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

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease that develops via one of the two primary carcinogenic routes: chemical carcinogenesis through exposure to tobacco and alcohol or virally induced tumorigenesis. Human papillomavirus (HPV)-positive (HPV þ ) and HPV-negative (HPV À ) 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 opportunities to address the challenges in the management of HNSCC. As summarized herein, side-by-side molecular characterization of HPV þ versus HPV À 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. Cancer Res; 75(3); 480-6. Ó2014 AACR. Oncogenic Role of Human PapillomavirusesHigh-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 cellcycle deregulation and inhibition of p53-mediated apoptosis (1, 2). E7 binds pRb, targeting it toward proteosomal degradation, in turn releasing the E2F transcription factor, resulting in CDKN2A (or p16) overexpression and cell-cycle progression (1).High-risk HPVs, predominantly types 16, 18, 31, 33, and 35, are estimated to cause approximately 5% of cancers worldwide, including 99% of cervical, 25% of head and neck (or 60% oropharyngeal), 70% of vaginal, 88% of anal, 43% of vulvar, and 50% of penile cancers, in order of prevalence (1-6). A significant subset of approximately 500,000 annual cases of head and neck squamous cell carcinoma (HNSCC) include approximately 85,000 HPV-associated tumors, establishing this as the second most common HPV-associated tumor site (3, 4). HPV type 16 is identified in over 90% of HPV-associated HNSCCs (4). The majority of the remaining HNSCCs are attributed to exposure to chemical carcinogens such as tobacco and alcohol.HPV-positive (HPV þ ) and HPV-negative (HPV À ) HNSCCs are separate entities associated with distinct etiology, clinical behavior, treatment outcomes, imaging and pathology appearance, and molecular profiles (2, 7). HPV þ HNSCC primarily involves the oropharynx (pr...

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

“…20 Loss of the tumor suppressor SMAD4, leading to abrogation of TGFb signaling, has been reported in HPV-HNSCC. 21 By combining deletion of important tumor suppressors, Pten and Tgfbr1, we constructed a spontaneous immune competent HNSCC mouse model (HPV-).…”

Integrating genomics in head and neck cancer treatment: Promises and pitfalls

“…A systematic search of the literature in PubMed was performed (before 9/2014) with the terms: HNSCC (restricted to mucosal carcinomas, excluding salivary gland, sinonasal cancers and mucosal melanomas) AND human papilloma virus (HPV) (68 references), mutation (68), oncogene (7700), tumor suppressor gene (TSG) (5170), driver (51), genomics (633), genetics AND sequencing (1592). Polymorphisms that might confer a genetic susceptibility to HNSCC [2] or epigenetic variations and chromosomal/copy number alterations were not specifically addressed.…”

“…Another limitation of WES is the lack of information provided on epigenetic variations. Epigenetic modulations play a crucial role in tumorigenesis, and although some epigenetic factors may lie in the exome, a considerable amount information resides in the noncoding DNA sequences [68]. This pitfall could be avoided using whole genome sequencing.…”

Epidemiology of HPV-Associated Oropharyngeal Squamous Cell Carcinoma

“…Further, several critically important molecular pathways, including TP53, RB1, NOTCH, WNT, NF-κB, and PIK3CA/AKT/MTOR that control the cell cycle, cell death, cell proliferation, and DNA synthesis are hijacked in HPV-positive OPSCC compared to HPV-negative tumors, resulting in a unique molecular phenotype in these tumors that might be druggable in a personalized genomic medicine approach (reviewed by Rampias et al 2014). Multiple recent articles discuss molecular genetic differences between HPV-positive and negative OPSCC/HNSCC, which is beyond the scope of this chapter (Sepiashvili et al 2015;The Cancer Genome Atlas 2015). Probably as a result of less chromosomal instability and fewer mutations in their tumors, patients with HPV-positive OPSCC have better disease-free and overall survival than those with HPV-negative tumors (Pytynia et al 2014).…”