title: Functional single nucleotide polymorphisms of the RASSF3 gene and susceptibility to squamous cell carcinoma of the head and neck.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Hongguang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC 27710, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wei
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC 27710, USA.
authors.forename: Yangkai
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hongping
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Guan
authors.affiliation: Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wang
authors.initials: W
authors.lastname: Li-E
authors.affiliation: 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.
authors.forename: Guojun
authors.initials: G
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Erich M
authors.initials: EM
authors.lastname: Sturgis
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC 27710, USA. Electronic address: qingyi.wei@dm.duke.edu.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC 27710, USA. Electronic address: zhensheng.liu@dm.duke.edu.
authors.forename: Zhensheng
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D014408:Biomarkers, Tumor; C454041:RASSF3 protein, human; D020559:Monomeric GTP-Binding Proteins
keywords: Apoptosis; Biomarker; Genetic susceptibility; Head and neck cancer; Polymorphism; RASSF3