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)
|