912395
  • Christensen BC, Smith AA, Zheng S, Koestler DC, Houseman EA, Marsit CJ, Wiemels JL, Nelson HH, Karagas MR, Wrensch MR, Kelsey KT, Wiencke JK. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. J Natl Cancer Inst. 2011 Jan 19;103(2):143-53. PMCID: PMC3022619

The laboratory’s investigations into DNA methylation expanded into investigation of whether this might be used as a biomarker of risk for disease, hypothesizing that epigenetic changes might signal environmental insult. Our work investigating blood-based DNA methylation gave rise to one of the first investigations of the association of changes in repetitive region DNA methylation and cancer. We also have shown that the Methylation profile is lineage dependent and can discriminate tissues of origin. This observation has lead us to recent work describing differentially methylated regions that distinguish lineage and phenotype of immune cells, using stored blood DNA. We believe that these observations will allow for the development of tremendously informative biomarkers of leukocyte lineage and activation, effectively allowing us to create the field of ‘immunoepidemiology of chronic disease’.

  • Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, Nelson HH, Karagas MR, Padbury JF, Bueno R, Sugarbaker DJ, Yeh RF, Wiencke JK, Kelsey KT. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet. 5(8):e1000602, 2009. PMCID:PMC2718614 
  • Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, Nelson HH, Wiencke JK and Kelsey KT. DNA Methylation Arrays as Surrogate Measures of Cell Mixture Distribution. BMC Bioinformatics 2012 May 8;13(1):86. PMCID:PMC3532182 
  • Lucas A. Salas, Devin C. Koestler, Rondi A. Butler, Helen M. Hansen, John K. Wiencke, Karl T. Kelsey and Brock C. Christensen. An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray. Genome Biology 2018 19:64  https://doi.org/10.1186/s13059-018-1448-7