In:
Genome Research, Cold Spring Harbor Laboratory, Vol. 29, No. 1 ( 2019-01), p. 1-17
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.
Type of Medium:
Online Resource
ISSN:
1088-9051
,
1549-5469
DOI:
10.1101/gr.241141.118
Language:
English
Publisher:
Cold Spring Harbor Laboratory
Publication Date:
2019
detail.hit.zdb_id:
1483456-X
SSG:
12
