title: A nonsynonymous single-nucleotide polymorphism in the PDZ-Rho guanine nucleotide exchange factor (Ser1416Gly) modulates the risk of lung cancer in Mexican Americans.
abstract: BACKGROUND
  Based on in vitro studies, Rho guanine nucleotide exchange factors (RhoGEFs) are key regulators of mitogenic and transforming pathways. At least 1 family member, PDZ-RhoGEF, also integrates signaling between monomeric Rho G proteins and heterotrimeric G proteins through a so-called regulator of G-protein signaling (RGS) domain. Recently, the authors reported that 3 single-nucleotide polymorphisms (SNPs) in 2 members of the RGS family were associated with significant reductions in the risk of cancer.
  
  
  METHODS
  For the current report, the authors studied the risk of lung cancer associated with a nonsynonymous SNP (rs868188; Ser1416Gly) in PDZ-RhoGEF in a large lung cancer case-control study of 2260 Caucasians and 369 Mexican Americans.
  
  
  RESULTS
  Compared with individuals who had the wild-type genotype (AA), Mexican Americans with the variant genotypes (AG and GG) had a significantly reduced risk for lung cancer (odds ratio [OR], 0.57; 95% confidence interval [95%CI], 0.34-0.94). The protective effect appeared to be more evident in younger individuals (OR, 0.42; 95%CI, 0.20-0.91), men (OR, 0.36; 95%CI, 0.18-0.71), and ever smokers (OR, 0.50; 95%CI, 0.29-0.88). A joint effect was observed between Ser1416Gly and polymorphisms in 2 cell-cycle control genes: p53 (intron 3) and cyclin D1 (CCND1). Tallying the variant alleles of the 4 RGS gene SNPs, a gene-dosage effect was apparent. Compared with individuals who had < 3 variant alleles, patients with > or = 3 variant alleles had a 51% reduction in lung cancer risk (OR, 0.49; 95%CI, 0.28-0.88).
  
  
  CONCLUSIONS
  To the authors' knowledge, this is the first epidemiological study to link PDZ-RhoGEF polymorphisms with cancer risk. The results suggest that there are interactions between RGS2, RGS6, and PDZ-RhoGEF and validate this family of proteins as key regulators of tumorigenesis.
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Dong
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Romeo
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: David M
authors.initials: DM
authors.lastname: Berman
mesh_terms: D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D005838:Genotype; D005998:Glycine / Q000032:analysis; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D008297:Male; D017058:Mexican Americans / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D064067:Rho Guanine Nucleotide Exchange Factors; D012307:Risk Factors; D012694:Serine / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
chemical_list: C577234:ARHGEF11 protein, human; D004273:DNA, Neoplasm; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D012694:Serine; D019204:GTP-Binding Proteins; D005998:Glycine