Tara J Nulton1, Nak-Kyeong Kim2, Laurence J DiNardo3, Iain M Morgan4, Brad Windle5. 1. Philips Institute for Oral Health Research, Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Virginia Commonwealth University, Box 980566, Richmond, VA 23298, USA. Electronic address: nultontj@vcu.edu. 2. VCU Massey Cancer Center, Box 980037, Richmond, VA 23298, USA; Department of Biostatistics, School of Medicine, Virginia Commonwealth University, Box 980032, Richmond, VA, USA. Electronic address: kyeong.kim@vcuhealth.org. 3. VCU Massey Cancer Center, Box 980037, Richmond, VA 23298, USA; Department of Otolaryngology - Head and Neck Surgery, School of Medicine, Virginia Commonwealth University, Box 980146, Richmond, VA 23298, USA. Electronic address: laurence.dinardo@vcuhealth.org. 4. Philips Institute for Oral Health Research, Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Virginia Commonwealth University, Box 980566, Richmond, VA 23298, USA; VCU Massey Cancer Center, Box 980037, Richmond, VA 23298, USA. Electronic address: immorgan@vcu.edu. 5. Philips Institute for Oral Health Research, Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Virginia Commonwealth University, Box 980566, Richmond, VA 23298, USA; VCU Massey Cancer Center, Box 980037, Richmond, VA 23298, USA. Electronic address: bwindle@vcu.edu.
Abstract
OBJECTIVES: We previously reported identifying three categories of HPV16-positive head and neck tumors based on The Cancer Genome Atlas (TCGA) RNA and DNA sequence data. Category 1 had truly integrated HPV16 genomes, category 2 had simple episomal genomes, and category 3 had novel episomes that were a hybrid between viral and human DNA. Using our categorization, we investigated in this study survival of patients with integrated HPV16 tumors versus patients with episomal HPV16 tumors. MATERIALS AND METHODS: The TCGA RNA-Seq sequence reads were used to quantify HPV E2 and E7 gene expression, which was used as a marker for HPV integration. RESULTS: The results demonstrate that integration is associated with poor survival; those patients with integrated HPV tumors fared no better than non-HPV tumors in their five-year survival. Integrated HPV in tumors was found strikingly to be prevalent in patients born earlier while episomal HPV was prevalent in patients born later. We also observed a fairly constant incidence of all HPV forms among head and neck cancer patients over the last eight years of this study (2006-2013). CONCLUSION: We propose our characterization of HPV integrated and episomal state is more accurate than previous studies that may have mischaracterized the hybrid HPV-human DNA episomes as integrated. The state of integrated HPV is associated with a poor clinical outcome. Results suggest that the incidence of integrated HPV among all HPV forms peaked and is decreasing. We discuss the importance of our findings for the management of HPV positive head and neck cancer.
OBJECTIVES: We previously reported identifying three categories of HPV16-positive head and neck tumors based on The Cancer Genome Atlas (TCGA) RNA and DNA sequence data. Category 1 had truly integrated HPV16 genomes, category 2 had simple episomal genomes, and category 3 had novel episomes that were a hybrid between viral and human DNA. Using our categorization, we investigated in this study survival of patients with integrated HPV16tumors versus patients with episomal HPV16 tumors. MATERIALS AND METHODS: The TCGA RNA-Seq sequence reads were used to quantify HPV E2 and E7 gene expression, which was used as a marker for HPV integration. RESULTS: The results demonstrate that integration is associated with poor survival; those patients with integrated HPV tumors fared no better than non-HPV tumors in their five-year survival. Integrated HPV in tumors was found strikingly to be prevalent in patients born earlier while episomal HPV was prevalent in patients born later. We also observed a fairly constant incidence of all HPV forms among head and neck cancerpatients over the last eight years of this study (2006-2013). CONCLUSION: We propose our characterization of HPV integrated and episomal state is more accurate than previous studies that may have mischaracterized the hybrid HPV-human DNA episomes as integrated. The state of integrated HPV is associated with a poor clinical outcome. Results suggest that the incidence of integrated HPV among all HPV forms peaked and is decreasing. We discuss the importance of our findings for the management of HPV positive head and neck cancer.
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