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: Jian Gu, Xifeng Wu, Qiong Dong, Martin J Romeo, Xin Lin, J Silvio Gutkind, David M Berman
• Journal: Cancer (Cancer) Vol. 106 Issue 12 Pg. 2716-24 (Jun 15 2006) ISSN: 0008-543X [Print] United States
• PMID: 16691626 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright 2006 American Cancer Society.

Chemical References

• ARHGEF11 protein, human
• DNA, Neoplasm
• Guanine Nucleotide Exchange Factors
• Rho Guanine Nucleotide Exchange Factors
• Tumor Suppressor Protein p53
• Cyclin D1
• Serine
• GTP-Binding Proteins
• Glycine

Topics

• Aged
• Alleles
• Case-Control Studies
• Cell Transformation, Neoplastic (genetics, pathology)
• Cyclin D1 (genetics, physiology)
• DNA, Neoplasm (analysis, genetics)
• Female
• GTP-Binding Proteins (physiology)
• Genotype
• Glycine (analysis)
• Guanine Nucleotide Exchange Factors (chemistry, genetics, physiology)
• Humans
• Lung Neoplasms (epidemiology, ethnology, genetics)
• Male
• Mexican Americans (genetics)
• Middle Aged
• Odds Ratio
• Polymorphism, Single Nucleotide (genetics)
• Rho Guanine Nucleotide Exchange Factors
• Risk Factors
• Serine (analysis)
• Signal Transduction (physiology)
• Tumor Suppressor Protein p53 (genetics, physiology)