Non-melanoma skin cancer (NMSC), consisting of cutaneous basal cell carcinoma and squamous cell carcinoma (cSCC), is the most common form of cancer in the world. In 2006, the estimated number of new NMSC cases in the United States rose to 3.5 million; of those, 700,000 were cSCCs. The most important factor for the development of primary cSCCs is cumulative exposure to ultraviolet radiation. Other environmental risk factors include viral infection, immunosuppression, chronic inflammation, and exposure to industrial carcinogens. Cancer development is not solely dependent on environmental factors as a genetic contribution for several cancers is well described. Population and family-based studies suggest that there is a genetic component to the development of cSCC. These studies suggest heritability for cSCC risk; however, the specific genetic factors remain elusive.
This dissertation is comprised of three related projects that explore the genetic contribution to cSCC. These studies utilize both skin cancer susceptible and resistant mice and human samples. Because human populations are heterogeneous, the use of mouse models to map genetic risk factors is ideal. Cancer susceptibility genes identified in the mouse have been confirmed in human studies suggesting this is an effective approach to identify true genetic risk factors. Previous studies using these mice identified skin tumor susceptibility loci, including the one of focus for this study, Skts5, as well as a small number of microRNAs (miRNAs) showing differential expression.
The goal of the first project was to identify and characterize novel skin cancer susceptibility genes in the mouse. We hypothesized that genes mapping to Skts5 which showed expression differences and/or sequence variations between cancer susceptible and resistant mice may be playing a role in tumorigenesis. We identified aryl hydrocarbon receptor (Ahr) as a potential candidate susceptibility gene. We performed in vitro functional analyses and revealed potential roles that Ahr may be playing in tumor development and progression.
The focus of the second project was to identify cancer susceptibility genes at the human SKTS5 locus using allele-specific imbalance and risk association studies. We hypothesized that human cSCC tumors would show allele-specific somatic genetic changes at SKTS5 and that these alterations would contribute to cSCC risk. Candidate genes identified in the mouse were analyzed in human samples. We identified single nucleotide polymorphisms and haplotypes in HDAC9 that conferred risk, supporting my hypothesis.
The goal of the third project was to identify and characterize miRNAs that are playing a role in cSCC tumorigenesis. This project utilized a miRNA microarray expression data set to compare expression in cSCC cancer susceptible and resistant mice. We hypothesized that miRNAs showing differential expression between the strains are important in the development of cSCC. This study identified six miRNAs and we performed in vitro functional characterization of miR-1.
Genetic discovery is important to not only understand the biology of disease, but to also facilitate better preventative measures and treatment options. The three studies of this dissertation give insight to genes and miRNAs contributing to cSCC development.