The molecular pathogenesis of head and neck squamous cell carcinoma

Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts 02114, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 06/2012; 122(6):1951-7. DOI: 10.1172/JCI59889
Source: PubMed


Squamous cell carcinoma of the head and neck (HNSCC) is a relatively common human cancer characterized by high morbidity, high mortality, and few therapeutic options outside of surgery, standard cytotoxic chemotherapy, and radiation. Although the most important risk factors are tobacco use and alcohol consumption, the disease is also linked to infection with high-risk types of human papilloma viruses (HPVs). Recent genetic analyses have yielded new insights into the molecular pathogenesis of this disease. Overall, while somatic activating mutations within classical oncogenes including PIK3CA and RAS occur in HNSCC, they are relatively uncommon. Instead genetic data point to a contribution of multiple tumor suppressor pathways, including p53, Rb/INK4/ARF, and Notch, in tumor initiation, progression, and maintenance. The increasingly refined knowledge of HNSCC genetics, combined with ever-more-sophisticated animal models and newer drug targeting strategies, should promote novel therapeutic approaches and improved disease outcomes.

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    • "all cases (Yu et al., 2011; Rothenberg and Ellisen, 2012; Chakrobarty et al., 2014). The murine double minute 2 (MDM2) protein is one of the most extensively studied regulators of p53 activity. "
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    ABSTRACT: Polymorphisms in the MDM2 309 (T>G) and TP53 72 (G>C) genes are reported to increase the susceptibility to head and neck cancer (HNC) in various populations. The risk for HNC is also strongly associated with etiologic habits such as smoking, alcohol consumption and/or chewing of betel quid (BQ). In a case-control study, we investigated the significance of the above polymorphisms alone, and upon interaction with one another as well as with various etiologic habits in determining HNC risk in a Northeast Indian population. Genotyping at 309 MDM2 and 72 TP53 in 122 HNC patients and 86 cancer free healthy controls was performed by PCR using allele specific primers, and the results were confirmed by DNA sequencing. Individuals with the GG mutant allele of MDM2 showed a higher risk for HNC in comparison to those with the TT wild type allele (OR=1.9, 95%CI: 1.1-3.3) (p=0.022). The risk was further increased in females by ~4-fold (OR=4.6, 95% CI: 1.1-19.4) (P=0.04). TP53 polymorphism did not contribute to HNC risk alone; however, interaction between the TP53 GC and MDM2 GG genotypes resulted in significant risk (OR=4.9, 95% CI: 0.2-105.1) (p=0.04). Smokers, BQ- chewers and alcohol consumers showed statistically significant and dose- dependent increase in HNC risk, irrespective of the MDM2 genotype. MDM2 genotype could serve as an important predictive biomarker for HNC risk in the population of Northeast India.
    Full-text · Article · Aug 2015 · Asian Pacific journal of cancer prevention: APJCP
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    • "Head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer globally, affects 600,000 new patients each year and is associated with high morbidity [1]. The most common sites for HNSCC are the pharynx/larynx, tongue and mouth [2]. "
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    ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) represent 95% of head and neck cancer with an incidence of over half a million people globally. The prognosis for patients with recurrent or metastatic HNSCC is generally poor with low 5-year survival rates despite treatment advances over the past few decades. Consequently, it is essential to search for new biomarkers and effective therapy options to optimize HNSCC treatment. Epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of tumours. EGFR has become one of most common targets for new therapies being investigated in HNSCC. In this way, multiple therapies targeting EGFR in HNSCC have been tested but response rates are still low especially in the recurrent or metastatic setting. This has been attributed to mechanisms of resistance to EGFR-targeted therapies. Afatinib, an oral small molecule ErbB Family Blocker that irreversibly binds to ErbB1 (EGFR), ErbB2 (HER2) and ErbB4 (HER4), is being investigated in HNSCC treatment with encouraging phase II results and several ongoing phase III trials. Results of these trials will help to understand the place of afatinib in the HNSCC treatment armamentarium. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Full-text · Article · Mar 2015 · Oral Oncology
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    • "However, the details of the mechanism of cancer transformation and tumor progression still remain uncertain [1] [3]. The evaluation of alternations between the expression of biological markers expressed by tumor cells, as well as in tumoral stroma cells, might lead to investigate novel therapeutic approaches in identification of the novel molecular targets for therapy [1]. Laryngeal cancers still cause the diagnostic and therapeutic problems, mainly as consequence of diagnostic delay related to the advanced stage of the disease in patients at the moment of diagnosis. "
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    ABSTRACT: Purpose: Laryngeal squamous cell carcinoma (LSCC) is an interesting diagnostic and therapeutic issue. The diagnostic delay is mainly a consequence of the lack of evident symptoms in the early stage of the disease. The purpose of current studies was the evaluation of the expression of p27(kip1) in primary and metastatic LSCC in correlation with patients' clinicopathological data. Material/methods: The indirect immunohistochemical studies were performed on the series of 60 sections (primary tumor: 20 cases of N(0) and 20 cases of N(+), and nodal meta: 20 cases), using primary antibody against p27(kip1) [clone 1B4]. The expression of analyzed protein was performed using automated morphometric methods. Results: The p27(kip1) nuclear expression was found in 100% (40/40) cases of primary tumor, and in 85% (17/20) cases of SCC meta at lymph nodes. In primary LSCC N(0) the expression of p27(kip1) was significantly higher compared to N(+) cases (p=0.036672). However, the p27(kip1) expression in SCC metastases was higher compared to the primary SCC. Moreover, the analyses based on the classification trees revealed the cutoff p27(kip1) expression in primary LSCC (IRS ≤ 76) which was characteristic for N(+) patients. Consequently, our analysis revealed that high expression of p27(kip1) (IRS>76) was characteristic for N(0) patients. Conclusions: Our results suggest that p27(kip1) might be useful prognostic factor of metastatic potential in laryngeal squamous cell carcinoma.
    Full-text · Article · Sep 2014 · Advances in Medical Sciences
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