Loss of heterozygosity of the human cytosolic glutathione peroxidase I gene in lung cancer

Abstract

The consistent deletion of 3p21 in lung cancer has led to intensive efforts to identify a lung tumor suppressor gene at this locus. We recently mapped the gene for the selenium-dependent drug-detoxifying enzyme glutathione peroxidase 1 (GPX1) to this location by in situ hybridization. We developed a polymerase chain reaction-based assay which demonstrated the existence of three GPX1 alleles characterized by the number of alanines in a polyalanine coding sequence in exon 1. These three alleles produced a heterozygote frequency of 70% in two separate populations: normal tissue DNA taken from Centre d'Etude du Polmorphisme Humain (CEPH) parents and normal tissue taken from cancer patients. In contrast, 10 heterozygote tumors were detected out of 64 lung cancer specimens. Linkage analysis of GPX1 to Genethon 3p markers in CEPH pedigrees demonstrated that GPX1 was located between the two microsatellite markers believed to flank the lung cancer deletion site. Nucleotide sequence analysis of GPX1 alleles did not reveal any mutations of this gene in lung tumors. However, sequence analysis did reveal that the three GPX1 alleles were characterized by three nucleotide substitutions in addition to the polyalanine polymorphism, including a substitution at codon 198 which results in either a proline or leucine at that position. Therefore, the different GPX1 alleles encode structurally different hGPx1 subunits. In addition, analysis of allele frequency suggests that the GPX1*ALA7 allele may occur less frequently in tumors with 3p21 deletions.

Association between the GCG polymorphism of the selenium dependent GPX1 gene and the risk of young onset prostate cancer

“…Besides the difference in the length of the polyalanine track the Ala6 allele is in complete linkage disequilibrium with an amino acid substitution (Leu198Pro) in the coding region and two more base substitutions outside the coding regions. 8 Thus, this allele is the most likely to code for a functionally different protein.…”

“…7 Therefore it is plausible that a genetic alteration or polymorphisms in the GPX1 gene may also have an effect on prostate cancer risk. The presence of a GCG repeat polymorphism coding for alanine residues in a polyalanine tract of GPX1 was described by Moscow et al 8 They have also reported that other polymorphisms co-segregate with one of the alleles, a proline to leucine substitution at codon 198, a T to C substitution at þ 2 and a G for A substitution at 7 592. In a recent study it was shown that the Pro198Leu polymorphism was significantly associated with the risk of developing lung cancer in a case -control study confirming the role of GPX1 as a potent risk factor in tumour development.…”

Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model

“…Perhaps the best candidate is GPx-1, because an association with polymorphisms and the risk of lung cancer has been reported, as has loss of heterozygosity at this locus in several cancer types (9)(10)(11)(12). In fact, an association between a polyalanine polymorphism in exon 1 and the risk of young-onset prostate cancer has been reported (28).…”

Untitled

“…A functional difference in GPx-1 genotype at codon 198 was demonstrated by exclusively expressing each allele in breast cancer cells and showing that the leucinecontaining allele is less responsive to selenium supplementation than the proline allele, suggesting a possible functional consequence for the allelic identity at the codon 198 (148). Furthermore, an additional common polymorphism exists in which a variable number of tandem alanine codons, 4, 5, or 6 repeats, are found in GPx1 exon 1 (235). A case-control study found an increased frequency of the polyalanine repeats in the prostate cancer cases compared with controls; however, the study found no significant association between Gpx1 genotype and the risk for prostate cancer (181).…”