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 Mitchell; Thomas 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

doi:10.1016/j.cell.2017.08.001

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 journal › Article › peer-review

169 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 language	English (US)
Pages (from-to)	1164-1174.e6
Journal	Cell
Volume	170
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2017.08.001
State	Published - Sep 7 2017

Keywords

E7 gene
HPV epidemiology
HPV genomics
HPV16
cervical carcinogenesis

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2017.08.001

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

Mirabello, L, Yeager, M, Yu, K, Clifford, GM, Xiao, Y, Zhu, B, Cullen, M, Boland, JF, Wentzensen, N, Nelson, CW, Raine-Bennett, T, Chen, Z, Bass, S, Song, L, Yang, Q, Steinberg, M, Burdett, L, Dean, M, Roberson, D, Mitchell, J, Lorey, T, Franceschi, S, Castle, PE, Walker, J, Zuna, R, Kreimer, AR, Beachler, DC, Hildesheim, A, Gonzalez, P, Porras, C, Burk, RD & Schiffman, M 2017, 'HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis', Cell, vol. 170, no. 6, pp. 1164-1174.e6. https://doi.org/10.1016/j.cell.2017.08.001

@article{5fbb9bcfb35f4e2b993850af5ed03787,

title = "HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis",

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.",

keywords = "E7 gene, HPV epidemiology, HPV genomics, HPV16, cervical carcinogenesis",

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

note = "Funding Information: We thank Ayax Perez Gallegos, Albert Einstein College of Medicine, for helpful input on HPV16 E6 protein structure. C.W.N. was supported by a Gerstner Scholars Fellowship from the Gerstner Family Foundation at the American Museum of Natural History . This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH . This project has been funded in whole or in part with federal funds from the National Cancer Institute , NIH ( HHSN261200800001E ); and, the National Cancer Institute ( CA78527 ) and the Einstein Cancer Research Center ( P30CA013330 ) from the National Cancer Institute (to R.D.B.). Work at IARC was supported by a grant from the Institut National du Cancer (INCa), France ( SHSESP 16-006 ). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Publisher Copyright: {\textcopyright} 2017",

year = "2017",

month = sep,

day = "7",

doi = "10.1016/j.cell.2017.08.001",

language = "English (US)",

volume = "170",

pages = "1164--1174.e6",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis

AU - Mirabello, Lisa

AU - Yeager, Meredith

AU - Yu, Kai

AU - Clifford, Gary M.

AU - Xiao, Yanzi

AU - Zhu, Bin

AU - Cullen, Michael

AU - Boland, Joseph F.

AU - Wentzensen, Nicolas

AU - Nelson, Chase W.

AU - Raine-Bennett, Tina

AU - Chen, Zigui

AU - Bass, Sara

AU - Song, Lei

AU - Yang, Qi

AU - Steinberg, Mia

AU - Burdett, Laurie

AU - Dean, Michael

AU - Roberson, David

AU - Mitchell, Jason

AU - Lorey, Thomas

AU - Franceschi, Silvia

AU - Castle, Philip E.

AU - Walker, Joan

AU - Zuna, Rosemary

AU - Kreimer, Aimée R.

AU - Beachler, Daniel C.

AU - Hildesheim, Allan

AU - Gonzalez, Paula

AU - Porras, Carolina

AU - Burk, Robert D.

AU - Schiffman, Mark

N1 - Funding Information: We thank Ayax Perez Gallegos, Albert Einstein College of Medicine, for helpful input on HPV16 E6 protein structure. C.W.N. was supported by a Gerstner Scholars Fellowship from the Gerstner Family Foundation at the American Museum of Natural History . This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH . This project has been funded in whole or in part with federal funds from the National Cancer Institute , NIH ( HHSN261200800001E ); and, the National Cancer Institute ( CA78527 ) and the Einstein Cancer Research Center ( P30CA013330 ) from the National Cancer Institute (to R.D.B.). Work at IARC was supported by a grant from the Institut National du Cancer (INCa), France ( SHSESP 16-006 ). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Publisher Copyright: © 2017

PY - 2017/9/7

Y1 - 2017/9/7

N2 - 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.

AB - 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.

KW - E7 gene

KW - HPV epidemiology

KW - HPV genomics

KW - HPV16

KW - cervical carcinogenesis

UR - http://www.scopus.com/inward/record.url?scp=85027115173&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027115173&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.08.001

DO - 10.1016/j.cell.2017.08.001

M3 - Article

C2 - 28886384

AN - SCOPUS:85027115173

SN - 0092-8674

VL - 170

SP - 1164-1174.e6

JO - Cell

JF - Cell

IS - 6

ER -

HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this