The INK4a gene encodes two distinct growth inhibitors--the cyclin-dependent kinase inhibitor p16Ink4a, which is a component of the Rb pathway, and the tumor suppressor p19Arf, which has been functionally linked to p53. Here we show that p19Arf potently suppresses oncogenic transformation in primary cells and that this function is abrogated when p53 is neutralized by viral oncoproteins and dominant-negative mutants but not by the p53 antagonist MDM2. This finding, coupled with the observations that p19Arf and MDM2 physically interact and that p19Rrf blocks MDM2-induced p53 degradation and transactivational silencing, suggests that p19Arf functions mechanistically to prevent MDM2's neutralization of p53. Together, our findings ascribe INK4a's potent tumor suppressor activity to the cooperative actions of its two protein products and their relation to the two central growth control pathways, Rb and p53.

Mice lacking the imprinted Cdk inhibitor p57(KIP2) have altered cell proliferation and differentiation, leading to abdominal muscle defects; cleft palate; endochondral bone ossification defects with incomplete differentiation of hypertrophic chondrocytes; renal medullary dysplasia; adrenal cortical hyperplasia and cytomegaly; and lens cell hyperproliferation and apoptosis. Many of these phenotypes are also seen in patients with Beckwith-Wiedemann syndrome, a pleiotropic hereditary disorder characterized by overgrowth and predisposition to cancer, suggesting that loss of p57(KIP2) expression may play a role in the condition.

Merkel Cell Virus (MCV) is a newly discovered polyomavirus, recently found in a rare skin cancer, Merkel cell carcinoma (MCC). However, MCV has also been detected in some normal tissue samples. We tested and compared the relative quantity of the MCV in a set of diverse human tissue samples with the MCC samples. The levels of MCV in MCCs were over 60 times higher than the highest values in all other tissues. Low quantities of MCV were detected in diverse tissue samples independently of malignant or benign histologic status. Higher levels of the virus were found in the upper aerodigestive tract, digestive system, and saliva compared to the lung and genitourinary system samples. These results confirm that MCV is widespread in the human body and suggest a possible fecal-oral transmission route similar to the Hepatitis A virus. Despite widespread presence of the virus, it appears that only neuroendocrine skin cells are susceptible to transformation by MCV.Merkel cell carcinomas (MCC) are rare neuroendocrine skin tumors that develop from neuroendocrine cells responsible for the sense of touch and pressure. The incidence of MCC has tripled over the past 20 years to about 1,500 cases a year. Increased ascertainment has at least in part contributed to this rise in incidence. People at risk include those with fair skin, excessive sunlight exposure, and a history of numerous nonmelanoma skin cancers. Additionally, patients under immunosuppression including solid organ transplant recipients, and patients with altered lymphocytic function such as patients with AIDS, lymphoma, and leukemia appear to be predisposed to MCC.

Background The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. Although most patients achieve complete remission with surgical treatment, those with advanced disease have a poor prognosis. The American Joint Committee on Cancer (AJCC) is responsible for the staging criteria for all cancers. For the past 20 years, the AJCC cancer staging manual has grouped all nonmelanoma skin cancers, including cSCC, together for the purposes of staging. However, based on new evidence, the AJCC has determined that cSCC should have a separate staging system in the 7th edition AJCC staging manual. Objective We sought to present the rationale for and characteristics of the new AJCC staging system specific to cSCC tumor characteristics (T). Methods The Nonmelanoma Skin Cancer Task Force of AJCC reviewed relevant data and reached expert consensus in creating the 7th edition AJCC staging system for cSCC. Emphasis was placed on prospectively accumulated data and multivariate analyses. Concordance with head and neck cancer staging system was also achieved. Results A new AJCC cSCC T classification is presented. The T classification is determined by tumor diameter, invasion into cranial bone, and high-risk features, including anatomic location, tumor thickness and level, differentiation, and perineural invasion. Limitations The data available for analysis are still suboptimal, with limited prospective outcomes trials and few multivariate analyses. Conclusions The new AJCC staging system for cSCC incorporates tumor-specific (T) staging features and will encourage coordinated, consistent collection of data that will be the basis of improved prognostic systems in the future.

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Cisplatin remains the most important chemotherapeutic agent for patients with human head and neck cancer. However, tumor cells often develop resistance to cisplatin-induced apoptosis. We previously found that head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin display a marked ATM-induced phosphorylation of DeltaNp63alpha. However, the mutated Np63-S385G failed to undergo phosphorylation by ATM kinase. We used HNSCC cell lines expressing the wild type DeltaNp63alpha or mutated DeltaNp63alpha-S385G to determine the effect of S385G mutation on the DeltaNp63alpha transcriptional activity and protein-protein interactions. The S385G mutation in DeltaNp63alpha dramatically abolished the upregulation/downregulation of downstream gene targets and the binding of DeltaNp63alpha-S385G to certain promoters. In contrast to the non-phosphorylated DeltaNp63alpha-S385G, the phospho-DeltaNp63alpha forms protein-protein complexes with NF-YA transcription factor and regulates the transcription of DDIT3 gene implicated in the programmed cell death of HNSCC cells upon cisplatin exposure. We suggest that the transcriptional activation of DeltaNp63alpha through its phosphorylation by ATM kinase in HNSCC cells exposed to cisplatin is a critical step in the subsequent sensitivity of certain human head and neck cancers to platinum therapy.

Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. In this study, we aimed to evaluate to the utility of aberrant promoter hypermethylation for detection in a panel of 10 genes (KIF1A, EDNRB, CDH4, TERT, CD44, NISCH, PAK3, VGF, MAL and FKBP4) in head and neck squamous cell carcinoma (HNSCC) via a candidate gene approach. We investigated methylation of the gene promoters by bisulfite modification and quantitative methylation-specific PCR (Q-MSP) in a preliminary study of a limited cohort of salivary rinses from healthy subjects (n 5 61) and patients with HNSCC (n 5 33). The methylation status of 2 selected genes (EDNRB and KIF1A) were then analyzed in 15 normal mucosa samples from a healthy population, 101 HNSCC tumors and the corresponding salivary rinses from 71 out of the 101 HNSCC patients were collected before treatment. The promoter regions of CDH4, TERT, VGF, MAL, FKBP4, NISCH and PAK3 were methylated in normal salivary rinses while no methylation of CD44 was observed in either normal salivary rinses or tumor samples. However, KIF1A and EDNRB were methylated in 98 and 97% of primary HNSCC tissues respectively and were only methylated in 2 and 6.6% of normal salivary rinses. In addition, KIF1A and EDNRB were methylated in 38 and 67.6% of salivary rinses from HNSCC patients, respectively. Promoter hypermethylation of KIF1A and EDNRB is a frequent event in primary HNSCC, and these genes are preferentially methylated in salivary rinses from HNSCC patients. KIF1A and EDNRB are potential biomarkers for HNSCC detection.Among human malignancies, head and neck cancer is the sixth most common cancer in the world. 1 More than 40,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed in the United States each year, with a mortality rate of 12,000 U.S. deaths annually. Survival rates have not improved significantly for patients with HNSCC in the past 30 years despite active clinical and basic science research addressing this issue. Molecular detection of HNSCC in body fluids has the potential to improve post-treatment surveillance, provide prognostic information, and influence therapy. Body fluids can potentially carry whole cells as well as protein, DNA and RNA species that allow for detection of cellular alterations related to cancer. In previous studies, body fluids such as sputum for lung cancer, 2 urine for urologic tumors, 3 salivary rinses for HNSCC, 4-7 and breast fluid for breast cancer 8 have been used in multiple detection strategies. [9][10][11][12][13] Silencing of tumor suppressor genes by means of promoter hypermethylation plays a role in head and neck carcinogenesis. 5 Measuring promoter hypermethylation by using real time quantitative methylation-specific PCR (Q-MSP) allows an objective, robust, and rapid assessment of promoter methylation status. The ability to quantify methylation

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