Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in head and neck squamous cell carcinomas
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RESEARCH
Open Access
Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in head and neck squamous cell carcinomas Christoph Bergmann1*, Hagen S Bachmann2, Agnes Bankfalvi3, Ramin Lotfi4, Carolin Pütter5, Clarissa A Wild1, Patrick J Schuler1, Jens Greve1, Thomas K Hoffmann1, Stephan Lang1, André Scherag5 and Götz F Lehnerdt1
Abstract Background: Chronic inflammation plays an important role in head and neck squamous cell carcinomas (HNSCC). This study addresses the impact of two single nucleotide polymorphisms (SNP) Asp299Gly and Thr399Ile of the toll-like receptor (TLR) 4 gene on the clinical outcome while accounting for the influence of adjuvant systemic therapy in a large cohort of HNSCC patients. Methods: Genotype analysis was done using DNA from tissue samples from 188 patients with HNSCC; TLR4 protein expression was assessed immunohistochemically in tissue microarrays. Classical survival models were used for statistical analyses. Results: Ten percent of patients with HNSCC presented with the TLR4 299Gly and 17% with the TLR4 399Ile allele. Patients with the heterozygous genotype TLR4 Asp299Gly had a significantly reduced disease-free and overall survival. Also, patients with the heterozygous genotype TLR4 Thr399Ile had a reduced disease-free survival. Notably, these associations seem to be attributable to relatively poor therapy response as e.g. reflected in a significantly shorter DFS among HNSCC patients carrying the Asp299Gly variant and receiving adjuvant systemic therapy. Conclusion: According to this study, TLR4 299Gly und 399Ile alleles may serve as markers for prognosis of head and neck cancer in patients with adjuvant systemic therapy, particularly chemotherapy, and might indicate therapy resistance. Keywords: Toll-like receptor 4, Single-nucleotide polymorphism, HNSCC
Background The functional relationship between inflammation and cancer has been described since 1863, at first by Virchow [1]. Many cancers arise from sites of chronic inflammation, where inflammatory cells orchestrate the tumor microenvironment fostering neoplastic processes like proliferation, survival, and migration [2]. The upper aero-digestive tract is chronically exposed to pathogens and toxic irritants. For example, human papilloma virus 16 DNA can be detected in up to 72% of oropharyngeal cancers [3]. Further, tobacco and alcohol consumption is implicated in 75% of head and neck squamous cell * Correspondence: [email protected] 1 Department of Otorhinolaryngology, University of Duisburg - Essen, Hufelandstrasse 55, 45127 Essen, Germany Full list of author information is available at the end of the article
carcinomas (HNSCC) [4,5]. Thus, infection and inflammation critically impact the development of HNSCC [6]. The family of mammalian Toll-like receptors (TLR) consists of 11 members and is mainly expressed on innate immune cells [7]. TLR play a pivotal role in immune responses to exogenous pathogen-associated (PAMPs) or to endogenous danger-/damage-associated molecular patterns (DAMPs).
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