Human papillomavirus and the landscape of secondary genetic alterations in oral cancers

Maura Gillison, Keiko Akagi, Weihong Xiao, Bo Jiang, Robert K.L. Pickard, Jingfeng Li, Benjamin J. Swanson, Amit D. Agrawal, Mark Zucker, Birgit Stache-Crain, Anne Katrin Emde, Heather M. Geiger, Nicolas Robine, Kevin R. Coombes, David Eric Symer

Research output: Contribution to journalArticle

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Abstract

Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5 -ATN-3 correlated with tobacco exposure. Universal expression of HPV E6 1 and E7 oncogenes was a sine qua non of HPV-positive OSCCs. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1, and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon (IFN) and nuclear factor kappa B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCCs, in contrast to their gains in HPV-negative OSCCs. High-ranking variant allele fractions implicated ZNF750, PIK3CA, and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalGenome Research
Volume29
Issue number1
DOIs
StatePublished - Jan 1 2019

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Mouth Neoplasms
Squamous Cell Carcinoma
Neoplasms
TNF Receptor-Associated Factor 3
Cytosine Deaminase
Tumor Suppressor Protein p53
Mutation
NF-kappa B
Virus Diseases
Genomics
Oncogenes
Interferons
Tobacco
Immunity
Alleles

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Human papillomavirus and the landscape of secondary genetic alterations in oral cancers. / Gillison, Maura; Akagi, Keiko; Xiao, Weihong; Jiang, Bo; Pickard, Robert K.L.; Li, Jingfeng; Swanson, Benjamin J.; Agrawal, Amit D.; Zucker, Mark; Stache-Crain, Birgit; Emde, Anne Katrin; Geiger, Heather M.; Robine, Nicolas; Coombes, Kevin R.; Symer, David Eric.

In: Genome Research, Vol. 29, No. 1, 01.01.2019, p. 1-17.

Research output: Contribution to journalArticle

Gillison, M, Akagi, K, Xiao, W, Jiang, B, Pickard, RKL, Li, J, Swanson, BJ, Agrawal, AD, Zucker, M, Stache-Crain, B, Emde, AK, Geiger, HM, Robine, N, Coombes, KR & Symer, DE 2019, 'Human papillomavirus and the landscape of secondary genetic alterations in oral cancers', Genome Research, vol. 29, no. 1, pp. 1-17. https://doi.org/10.1101/gr.241141.118
Gillison, Maura ; Akagi, Keiko ; Xiao, Weihong ; Jiang, Bo ; Pickard, Robert K.L. ; Li, Jingfeng ; Swanson, Benjamin J. ; Agrawal, Amit D. ; Zucker, Mark ; Stache-Crain, Birgit ; Emde, Anne Katrin ; Geiger, Heather M. ; Robine, Nicolas ; Coombes, Kevin R. ; Symer, David Eric. / Human papillomavirus and the landscape of secondary genetic alterations in oral cancers. In: Genome Research. 2019 ; Vol. 29, No. 1. pp. 1-17.
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