Characterization of HPV and host genome interactions in primary head and neck cancers.
Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.
|Year of Publication
Proc Natl Acad Sci U S A
2014 Oct 28
|PubMed Central ID
P30 CA016672 / CA / NCI NIH HHS / United States
U24 CA143882 / CA / NCI NIH HHS / United States
K08 CA163677 / CA / NCI NIH HHS / United States
K08 DE024774 / DE / NIDCR NIH HHS / United States
U24 CA144025 / CA / NCI NIH HHS / United States
R01 CA098372 / CA / NCI NIH HHS / United States
P30 CA177558 / CA / NCI NIH HHS / United States
U24 CA143867 / CA / NCI NIH HHS / United States
R01 DE023685 / DE / NIDCR NIH HHS / United States