Genetic Polymorphism of Cytochrome P450 1B1 (C432G) Is Associated with An Increased Treatment-Related Mortality and Lower Overall Survival in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Abstract

Background. The human cytochrome P450 1B1 (CYP 1B1) is a key enzyme involved in the production of reactive metabolites and in the activation of environmental carcinogens. Several polymorphisms were identified in CYP 1B1 gene; four of them are single nucleotide polymorphisms and give rise to amino acidic substitutions. The CYP 1B1 codon 432 polymorphism leads to a three-fold higher 4-hydroxylase activity for the variant CYP 1B1 isozymes than the wild types. Never before the influence of genetic polymorphisms of CYP 1B1 (C432G) on patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT), was evaluated.Methods. Here we genotyped in a retrospective study 384 recipients (R) (and their donors (D)) for CYP 1B1 (C432G) expression that underwent allogeneic HSCT for various diseases and analyzed their outcome. Genotyping of CYP 1B1 (C432G) was performed by real-time PCR.Results. 170 R (44.3%) were genotyped as homozygous wild-type gene C/C, 157 R (40.9%) were genotyped as heterozygous genotype C/G and 57 R (14.8%) were genotype as homozygous gene mutation G/G. From the 167 D (43.5%) were C/C, 164 D (42.7%) were C/G, and 53 D (13.8%) had a homozygous gene mutation G/G. A homozygous CYP 1B1 gene mutation G/G was found on 18 R/D side (4.7%). Calculated genotype frequencies did not differ from that reported earlier by other studies for Caucasians. Five-year estimate for treatment-related mortality (TRM) and overall survival (OS) were statistically different in genotype C/G- and G/G- R with 33 ± 4%, and 49 ± 4% compared to homozygous wild-type gene C/C- R (18 ± 3%, and 59 ± 4%, respectively, [p<0.03]), whereas the five-year estimate for relapse rate (RR) was not different between the groups. No differences for five-year estimates for TRM, RR, or OS were seen in R with either genotype C/C-, C/G- or G/G- D. No statistic differences were found in the incidence of acute GVHD grade 2–4 on R- or on D- side with variant CYP 1B1 (C432G) polymorphisms. Surprisingly, the five-year estimate for TRM, RR, and OS were statistically different in homozygous gene mutation G/G on R/D site with 57 ± 2%, 81 ± 2%, and 16 ± 1% compared to all other CYP 1B1 genotypes with 28 ± 3%, 26 ± 2%, and 55 ± 3%, respectively [TRM, p<0.01; RR and OS, p<0.001]). Multivariate analysis confirmed that CYP 1B1 (C432G) homozygous gene mutation G/G on R/D site had an increased risk for TRM and RR (p<0.02), whereas the mutation G/G on R/D site revealed a worse OS (p<0.01).Conclusions. These results suggest that recipients with genetic polymorphism of CYP 1B1 do have an increased TRM, RR and lower OS after transplantation. Genotyping for CYP 1B1 (C432G) might help to identify patients with higher risk for allogeneic transplantation.