Human Papillomavirus (HPV) Genomics Project: Exploring The Carcinogenicity Of HPV Worldwide

Gary CLIFFORD, IARC, France
MIRABELLO L. 2 , SCHIFFMAN M. 2 , TENET V. 1 , WENTZENSEN N. 2 , CULLEN M. 2,3 , BOLAND J. 2,3 , ZHANG X. 3 , FRANCESCHI S. 1 , YU K. 2 , YANG Q. 3 , BURK R. 4 , YEAGER M. 2,3

1 International Agency for Research on Cancer, Lyon, France
2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, U.S.A.
3 Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, U.S.A.
4 Albert Einstein College of Medicine

Objectives: High-risk HPV types, as well as variant lineages of HPV16, differ considerably in carcinogenicity despite close evolutionary relatedness. However, methods to assess the genetic basis of such variation have been lacking.  We seek to leverage the type of next-generation sequencing technologies and analyses that have been developed for human genomics, to study the viral genetic component of cervical cancer risk.
Methods: Using an Ampliseq and Ion Torrent-based method developed at NCI U.S.A., we are sequencing DNA derived from FFPE, frozen biopsies or cervical cell samples from 2364 HPV16-positive women: 1521 cervical cancer cases, 213 CIN2/3, and 630 controls. Cervical samples have been collected worldwide from 37 diverse populations during 30 years by the International Agency for Research on Cancer (IARC) studies on HPV and cancer. Using case-control comparisons, we are evaluating associations between viral genetic variation and cancer risk, including (1) comparison of viral lineages and sublineages, (2) individual SNPs, and (3) gene-level associations. We are also studying human genetic variation and ancestry in relationship to HPV16 genetic variation and cancer risk.
Results: At the time of abstract submission, whole viral genome sequences have been obtained and analyzed for 1,550 HPV16-positive samples (1,044 cervical cancer cases, 118 CIN2/3, and 388 controls). Variation in the HPV16 E1 and URR regions are strongly and significantly associated with cervical cancer risk. Completed findings for 2,364 HPV16-positive women in the IARC biobank will present the final results at the meeting. 
Conclusions: Based on preliminary data, the chance of this approach defining viral genetic determinants of cervical cancer risk appears high, and we are planning to apply it to other high-risk HPV types. This technology now permits much larger studies and more complete genotype-phenotype examinations of HPV genomes than previously possible.