The prognostication of head and neck squamous cell carcinoma (HNSCC) is largely based upon the tumor size and location and the presence of lymph node metastases. Here we show that gene expression patterns from 60 HNSCC samples assayed on cDNA microarrays allowed categorization of these tumors into four distinct subtypes. These subtypes showed statistically significant differences in recurrence-free survival and included a subtype with a possible EGFR-pathway signature, a mesenchymal-enriched subtype, a normal epithelium-like subtype, and a subtype with high levels of antioxidant enzymes. Supervised analyses to predict lymph node metastasis status were approximately 80% accurate when tumor subsite and pathological node status were considered simultaneously. This work represents an important step toward the identification of clinically significant biomarkers for HNSCC.

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...

OTSCC is increasing among young white individuals age 18 to 44 years, particularly among white women. Young white women may be a new, emerging head and neck cancer patient population.

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.

Because cancer cachexia differs significantly from starvation, nutritional supplementation must be used in conjunction with other anti-cachexia agents to reverse the chronic systemic inflammatory state and the effects of circulating tumor-derived factors seen in cachexia. Careful identification of patients at risk and those suffering from this syndrome will lead to better outcomes and treatments. Ultimately, more research is needed to better treat this devastating condition.

Differentiating rat neurons express high levels ofthe protooncogene product pp6Cr, a 60-kDa tyrosine kinase of unknown function encoded by c-src. pp6-src was found to be concentrated at least 9-fold in membranes from a subcellular fraction of nerve growth cones, the motile tips of outgrowing neuronal processes. Indirect immunofluorescence staining of cultured chick retinal explants showed pp60 in neuronal growth cones and processes, with the antigen particularly concentrated in growth cones of long neurites. pp6O'c in growth cone membranes was an active tyrosine-specific protein kinase with elevated tyrosine-specific protein kinase activity and reduced electrophoretic mobility characteristic of the form of pp6O'-in central nervous system neurons. pp6O-'c was present at lower levels in subceflular fractions from mature rat brain but synaptosomal membranes were not enriched. Preferential localization of an active form of pp6O'-' in nerve growth cone membranes and persistence of pp6O0c in mature neurons suggest that this tyrosine kinase is important in growth conemediated neurite extension and synaptic plasticity.localization of pp60csrc to a functionally specialized region of the central nervous system neuron would provide major insight into its biological function. Yet, the complexity of cell types and processes in histological sections of the neural retina and cerebellum, in which pp6Oc-src expression has been characterized immunocytochemically, precluded conclusions about its subcellular location (10, 11).Located at the tip of the outgrowing neurite is the nerve growth cone, a motile structure rich in cytoskeletal elements, that guides the neurite through the developing tissue. In this report we demonstrate that the activated form of pp60c-src is highly concentrated in membranes of a subcellular fraction enriched in nerve growth cones from fetal rat brain, and pp60C-src antibodies preferentially bind the growth cone and proximal axon shaft of neurons in culture. These results suggest that pp6Oc-src is important in growth cone-mediated axon extension, a process that depends on selective cellsurface adhesion and cytoskeletal modulation.The normal cellular c-src gene encodes a 60-kDa tyrosinespecific protein kinase (pp6c-src) that is homologous to the transforming protein of Rous sarcoma virus (1-4). pp60c-src is highly conserved in evolution and exhibits homology with growth factor receptor/tyrosine kinases, leading to the suggestion that pp6-src plays a crucial role in the growth or development of animal cells. However, despite intensive investigation, the biological role of pp60c-src remains unknown.Analysis of pp6O-src expression in the developing nervous system has indicated that pp60c-src is probably important in neuronal differentiation. pp6-src is expressed in a wide variety of cell types, but highest levels are present in embryonic nervous tissues (5-12). Two phases of pp60csrc expression in the neural lineage have been identified by immunocytochemical staining of developing embryos. An early phas...

Background. Animal models suggest that cyclooxygenase-2 (COX-2) inhibitors may be beneficial in suppressing cancer cachexia. We investigated the effect of short-course celecoxib on body composition, inflammation, and quality of life (QOL) in patients with cancer cachexia in a phase II clinical pilot trial.Methods. Eleven cachectic patients with head and neck or gastrointestinal cancer were randomly assigned to receive placebo or celecoxib for 21 days while awaiting the initiation of cancer therapy. Body composition, resting energy expenditure, QOL, physical function, and inflammatory markers were measured on days 1 and 21.Results. Patients receiving celecoxib experienced statistically significant increases in weight and body mass index (BMI), while patients receiving placebo experienced weight loss and a decline in BMI. Patients receiving celecoxib also had increases in QOL scores.Conclusions. This syndrome is distinct from starvation in that it involves preferential wasting of lean body mass (LBM) while visceral proteins are preserved; elevated systemic inflammation, including increased levels of acute phase proteins and inflammatory cytokines; and elaboration of tumor-derived catabolic factors.2 Cachexia remains difficult to treat, with few U.S. Food and Drug Administrationapproved therapeutic options other than megestrol acetate, dronabinol, and oxandrolone.2 These

Quantitative RT-PCR detection of cytokeratin 5 or 14 is a sensitive new molecular technique that may be used for detection of cervical micrometastases in head and neck cancer.