CYP17, GSTP1, PON1 and GLO1gene polymorphisms as risk factors for breast cancer: an Italian case-control study

Abstract

BackgroundEstrogens, environmental chemicals with carcinogenic potential, as well as oxidative and carbonyl stresses play a very important role in breast cancer (BC) genesis and progression. Therefore, polymorphisms of genes encoding enzymes involved in estrogen biosynthesis pathway and in the metabolic activation of pro-carcinogens to genotoxic intermediates, such as cytochrome P450C17α (CYP17), endogenous free-radical scavenging systems, such as glutathione S-transferase (GSTP1) and paraoxonase 1 (PON1), and anti-glycation defenses, such as glyoxalase I (GLO1), could influence individual susceptibility to BC. In the present case-control study, we investigated the possible association of CYP17 A1A2, GSTP1 ILE105VAL, PON1 Q192R or L55M, and GLO1 A111E polymorphisms with the risk of BC.MethodsThe above-said five polymorphisms were characterized in 547 patients with BC and in 544 healthy controls by PCR/RFLP methods, using DNA from whole blood. To estimate the relative risks, Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression after adjusting for the known risk factors for BC.ResultsCYP17 polymorphism had no major effect in BC proneness in the overall population. However, it modified the risk of BC for certain subgroups of patients. In particular, among premenopausal women with the A1A1 genotype, a protective effect of later age at menarche and parity was observed. As to GSTP1 and PON1 192 polymorphisms, the mutant Val and R alleles, respectively, were associated with a decreased risk of developing BC, while polymorphisms in PON1 55 and GLO1 were associated with an increased risk of this neoplasia. However, these findings, while nominally significant, did not withstand correction for multiple testing.ConclusionGenetic polymorphisms in biotransformation enzymes CYP17, GSTP1, PON1 and GLO1 could be associated with the risk for BC. Although significances did not withstand correction for multiple testing, the results of our exploratory analysis warrant further studies on the above mentioned genes and BC.

Promoter methylation and gene polymorphism are two independent events in regulation of GSTP1 gene expression

“…First is the substitution mutation in codon 105 of exon 5, which causes substitution of the isoleucine with valine at nucleotide position 313 (A to G transition) 31 with the mutant genotype (containing valine allele) effecting the enzyme activity as well as specificity. 19 This observation has been confirmed by the number of published studies concerning the role of this single-nucleotide polymorphism in relation to the individuals' susceptibility to the various diseases 32 including many cancers, mainly breast cancer, 24,25,[33][34][35] bladder cancer, testicular cancer, and prostate cancer. [36][37][38] The epigenetic silencing of this gene in the form of CpG hypermethylation is the second mechanism involved in the cancer progression.…”

HMGB1, S100 proteins and other RAGE ligands in cancer - markers, mediators and putative therapeutic targets

“…We studied the Glu111Ala polymorphism of glyoxalase I in patients with breast cancer 36 and were able to show that the higher frequency of the mutated C allele was found in patients with negative estrogen receptors and in patients and more advanced disease (clinical stage III) compared to controls (P < 0.05) suggesting that the presence of the C allele could be a negative prognostic factor in breast cancer. In a large Italian study of patients with breast cancer cancer 37 polymorphism of glyoxalase I was associated with breast cancer in univariate analysis but a number of confounding factors obfuscate the results. In another large study in Malaysian patients with breast cancer 38 the genotype and allele frequencies of Ala111Glu glyoxalase I polymorphism were not significantly different for patients and controls.…”

Association Between PON1 L55M Polymorphism and PON1 Enzyme Activity in Patients with Leukemia.

“…Accordingly PON1 L55M polymorphism was associated with an increased risk of developing childhood leukemia (LM + MM, OR 1.93, 95%CI 1.32-2.81). 34 Moreover, some researchers observed an increased risk associated with the MM genotype for breast [30][31][32] , and prostate cancer. 33 Similarly, within the meta-analysis of 21 case-control studies involving 5.627 cases and 6.390 controls, it was observed that PON1 L55M polymorphism was associated with an increased risk for breast, prostate, and ovarian cancer.…”