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      New Concepts for Translational Head and Neck Oncology: Lessons from HPV-Related Oropharyngeal Squamous Cell Carcinomas

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          Human papillomavirus (HPV) infection is well established as an etiological agent responsible for a number of pathologies affecting the stratified epithelia of skin and anogenital sites. More recently, the infection by (mucosal) high-risk HPV types has also been found to be causally associated with squamous cell carcinoma in the head and neck region (HNSCC), especially in the oropharynx. Intriguingly, HPV-related oropharyngeal squamous cell carcinomas (OPSCC) represent a distinct clinical entity compared to HPV-negative tumors with particular regard to treatment–response and survival outcome. The association between HPV infection and OPSCC may therefore have important implications for the prevention and/or treatment of OPSCC. The improved survival of patients with HPV-related tumors also raises the question, as to whether a better understanding of the underlying differences may help to identify new therapeutic concepts that could be used in targeted therapy for HPV-negative and improved therapy for HPV-positive cancers. This review summarizes the most recent advances in our understanding of the molecular principles of HPV-related OPSCC, mainly based on functional genomic approaches, but also emphasizes the significant role played by the tumor microenvironment, especially the immune system, for improved clinical outcome and differential sensitivity of HPV-related tumors to current treatment options.

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          Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

          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 papillomavirus (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. 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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            ATM and related protein kinases: safeguarding genome integrity.

             Yosef Shiloh (2003)
            Maintenance of genome stability is essential for avoiding the passage to neoplasia. The DNA-damage response--a cornerstone of genome stability--occurs by a swift transduction of the DNA-damage signal to many cellular pathways. A prime example is the cellular response to DNA double-strand breaks, which activate the ATM protein kinase that, in turn, modulates numerous signalling pathways. ATM mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia (A-T). Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.
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              Head and neck cancer.

              Most head and neck cancers are squamous cell carcinomas that develop in the upper aerodigestive epithelium after exposure to carcinogens such as tobacco and alcohol. Human papillomavirus has also been strongly implicated as a causative agent in a subset of these cancers. The complex anatomy and vital physiological role of the tumour-involved structures dictate that the goals of treatment are not only to improve survival outcomes but also to preserve organ function. Major improvements have been accomplished in surgical techniques and radiotherapy delivery. Moreover, systemic therapy including chemotherapy and molecularly targeted agents--namely, the epidermal growth factor receptor inhibitors--has been successfully integrated into potentially curative treatment of locally advanced squamous-cell carcinoma of the head and neck. In deciding which treatment strategy would be suitable for an individual patient, important considerations include expected functional outcomes, ability to tolerate treatment, and comorbid illnesses. The collaboration of many specialties is the key for optimum assessment and decision making. We review the epidemiology, molecular pathogenesis, diagnosis and staging, and the latest multimodal management of squamous cell carcinoma of the head and neck.

                Author and article information

                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Research Foundation
                15 March 2012
                11 April 2012
                : 2
                1simpleDepartment of Otolaryngology, Head and Neck Surgery, Research Group Experimental Head and Neck Oncology, University Hospital Heidelberg Heidelberg, Germany
                2simpleDivision of Genome Modifications and Carcinogenesis (F020), Infection and Cancer Program, German Cancer Research Center Heidelberg, Germany
                3simpleJunior Group Molecular Mechanisms of Head and Neck Tumors (A102), DKFZ-ZMBH Alliance, German Cancer Research Center Heidelberg, Germany
                Author notes

                Edited by: Seungwon Kim, University of Pittsburgh School of Medicine, USA

                Reviewed by: Herbert Loong, Prince of Wales Hospital, Hong Kong; Guilherme Rabinowits, Dana-Farber Cancer Institute, USA

                *Correspondence: Jochen Hess, Department of Otolaryngology, Head and Neck Surgery, Experimental Head and Neck Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany. e-mail: jochen.hess@

                This article was submitted to Frontiers in Head and Neck Cancer, a specialty of Frontiers in Oncology.

                Copyright © 2012 Kostareli, Holzinger and Hess.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 118, Pages: 10, Words: 9769
                Review Article

                Oncology & Radiotherapy

                transcriptome, hnscc, genome, hpv, epigenome, opscc


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