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. Twentyfive 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.cancer | head and neck | papilloma virus | genome rearrangement | integration sites H ead and neck cancer (HNC) is a heterogeneous group of tumors characterized by a common anatomic origin, and most such tumors develop from within the mucosa and are classified as head and neck squamous cell carcinomas (HNSCCs) (1). HNSCC, the sixth most common cancer diagnosed worldwide and the eighth most common cause of cancer death (2), is frequently associated with human papillomavirus (HPV) infection (3, 4). Depending on the anatomic site of the tumor, HPV prevalence is estimated at 23-36% (5). HPV-positive HNSCCs form a distinct subset of HNCs that differs from HPV-negative HNSCCs in tumor biology and clinical characteristics, including superior clinical outcomes (6-9).The molecular pathogenesis of HPV-driven HNSCC also seems distinct from HPV-negative tumors, with previous studies showing a divergent spectrum of alterations in gene expression, mutations, amplifications, and deletions as well as distinct epigenome alterations (10-15). HPV is known to drive tumorigenesis through the actions of its major oncoproteins E6 and E7, which target numerous cellular pathways, including inactivation of p53 and the retinoblastoma (Rb) protein (16-18). Together with E5, they also play an important role in immune evasion, being involved in both innate and adaptive immunity (19,20).Initially after infection, HPV is identified in circular extrachromosomal particles or episomes. A critical step in progression to cancer is the integration of viral DNA into the host cell Significance A significant proportion of head and neck cancer is driven by human papil...

Head and neck cancers (HNCs) are a highly heterogeneous group of tumours that are associated with diverse clinical outcomes. Recent evidence has demonstrated that human papillomavirus (HPV) is involved in up to 25% of HNCs; particularly in the oropharyngeal carcinoma (OPC) subtype where it can account for up to 60% of such cases. HPVs are double-stranded DNA viruses that infect epithelial cells; numerous HPV subtypes, including 16, 18, 31, 33, and 35, drive epithelial cell transformation and tumourigenesis. HPV positive (HPV+) HNC represents a distinct molecular and clinical entity from HPV negative (HPV−) disease; the biological basis for which remains to be fully elucidated. HPV positivity is strongly correlated with a significantly superior outcome; indicating that such tumours should have a distinct management approach. This review focuses on the recent scientific and clinical investigation of HPV+ HNC. In particular, we discuss the importance of molecular and clinical evidence for defining the role of HPV in HNC, and the clinical impact of HPV status as a biomarker for HNC.

Nasopharyngeal carcinoma (NPC) is a unique epithelial malignancy arising from the superior aspect of the pharyngeal mucosal space, associated with latent Epstein-Barr virus infection in most cases. The capacity to characterize cancer genomes in unprecedented detail is now providing insights into the genesis and molecular underpinnings of this disease. Herein, we provide an overview of the molecular aberrations that likely drive nasopharyngeal tumor development and progression. The contributions of major Epstein-Barr virus-encoded factors, including proteins, small RNAs, and microRNAs, along with their interactions with pathways regulating cell proliferation and survival are highlighted. We review recent analyses that clearly define the role of genetic and epigenetic variations affecting the human genome in NPC. These findings point to the impact of DNA methylation and histone modifications on gene expression programs that promote this malignancy. The molecular interactions that allow NPC cells to evade immune recognition and elimination, which is crucial for the survival of cells expressing potentially immunogenic viral proteins, are also described. Finally, the potential utility of detecting host and viral factors for the diagnosis and prognosis of NPC is discussed. Altogether, the studies summarized herein have greatly expanded our knowledge of the molecular biology of NPC, yet much remains to be uncovered. Emerging techniques for using and analyzing well-annotated biospecimens from patients with NPC will ultimately lead to a greater level of understanding, and enable improvements in precision therapies and clinical outcomes.