Genetic and epigenetic determinants of premalignant states in the skin

Faculty: Dr. David Chen

Keratinocyte carcinomas, which include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common types of cancer.  While overall cancer deaths declined in the past two decades, non-melanoma skin cancer, more than any other tumor type, exhibited an increase in cancer deaths particularly in men. This trend continues in contemporary analysis, even while mortality for many other cancers, including melanoma, trends downward. 

The best-defined risk factors for the development of any skin cancer in fair-skinned populations include immune suppression, aging, and sun exposure.  The interplay between intrinsic and extrinsic factors that modify cancer risk drives the unifying theme of my laboratory investigation: defining the genetic and epigenetic drivers of premalignant states in skin cancer.  Three lines of inquiry stem from this theme: 

Characterizing aging phenotypes in murine skin.  We have found the development of canonical, differentially methylated regions of DNA in aging mouse epidermis by whole genome bisulfite sequencing.  These changes are progressive, suggesting a programmed shift in DNA methylation with age.  We are investigating the mechanisms underlying this change, its functional consequences, and whether they modify cancer susceptibility. 

Characterizing epigenetic perturbations that result in premalignant skin phenotypes. Skin-directed de novo DNA methyltransferase deficiency causes a bona fide premalignant state in which we identified a focal, canonical DNA hypomethylation phenotype and an associated expansion of the proliferative fraction of cells in premalignant Dnmt3a-deficient murine epidermal keratinocytes.  We are investigating the consequences of oncogenic drivers in Dnmt3a deficient keratinocytes, in vivo, to try to understand the mechanism by which Dnmt3a contributes to tumorigenesis. We are also exploring other epigenetic modifiers and their role in modifying tumor susceptibility. 

Characterizing genetic and functional changes in human premalignant and malignant skin. Several premalignant conditions exist in human skin, including actinic keratoses (SCC) and melanocytic nevi (melanoma).  We are investigating the genetic and epigenetic alterations that contribute to these premalignant states in the skin, as well as the mechanisms by which they are restrained from oncogenic transformation.