Hongguang Guo1, Hongliang Liu2, Jianhua Wei3, Yangkai Li2, Hongping Yu3, Xiaoxiang Guan3, Wang Li-E3, Guojun Li4, Erich M Sturgis4, Qingyi Wei5, Zhensheng Liu6. 1. Department of Otolaryngology and Head & Neck Surgery, Navy General Hospital, Beijing, China; Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. 2. Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC 27710, USA. 3. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. 4. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. 5. Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC 27710, USA. Electronic address: qingyi.wei@dm.duke.edu. 6. Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC 27710, USA. Electronic address: zhensheng.liu@dm.duke.edu.
Abstract
BACKGROUND: RASSF3 suppresses tumour formation through uncertain mechanisms, but it is an important gene of p53-dependent apoptosis. RASSF3 depletion impairs DNA repair after DNA damage, leading to polyploidy. The authors hypothesised that potential functional single-nucleotide polymorphisms (SNPs) of RASSF3 are associated with risk of squamous cell carcinoma of the head and neck (SCCHN). METHODS: The authors used a functional SNP approach to evaluate the associations between common (minor allele frequency⩾0.05), putative functional variants in RASSF3 and risk of SCCHN. Four selected such functional SNPs (rs6581580 T>G, rs7313765 G>A, rs12311754 G>C and rs1147098 T>C) in RASSF3 were identified and genotyped in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. RESULTS: The authors found that two SNPs were significantly associated with SCCHN risk. Carriers of the variant rs6581580G and rs7313765A alleles were at a reduced SCCHN risk, compared with the corresponding common homozygotes [adjusted odds ratio (OR)=0.75 and 0.73 and 95% confidence interval (CI)=0.62-0.91 and 0.60-0.88, respectively, for dominant models; and Ptrend=0.012 and 0.041, respectively, for additive models], particularly for non-oropharyngeal tumours (adjusted OR=0.68 and 0.60 and 95% CI=0.53-0.86 and 0.47-0.77, respectively, for dominant models). In the genotype-phenotype correlation analysis of peripheral blood mononuclear cells from 102 cancer-free controls, the rs6581580 GG genotype was associated with significantly increased expression levels of RASSF3 mRNA (P=0.038), compared with the TT genotype. Additional functional experiments further showed that variant G allele of rs6581580 had a significantly stronger binding affinity to the nuclear protein extracts than the T allele. CONCLUSION: Taken together, these findings indicate that the RASSF3 promoter rs6581580 T>G SNP is potentially functional, modulating susceptibility to SCCHN among non-Hispanic whites. Larger replication studies are needed to confirm our findings.
BACKGROUND:RASSF3 suppresses tumour formation through uncertain mechanisms, but it is an important gene of p53-dependent apoptosis. RASSF3 depletion impairs DNA repair after DNA damage, leading to polyploidy. The authors hypothesised that potential functional single-nucleotide polymorphisms (SNPs) of RASSF3 are associated with risk of squamous cell carcinoma of the head and neck (SCCHN). METHODS: The authors used a functional SNP approach to evaluate the associations between common (minor allele frequency⩾0.05), putative functional variants in RASSF3 and risk of SCCHN. Four selected such functional SNPs (rs6581580 T>G, rs7313765 G>A, rs12311754 G>C and rs1147098 T>C) in RASSF3 were identified and genotyped in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. RESULTS: The authors found that two SNPs were significantly associated with SCCHN risk. Carriers of the variant rs6581580G and rs7313765A alleles were at a reduced SCCHN risk, compared with the corresponding common homozygotes [adjusted odds ratio (OR)=0.75 and 0.73 and 95% confidence interval (CI)=0.62-0.91 and 0.60-0.88, respectively, for dominant models; and Ptrend=0.012 and 0.041, respectively, for additive models], particularly for non-oropharyngeal tumours (adjusted OR=0.68 and 0.60 and 95% CI=0.53-0.86 and 0.47-0.77, respectively, for dominant models). In the genotype-phenotype correlation analysis of peripheral blood mononuclear cells from 102 cancer-free controls, the rs6581580 GG genotype was associated with significantly increased expression levels of RASSF3 mRNA (P=0.038), compared with the TT genotype. Additional functional experiments further showed that variant G allele of rs6581580 had a significantly stronger binding affinity to the nuclear protein extracts than the T allele. CONCLUSION: Taken together, these findings indicate that the RASSF3 promoter rs6581580 T>G SNP is potentially functional, modulating susceptibility to SCCHN among non-Hispanic whites. Larger replication studies are needed to confirm our findings.
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