Predictive potential of ABCB1, ABCC3, and GSTP1 gene polymorphisms on osteosarcoma survival after chemotherapy

Abstract

Genetic polymorphisms in drug metabolism and transport genes can influence the pharmacokinetics and pharmacodynamics of chemotherapy drugs. We investigated the role of genes involved in metabolic and transport pathways in response to chemotherapy and clinical outcome of osteosarcoma patients. The association between the eight polymorphisms with response to chemotherapy and clinical outcome of patients was carried out by unconditional logistic regression analysis and Cox proportional hazard models. Of 186 patients, 98 patients showed good response to chemotherapy, 64 died, and 97 showed progression at the end of the study. Patients carrying ABCB1 rs1128503 TT genotype and T allele were more likely to have a good response to chemotherapy. ABCC3 rs4148416 TT genotype and T allele and GSTP1 rs1695 GG genotype and G allele were associated with poor response to chemotherapy. In the Cox proportional hazards model, after adjusting for potential confounding factors, patients carrying ABCB1 rs1128503 TT genotype and T allele were associated with lower risk of progression-free survival (PFS) and overall survival (OS). ABCC3 rs4148416 TT genotype and T allele and GSTP1 rs1695 GG genotype and G allele were correlated with high risk of PFS and OS. The ABCB1 TT and GSTP1 GG genotypes were significantly associated with a shorter OS. In conclusion, variants of ABCB1 rs128503, ABCC3 rs4148416, and GSTP1 rs1695 are associated with response to chemotherapy and PFS and OS of osteosarcoma patients; these gene polymorphisms could help in the design of individualized therapy.

Role of pharmacogenetics of drug-metabolizing enzymes in treating osteosarcoma

“…However, in a large Chinese study, association between the variant genotype and good response to chemotherapy was found [69]. Additional associations between the variant genotype and poor overall and/or event-free survival [65][66][67][68] or higher risk of death [64,68] were reported. Association with leukopenia and cardiotoxicity was found by Windsor et al [65].…”

“…Most concordant results have been published regarding the GSTP1 Ile105Val (rs1695) polymorphism ( Table 4). Associations between the variant genotype and poor histological response to chemotherapy were reported in four studies [65][66][67][68]. However, in a large Chinese study, association between the variant genotype and good response to chemotherapy was found [69].…”

“…PCR-based Non-null alleles with increased risk for OS [58] Brazil ( [67] Information regarding the number of patients with metastases at diagnosis and the drugs used for treatment are reported in the table when they were provided in the publication. Among these, two studies analyzed pediatric tumors including few patients with OS [58,59].…”

“…PCR-based Non-null alleles with increased risk for OS [58] Brazil ( [67] Information regarding the number of patients with metastases at diagnosis and the drugs used for treatment are reported in the table when they were provided in the publication. the GSTM1 null allele and treatment delay was described in Caucasian patients [65], whereas in the same study the GSTT1 null allele was associated with poor event-free survival.…”

Association of GRM4 gene polymorphisms with susceptibility and clinicopathological characteristics of osteosarcoma in Guangxi Chinese population

“…The rs8103851 polymorphism of the PRKCG gene is correlated to metastatic osteosarcoma and could be the risk factors for metastatic osteosarcoma [28]. In addition, ABCB1, ABCC3, and GSTP1 polymorphisms may affect osteosarcoma treatment efficacy [29,30]. However, since the functional genes for osteosarcoma are not very clear, much research is still being done in this field.…”