A nonsynonymous single-nucleotide polymorphism in the PDZ-Rho guanine nucleotide exchange factor (Ser1416Gly) modulates the risk of lung cancer in Mexican Americans.
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.
Gu
Jian
J
Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Wu
Xifeng
X
Dong
Qiong
Q
Romeo
Martin J
MJ
Lin
Xin
X
Gutkind
J Silvio
JS
Berman
David M
DM
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
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