Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma: a pilot study.

Abstract

Osteosarcoma is the most common malignant bone tumor in children and young people. Efficacy of multiagent MAP (methotrexate, doxorubicin [Adriamycin], cisplatin) chemotherapy may be influenced by multiple cellular pathways. This pilot study aimed to investigate the association of 36 candidate genetic polymorphisms in MAP pathway genes with histological response, survival, and grade 3-4 chemotherapy toxicity in osteosarcoma. Blood samples were obtained from 60 patients who had completed MAP chemotherapy. All patients were manually genotyped for 5 polymorphisms. The remaining 31 polymorphisms were genotyped in 50 patients using the Illumina 610-Quad microarray. Associations between candidate polymorphisms and histological response, progression-free survival, and toxicity were estimated using Pearson chi-square and Fisher exact tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model. Poor histological response was increased in variants of ABCC2 c.24C>T (P = .011) and GSTP1 c.313A>G p.Ile(105)Val (P = .009), whereas MTHFD1 c.1958G>A p.Arg(653)Gln was protective (P = .03). Methotrexate toxicity was increased in variants of MTHFR c.1298A>C p.Glu(429)Ala (P = .038), ABCB1 c.3435T>C Ile(145)Ile (P = .027), and ABCC2 c.3563T>A p.Val(1188)Glu (P = .028). Variants of GSTP1 c.313A>G p.Ile(105)Val were at increased risk of myelosuppression (P = .024) and cardiac damage (P = .008). This pilot study represents the most comprehensive study to date examining the role of genetic polymorphisms in osteosarcoma. Although small and retrospective, it shows that several polymorphisms appear to significantly influence toxicity and clinical outcome. These deserve prospective validation in the hope of optimizing treatment for resistant disease and reducing the late effects burden.