Novel Insights into Head and Neck Cancer using Next-Generation 'Omic' Technologies

摘要

Abstract Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease that develops via one of the two primary carcinogenic routes: chemical cardnogenesis through exposure to tobacco and alcohol or virally induced tumorigenesis. Human papillomavirus (HPV)-positive (HPV+) and HPV-negative (HPV-) HNSCCs represent distinct clinical entities, with the latter associated with significantly inferior outcome. The biologic basis of these different outcomes is an area of intense investigation; their therapeutic regimens are currently also being reevaluated, which would be significantly facilitated by reliable biomarkers for stratification. With the advent of the omics era and accelerated development of targeted therapies, there are unprecedented oppor tunities to address the challenges in the management of HNSCC. As summarized herein, side-by-side molecular characterization of HPV^ versus HPV~ HNSCC has revealed distinct molecular landscapes, novel prognostic signatures, and potentially targetable biologic pathways. In particular, we focus on the evidence acquired from genome-wide omics pertinent to our understanding of the clinical behavior of HNSCC and on insights into personalized treatment opportunities. Integrating, mining, and validating these data toward clinically meaningful outcomes for patients with HNSCC in conjunction with systematic verification of the functional relevance of these findings are critical steps toward the design of personalized therapies. Oncogenic Role of Human Papillomaviruses High-risk human papillomaviruses (HPV) are double-stranded DNA viruses that infect epithelial cells (1). Tumorigenesis by high-risk HPVs is driven by their two main viral oncogenes, E6 and E7, which inactivate p53 and pRb, respectively, leading to cell-cycle deregulation and inhibition of p53-mediated apoptosis (1,2). ￡7binds pRb, targeting it toward proteosomal degradation, in turn releasing the E2F transcription factor, resulting in CDKN2A (or pi6) overexpression and cell-cycle progression (1).