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.
(Copyright 2006 American Cancer Society.)