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Whole-Genome Sequencing of HPV 16 Reveals New Criterion for Carcinogenicity

, by DCEG Staff

Loading next-generation robotics for studies of human papillomavirus DNA

A large genomic analysis of human papillomavirus (HPV) shines new light on the influence of viral genetic diversity on carcinogenicity of the high-risk type HPV 16. Investigators in the Division of Cancer Epidemiology and Genetics, National Cancer Institute, led by Lisa Mirabello, Ph.D., M.S., and collaborators, observed that a particular genetic sequence of the E7 oncogene is common to virtually all cervical cancers caused by HPV 16 worldwide. The study was published online in the journal Cell on September 7, 2017.

HPV 16 causes about half of all cervical cancer cases worldwide. Most infections clear on their own, but the few that persist can cause precancer, which could ultimately develop into cancer. It is not known why these common and typically benign HPV 16 infections only sometimes cause cancer. Prior studies by DCEG scientists and others have shown that HPV 16 can be divided into ten sublineages that confer strong differences in risk of precancer and cancer, but the team hoped that even finer distinctions could lead to a greater understanding of the molecular mechanisms of viral carcinogenesis.

The researchers first examined genetic diversity of HPV 16 found in samples taken from women in four studies. A surprisingly low percentage of distinct viral genomes, or isolates, were identified in more than one woman, about 15-25 percent depending on the cohort, suggesting a much greater viral genetic diversity between women than was previously thought. Conversely, viral diversity was low within individuals at multiple HPV 16-positive body sites: in evaluating cervical samples paired with oral, anal, or vulvar samples, 82 percent of the HPV 16 genomes sequenced were the same at both sites.

When they compared the HPV 16 genome sequences of the cases and controls, they discovered that the controls, the benign infections, had significantly more protein-changing variants throughout the genome. In particular, samples taken from cervical cancer cases around the world were devoid of protein-changing variants in the E7 oncogene, compared to higher levels in the controls. Further study of the E7 region revealed that the majority of these rare variants observed in the controls were potentially due to the activity of human APOBEC3 cytidine deaminases, DNA editing enzymes that are thought to be part of the innate immune system and have antiviral effects. In stark contrast, variation in the other major HPV 16 oncogene, E6, was not significantly different between cases and controls. Furthermore, E6 had more protein-changing variants than E7 in the cancer cases. These results suggest that the uniquely potent carcinogenicity of HPV 16 hinges on the conservation of the E7 protein.

This work has major implications for the study of cervical cancer etiology and prevention. Future research is required to characterize HPV 16 genetic variation in increasing depth and to understand the specific molecular mechanisms behind E7 carcinogenic properties.

Reference: Mirabello L, et al. HPV16 E7 genetic conservation is critical to carcinogenesis. Cell. September 7, 2017. DOI:

This research was featured on the NCI Cancer Currents blog.

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