title: Genetic variations in regulator of G-protein signaling genes as susceptibility loci for second primary tumor/recurrence in head and neck squamous cell carcinoma.
abstract: Curatively treated patients with early-stage head and neck squamous cell carcinoma (HNSCC) are at high risks for second primary tumor (SPT) and recurrence. The regulator of G-protein signaling (RGS) is important in essential signaling transduction and cellular activities. We hypothesize that genetic variations of RGS may modulate the risk of SPT/recurrence in patients with early-stage HNSCC. In a nested case-control study, we evaluated 98 single-nucleotide polymorphisms (SNPs) in 17 RGS genes for the risk of SPT/recurrence among 450 HNSCC patients. Eight SNPs showed significant associations with the risk of SPT/recurrence, with the most significant one of rs2179653, which is located in the 5'-flanking region of RGS2 gene. Under a recessive genetic model, the homozygous variant genotype of this SNP was associated with 2.95-fold [95% confidence interval (CI): 1.52-5.74] increased risk of SPT/recurrence. This association remained significant after the adjustment for multiple comparisons. Cumulative effects analysis revealed that the risk increased significantly with the increasing numbers of unfavorable genotypes. Compared with subjects carrying 0-2 unfavorable genotypes, the hazard ratios (95% CIs) for those carrying 3 or 4+ were 1.73 (1.10-2.70) and 3.05 (1.92-4.83), respectively. Furthermore, survival tree analysis revealed potential higher order gene-gene interactions and indicated different outcomes based on distinct genotype profiles. Genetic variations of RGS genes may modulate the susceptibility to SPT/recurrence in early-stage HNSCC patients individually and cumulatively. Our results stressed the importance of taking a polygenic approach to evaluate the cumulative and interaction effects of genetic variations in the prediction of cancer risk and prognosis.
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Wang
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Hushan
authors.initials: H
authors.lastname: Yang
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Edward
authors.initials: E
authors.lastname: Kim
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: David W
authors.initials: DW
authors.lastname: Chang
authors.forename: Reuben
authors.initials: R
authors.lastname: Lotan
authors.forename: Waun K
authors.initials: WK
authors.lastname: Hong
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020710:RGS Proteins / Q000235:genetics*
chemical_list: D020710:RGS Proteins; C456322:RGS13 protein, human; C087182:RGS2 protein, human