HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis

Lisa Mirabello, Meredith Yeager, Kai Yu, Gary M. Clifford, Yanzi Xiao, Bin Zhu, Michael Cullen, Joseph F. Boland, Nicolas Wentzensen, Chase W. Nelson, Tina Raine-Bennett, Zigui Chen, Sara Bass, Lei Song, Qi Yang, Mia Steinberg, Laurie Burdett, Michael Dean, David Roberson, Jason MitchellThomas Lorey, Silvia Franceschi, Philip E. Castle, Joan Walker, Rosemary Zuna, Aimée R. Kreimer, Daniel C. Beachler, Allan Hildesheim, Paula Gonzalez, Carolina Porras, Robert D. Burk, Mark Schiffman

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Although most cervical human papillomavirus type 16 (HPV16) infections become undetectable within 1–2 years, persistent HPV16 causes half of all cervical cancers. We used a novel HPV whole-genome sequencing technique to evaluate an exceptionally large collection of 5,570 HPV16-infected case-control samples to determine whether viral genetic variation influences risk of cervical precancer and cancer. We observed thousands of unique HPV16 genomes; very few women shared the identical HPV16 sequence, which should stimulate a careful re-evaluation of the clinical implications of HPV mutation rates, transmission, clearance, and persistence. In case-control analyses, HPV16 in the controls had significantly more amino acid changing variants throughout the genome. Strikingly, E7 was devoid of variants in precancers/cancers compared to higher levels in the controls; we confirmed this in cancers from around the world. Strict conservation of the 98 amino acids of E7, which disrupts Rb function, is critical for HPV16 carcinogenesis, presenting a highly specific target for etiologic and therapeutic research.

Original languageEnglish (US)
Pages (from-to)1164-1174.e6
JournalCell
Volume170
Issue number6
DOIs
StatePublished - Sep 7 2017

Keywords

  • E7 gene
  • HPV epidemiology
  • HPV genomics
  • HPV16
  • cervical carcinogenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Mirabello, L., Yeager, M., Yu, K., Clifford, G. M., Xiao, Y., Zhu, B., Cullen, M., Boland, J. F., Wentzensen, N., Nelson, C. W., Raine-Bennett, T., Chen, Z., Bass, S., Song, L., Yang, Q., Steinberg, M., Burdett, L., Dean, M., Roberson, D., ... Schiffman, M. (2017). HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis. Cell, 170(6), 1164-1174.e6. https://doi.org/10.1016/j.cell.2017.08.001