<p> Anal squamous cell carcinoma (SCC) which is strongly associated with human papilloma virus (HPV) infection is a rare cancer but its incidence is increasing throughout the world. Even though it represents just 0.4% of all new cancer cases in the US, the mortality rate is estimated at 14%, which is comparable to both breast and prostate cancer mortality rates. To decrease the high rate of mortality and morbidity of anal cancer there is an enormous need for early detection and prevention strategies. Besides understanding the role of HPV infection, we also need to comprehend the basics of genetics and epigenetics involved in anal cancer progression. With both the highest incidence rate and a lower survival rate among African-American men, we are interested in understanding the relationship of HPV, miRNAs and somatic mutations associated with the African-American population in anal cancers. This was accomplished by (1) identifying and determining HPV genotypes associated with anal condylomas, pre-malignant/dysplastic lesions and malignant anal SCC through type specific genotyping, (2) profiling miRNAs in anal SCC based on gender and type of HPV infection to identify novel biomarkers using Nanostring technology, and (3) by identifying oncogenic mutations associated with anal lesions, transformation and progression using novel next generation sequencing methods. Common HPV genotypes associated with our samples included HPV-11, 16, 6, 32, 35, 51, 58, 59, and 68, of which HPV-32, 51, 59 and 68 are not protected by the current FDA approved nonavalent vaccine. Furthermore, 10 of 800 known human miRNAs were significantly dysregulated in SCC samples; these miRNAs (miR-451a, miR-1185-13p, miR-637, miR-4525a-5p, miR-1275, miR-1303, miR-600, miR-892b, miR-297 and miR-944) target tumor suppressor and oncogenes and potentially play an oncomir role in cancer progression. <i>TP53, PIK3CA, PDGFRA, HRAS</i>, and <i> RET</i> were some of the most frequently found somatic mutations in the sample set and it was observed that the accumulation of mutations begin at the condyloma stage. In conclusion, it was determined that three key factors determine the possible progression of anal cancer and can therefore aid in future development of novel targeted therapy approaches: type of HPV infection, epigenetic factors involving miRNAs, and genetic factors such as &lsquo;driver&rsquo; somatic mutations that an individual accumulates over their lifetime.</p><p>

<p> There are approximately 230,000 new diagnoses of prostate cancer every year in the U.S., making prostate cancer the most diagnosed cancer in men. It is responsible for approximately 30,000 deaths per year, with only lung cancer taking more lives. An important distinction must be made in men with prostate cancer. The majority of men with prostate cancer have a relatively indolent form of the disease, meaning high survival rates (100% survival 5 years after diagnosis) and no invasion of the tumor to other organs. However, approximately 4% of men are diagnosed with an aggressive form of the disease, and for these men, the survival rate is a mere 30% after 5 years. And for many patients, it is clinically difficult to differentiate between the indolent and the aggressive forms of the disease. Therefore, it is imperative to develop new genetic models of prostate cancer, and the mouse is an excellent model organism in which to do so. In 2009, mice were used to discover a new type of stem cell, called a castration-resistant Nkx3.1-?expressing cell in the luminal cell population of the prostate. We have used a mouse model targeting these cells to study the roles of two tumor suppressors, adenomatous polyposis coli (Apc) and Smad4. Apc down-regulates the Wnt signaling pathway, which is a carcinogenic pathway in the prostates of humans and mice. Deletion of Apc in mice causes an increase of Wnt signaling and prostate cells to proliferate but not invade, which represents a relatively indolent, precancerous phenotype. Smad4 is a transcription factor that controls the signaling of two pathways: transforming growth factor &beta; and bone morphogenetic protein signaling. Deletion of Smad4 causes these pathways to shut off. When Apc and Smad4 are deleted simultaneously, mice develop aggressive, invasive prostate cancer. This work suggests that these two tumor suppressors &ndash; and the pathways they control &ndash; are important regulators of prostate cancer, could allow for clinicians to differentiate between indolent and aggressive disease, and should be targeted therapeutically in prostate cancer patients.</p><p>

<p> The word "cancer" rarely stands alone, usually prefaced with its anatomical location: lung cancer, prostate cancer, brain cancer. With the advancement of high-throughput omics approaches, specific oncogenic events are reorganizing the landscape of cancer classification, at once creating commonalities between cancers arising in diverse anatomical locations and dividing organ-centric classifications of cancer into a multitude of subtypes. The term "precision medicine" postulates that these new, data-driven groupings based on molecular characterization are the key to making rational therapeutic choices. </p><p> The majority of this dissertation addresses the disconnect between extensive molecular characterization and poor cancer therapy outcomes for patients with glioblastoma multiforme (GBM). Despite clear evidence that hyperproduction of the ligand for PDGFR (platelet-derived growth factor receptor &alpha;) is sufficient to generate GBM of the proneural subtype, anti-PDGFR&alpha; therapeutics have proven disappointing in clinical trials. Cell adaptation contributes to therapeutic escape. In GBM, proneural tumor cells adopt transcriptional profiles of the mesenchymal subtype. The interconversion between the proneural and mesenchymal transcriptional classes within a tumor population presents both a challenge and an opportunity for therapeutic approaches. The proneural subtype has a proliferation phenotype and presents druggable targets such as PDGFR&alpha;. The mesenchymal subtype presents an invasive phenotype, but the targets are more challenging to drug. The typical screening for combination therapies that synergize to induce cell death is not as advantageous here, where the disease management is expected to include cytostatic drugs that act on two different aspects of the phenotype: proneurally mediated proliferation and mesenchymally mediated invasion. This work examines the applicability of a combination approach against a proneural target, PDGFR&alpha;, and mesenchymal targets in the STAT3 (signal transducer and activator of transcription 3) pathway, in the context of a proneural model of GBM.</p><p> The work is concluded with collection of work applying precision medicine in other disease contexts, most notably canine lymphoma.</p><p>

Loss of p53 function can lead to a variety of cancers, including breast cancer. Mice heterozygous for the p53 gene (designated Trp53 +/−) develop spontaneous mammary tumors, but this depends on the strain background and has been linked to a locus on chromosome 7 (designated SuprMam1). Mammary tumors are common in BALB/c-Trp53 +/−females, but are rare in C57BL/6-Trp53 +/− mice. Prevalence of genomic instability appears to contribute to the phenotype as loss of heterozygosity (LOH) is significantly more common among tumors arising in BALB/c-Trp53+/− mice compared to C57BL/6J-Trp53+/− mice. This increased LOH in BALB/c-Trp53+/− tumors was shown to be due to recombination events. The BALB/c strain has been shown to have a deficiency in non-homologous end joining (NHEJ) of DNA double strand breaks (dsb), however, this does not account for the increase of LOH events in tumors. Our hypothesis was that BALB/c-Trp53 +/− mice are more susceptible to mammary tumors due to impaired Homologous Recombination Repair (HRR) leading to LOH. Using the COMET assay, we demonstrate that dsbs persist longer in BALB/c-Trp53 +/− mouse embryonic fibroblasts (MEFs) compared to C57BL/6J- Trp53+/− MEFs. Similarly, co-localization of H2AX and the homologous recombination protein RAD51 remain at dsbs longer in BALB/c-Trp53+/− MEFs compared to C57BL/6-Trp53+/− MEFs. Palb2 , a gene that lies within the SuprMam1 interval and has been shown to contribute to heritable breast cancer, was chosen as an initial candidate gene. No coding SNPs or expression differences of Palb2 were found in the mammary glands between the two strains. Additional fine mapping and use of a filtering criteria in the SuprMam1 region yielded an additional 34 candidate genes. We demonstrate no significant differences in any of these genes in whole mammary glands and primary mammary epithelial cells between the two strains. Finally, using a congenic mouse strain, we demonstrate the lack of irradiation (IR) sensitivity alleles within the SuprMam1 region. These results suggest a possible defect in HRR in the BALB/c strain that is unlikely related to Palb2. The gene or genes responsible for increased mammary tumor incidence in the BALB/c-Trp53+/− remain to be identified.