Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papilloma virus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA and HRAS, we identified mutations in FBXW7 and NOTCH1. Interestingly, nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

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In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.

Disruptive TP53 mutations in tumor DNA are associated with reduced survival after surgical treatment of squamous-cell carcinoma of the head and neck.

Despite recent advances in the diagnosis and treatment of head and neck cancer, there has been little evidence of improvement in 5-year survival rates over the last few decades. To determine more accurate trends in site-specific outcomes as opposed to a more general overview of head and neck cancer patients, we analyzed the site-specific data collected in the Surveillance, Epidemiology, Population-based cancer statistics in the United States (US) for 2004 is expected to yield 28,260 new cases of oral cavity and pharynx cancer and 20,260 new cases of larynx cancer, with a mortality of 7,230 and 3,830 deaths per year, respectively. 1 Despite improvements in diagnosis and treatment, in the last 3 decades there have been no changes in the 5-year survival rate for larynx cancer patients and only a slight but significant improvement for oral cavity and pharynx cancer patients when comparing patients treated during 1973-1977 (5-year survival rate of 53%) to patients treated during 1993-1997 (5-year survival rate of 56%) according to results based on data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. 2 This slight change in survival was first noted in the 2002 publication, 2 but these data can still be interpreted as indicating that "there is no change in prognosis for the last 2 decades" for head and neck cancer (HNC). However, during the last 2 decades many articles have consistently demonstrated advances in treatment, most notably the use of combination therapy (adjuvant radiotherapy after surgery, concurrent chemotherapy and radiotherapy) with improvements in survival rates. [3][4][5][6] In addition, improvements in radiotherapy and perioperative care, as well as prevention of chemotherapy-related complications, have resulted in increased quality of life and decreased treatment-related mortality. 6 Another important factor that may influence survival includes lead-time bias. New technologies such as fiberoptic laryngoscopy, more widespread dental professional screening for oral cancer and higher-resolution radiological techniques may result in earlier stage diagnosis for some tumors, as well as more accurate staging. 7-9 Such improvements in diagnosis may also occur in a site-specific manner.In addition, treatment for head and neck cancer has evolved and become site-specific with treatment modalities individualized for specific anatomic sites and stages. 4,6 Therefore, analysis of head and neck cancer as a group may obscure important differences in survival trends for site-specific tumors that are dependent upon site-specific treatment advances.For all historical periods, specific head and neck cancer sites have had very different treatment approaches and more importantly, different 5-year survival rates. For example, lip cancer has a 5-year survival rate over 80%, while hypopharynx cancer survival rates reach only about 30%. 4 It is also possible that the stage and site distribution of cancer cases has changed over time. Unfortunately, conventional methods of ...

Phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) are agents currently in clinical use for nonmalignant conditions. We report the use of PDE5 inhibitors as modulators of the antitumor immune response. In several mouse tumor models, PDE5 inhibition reverses tumor-induced immunosuppressive mechanisms and enables a measurable antitumor immune response to be generated that substantially delays tumor progression. In particular, sildenafil, down-regulates arginase 1 and nitric oxide synthase–2 expression, thereby reducing the suppressive machinery of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) recruited by growing tumors. By removing these tumor escape mechanisms, sildenafil enhances intratumoral T cell infiltration and activation, reduces tumor outgrowth, and improves the antitumor efficacy of adoptive T cell therapy. Sildenafil also restores in vitro T cell proliferation of peripheral blood mononuclear cells from multiple myeloma and head and neck cancer patients. In light of the recent data that enzymes mediating MDSC-dependent immunosuppression in mice are active also in humans, these findings demonstrate a potentially novel use of PDE5 inhibitors as adjuncts to tumor-specific immune therapy.

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...

Many tumour types have been reported to have deletion of 9p21 (refs 1-6). A candidate target suppressor gene, p16 (p16INK4a/MTS-1/CDKN2), was recently identified within the commonly deleted region in tumour cell lines. An increasing and sometimes conflicting body of data has accumulated regarding the frequency of homozygous deletion and the importance of p16 in primary tumours. We tested 545 primary tumours by microsatellite analysis with existing and newly cloned markers around the p16 locus. We have now found that small homozygous deletions represent the predominant mechanism of inactivation at 9p21 in bladder tumours and are present in other tumour types, including breast and prostate cancer. Moreover, fine mapping of these deletions implicates a 170 kb minimal region that includes p16 and excludes p15.