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. TP53, PIK3CA, PDGFRA, HRAS, and RET 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 ‘driver’ somatic mutations that an individual accumulates over their lifetime.
|Advisor:||Abbas, Muneer, Ricks-Santi, Luisel|
|Commitee:||Doumatey, Ayo, Kanaan, Yasmine, StubbsIII, John, Thompson, Karl|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 79/07(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics, Oncology|
|Keywords:||Anal cancer, HPV, Next generation sequencing, Somatic mutations, miRNA expression|
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