Speakers at ICG-13

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Biography

David I Smith received his Ph.D. in Biochemistry from the University of Wisconsin in Madison in 1978. After postdoctoral fellowships at the Albert Einstein College of Medicine and the University of California, Irvine, he became an Assistant Professor at Wayne State University in 1985. In 1996 he joined the Department of Laboratory Medicine and Pathology at the Mayo Clinic. He is currently the head of the Technology Assessment Committee for the Mayo Clinic Center for Individualized Medicine with the responsibility of evaluating new technologies that could have a dramatic impact on basic research and its’ clinical translation. His laboratory studies the common fragile sites which are regions of profound instability found in all individuals. His laboratory also studies the various ways that human papillomavirus (HPV) is involved in the development of different cancers. He has been actively collaborating with BGI for the past several years and has with them been using whole genome sequencing to study the physical status of HPV in oropharyngeal squamous cell carcinomas.


Abstract

Using whole genome sequencing on the BGI sequencing platform to study human papillomaviruses role in the development of oropharyngeal squamous cell carcinoma

David I Smith, Ph.D.1, Jintu Wang, Ph.D.2, and Ge Gao, Ph.D.1

(1) Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; and (2) BGI, Shenzhen, China

Human papillomavirus (HPV) is involved in the development of a number of anogenital cancers and has been increasingly been involved in the development of a subset of head and neck cancers, namely oropharyngeal squamous cell carcinoma (OPSCC). The current accepted model for how HPV is involved in the development of different cancers was developed from the analysis of several cervical cancer cell lines and primary tumors (1). It is also assumed that this model applies for all HPV-driven cancers. However, there is much greater complexity with OPSCC as most of these patients also have a history of drinking and smoking. Furthermore not all HPV-positive OPSCCs are the same as some have high expression of the HPV-specific oncogenes, while others have much lower expression. To study HPVs physical status in OPSCC we previously utilized mate-pair next generation low pass sequencing on the Illumina sequencing platform. This revealed that HPV was integrated in the human genome in only 30% of HPV-positive OPSCCs (2). In this study we have used the BGI sequencing platform to generate 30-50X whole genome sequencing (WGS) data from 34 OPSCCs, 28 of which were HPV-positive. Since the entire HPV genomes present in these samples are also sequenced at depth by this WGS-based approach we could begin to characterize the precise physical status of HPV and what effect HPV integration, when it occurred, had on both the HPV and the human genome at the site of integration. This revealed that there was much greater complexity in HPV-driven OPSCC. The copy number in these samples varied from a single copy of the HPV genome to hundreds of HPV copies. Over half the samples had HPV integrated somewhere within the human genome, but we see many instances where there is both integrated and episomal copies of HPV present in a single tumor. We identified some very novel deletions and other alterations of the HPV genome in these tumors. Sometimes these occurred as a result of HPV integration and other times were present in the episomal copies of HPV. Finally, we demonstrate that the HPV integration event itself is quite disruptive to the HPV genome and could also result in amplification of human sequences at and around the integration site. Our results demonstrate that the classical model for HPVs role in cancer formation does not apply to OPSCC and further questions whether it is even valid for cervical cancer.

References

(1)    zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat. Rev Cancer 2002; 2(5): 342-350.

(2)    Gao G, Johnson SH, Kasperbauer JL, Eckloff BW, Tombers BW, Vasmatzis G, and Smith DI. Mate-pair sequencing of oropharyngeal squamous cell carcinomas reveals that HPV integration occurs much less frequently than in cervical cancer. J Clin Virol 2014: 59(3): 195-200.

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