The current model of colorectal carcinogenesis is characterized by a gradual accumulation of genetic alterations leading to the development of polyps, which subsequently become primary carcinomas. Recent studies have suggested that Human Papillomavirus (HPV) infections may also play a role in the development of colorectal cancer (CRC). HPV infections are the most frequently sexually transmitted diseases in the world and some evidence supports that hematogenous spread of this virus may also be possible. The association between HPV infections and the development of cervical and anogenital cancer has been clearly established. Several studies have identified the presence of HPV in colorectal tissues suggesting that infection may be associated with the development and progression of CRC. However, the possible role of HPV and the mechanistic pathways leading to colorectal carcinogenesis remain to be defined. The overall objective of this application is to detect the presence, integration status and viral load of HPV, and to determine the expression level of key HPV oncogenes (E6 and E7) to elucidate if HPV is a risk factor for CRC. Our central hypothesis is that integration of the HPV oncogenes (E6 and E7) into the human genome cause cell cycle dysregulation, leading to the development of neoplasia in colorectal tissues. The following aims have been proposed: (1) Aim 1. To assess the prevalence of HPV DNA in malignant (cases) and non- malignant (controls) colorectal tissues in order to determine if there is an association between HPV infection and CRC (using nested PCR to detect HPV-16 and HPV-18 DNA;sequencing of PCR products for HPV genotyping). (2) Aim 2. To examine the genotype distribution of HPV in colorectal tissues HPV L1 positive cases, and determine integration of HPV genes into tumor genome (using nested PCR with primers specific for HPV-16 E6/E7, and HPV-18 E6/E7 viral oncogenes;integration status assessed with quantitative Real- Time PCR). (3) Aim 3. To quantify the mRNA expression levels of the HPV-16 and HPV-18 viral oncogenes E6 and E7 in HPV-positive cases (using QRT-PCR Taqman reaction strategy). We propose to describe the relationship of HPV infection and CRC, using a sound study design and validated laboratory methods, in a well-characterized population of Hispanic patients. We anticipate that our proposal will fill an existing gap regarding the role of HPV-infection in CRC and will examine the biological mechanisms responsible for colon carcinogenesis. Identification of HPV as an etiologic factor in CRC carcinogenesis may impact current molecular models, prevention strategies and treatment algorithms.
The etiology for the majority of CRC cases is still unknown, with most cases classified as sporadic. Identification of HPV as an etiologic factor in CRC carcinogenesis, even for a small fraction of cases, may have immediate impact to current molecular carcinogenic models, prevention strategies and treatment algorithms. As HPV-infection is highly prevalent in minority and underserved populations, our findings may have considerable effect in decreasing the burden of CRC among high-risk populations.
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