Abstract

Using Next Generation Sequencing to Study How Human Papillomavirus is responsible for the Development of a Number of Different Cancers

David Smith, Professor, Mayo Clinic

Human papillomavirus (HPV) is responsible for the development of virtually all cervical cancers. HPV is also found in 85% of anal cancers and in over half of vulvar and penile cancers. This virus is also responsible for the epidemic increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the United States over the past several decades. The model for how HPV causes cancer is based upon studies in cervical cancer. Women who are infected with HPV and do not clear the virus are at increased risk of developing cervical cancer. However, HPV infection alone only immortalizes cells and thus additional alterations are required before invasive and metastatic cervical cancer can develop. Most invasive cervical cancers have HPV integrated into the human genome and that integration event causes overexpression of the two HPV-specific oncoproteins HPV E6 and E7. Since HPV has been found to be integrated in multiple positions throughout the genome in different cervical cancers it was thought that the site of integration was unimportant. We utilized whole exome next generation sequencing (NGS) of cervical adenocarcinomas found in Hong Kong women and found that in 13 of 15 cancers studied that HPV had integrated close to exonic sequences and that many of the human genes involved could play important roles in cancer development. This suggests that HPV integration in not random and could play an important role in the eventual cancer that develops. We have also been studying OPSCCs, using both RNA sequencing and mate-pair whole genome sequencing (WGS). The mate-pair WGS revealed that HPV integration was much less common in OPSCC than in cervical cancers, thus most OPSCCs have H