Details

Autor(en) / Beteiligte

• Gillison, Maura L
• 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 E

Titel

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

Ist Teil von

• Genome research, 2019-01, Vol.29 (1), p.1-17

Ort / Verlag

United States

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 and oncogenes was a sine qua non of HPV-positive OSCCs. Significant enrichment of somatic mutations was confirmed or newly identified in , , , , , , , , , , , , , , , , and 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 ) and 14q (including and ) were recurrently lost in HPV-positive OSCCs, in contrast to their gains in HPV-negative OSCCs. High-ranking variant allele fractions implicated , , and 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.