Risk and prognosis of prostate cancer patients treated with radical prostatectomy and radiation in relation to glutathione transferase polymorphisms

Citosolna familija enzima glutation transferaza (GST) ostvaruje plejotropnu ulogu u nastanku, progresiji i hemorezistenciji različitih solidnih tumora. Može se pretpostaviti da bi polimorfizmi GSTM1, GSTT1, GSTP1, GSTO1 i GSTO2 gena mogli doprineti nastanku i progresiji karcinoma prostate. Cilj ove studije je bio razjašnjavanje pojedinačnog i kombinovanog efekta šest GST polimorfizama, uključujući GSTM1 i GSTT1 delecione, kao i GSTP1 (rs1695 i rs1138272), GSTO1 (rs4925) i GSTO2 (rs156697) polimorfizme u podložnosti za nastanak karcinoma prostate, uključujući i njihov modifikujući efekat na ukupno preživljavanje ovih bolesnika. Materijal i metode: Genotipizacija je izvedena kod 237 bolesnika sa karcinomom prostate i 236 kontrola uparenih po godinama korišćenjem multipleks PCR za delecione GST polimorfizme i kvantitativni PCR za polimorfizme izmene jednog nukleotida. Efekat GST polimorfizama u proceni predikcije mortaliteta je analiziran Koks regresionim modelom, dok je Kaplan-Majer analiza korišćena za utvrđivanje razlika u preživljavanju. Rezultati: Naši rezultati su pokazali da su homozigotni nosioci oba varijantna GSTO1*A/A i GSTO2*G/G genotipa u povećanom riziku za nastanak karcinoma prostate. Analizom haplotipa je potvrđeno da je H2 haplotip (GSTO1*A/GSTO2*G) visoko rizičan. Pored toga, pokazano je da su nosioci bar jednog od varijantnih GSTP1*Val (rs1138272) ili GSTP1*Val (rs1695) alela u povećanom riziku za razvoj ovog karcinoma u poređenju sa nosiocima referentnih alela (OR = 4,93; 95%CI: 2,89-8,40; p < 0,001 odnosno OR = 1,8; 95%CI: 1,19-2,73; p=0,006)...Considering pleiotropic roles of cytosolic glutathione transferase (GST) family of enzymes in development, progression and chemoresistance of various solid tumors, we hypothesized that polymorphisms in GSTM1, GSTT1, GSTP1, GSTO1 and GSTO2 genes might contribute to prostate cancer (PC) development and progression. The aim of the study was to elucidate the independent and combined effect of six different GST polymorphisms, including GSTM1 and GSTT1-deletion polymorphisms, as well as, GSTP1 (rs1695 and rs1138272), GSTO1 (rs4925) and GSTO2 (rs156697) polymorphisms in susceptibility to prostate cancer, along with their modifying effect on the overall survival in these patients. Methods: Genotyping was performed in 237 PC cases and 236 age-matched controls by multiplex PCR for deletion GST polymorphisms and quantitative PCR for single nucleotide polymorphisms (SNPs). The effect of GST polymorphisms on predicting mortality was analyzed by the Cox proportional hazard models, while Kaplan-Meier analysis was performed to assess differences in survival. Results: We found that homozygous carriers of both GSTO1*A/A and GSTO2*G/G variant genotypes are at increased PC risk. This was further confirmed by haplotype analysis, showing H2 haplotype (GSTO1*A/GSTO2*G) as a high-risk combination. Moreover, carriers of either GSTP1*Val (rs1138272) or GSTP1*Val (rs1695) variant alleles had increased PC risk in comparison to those with both referent alleles (OR = 4.93, 95%CI: 2.89-8.40, p < 0.001 and OR = 1.8, 95%CI: 1.19-2.73, p=0.006, respectively)..