Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, Netherlands
Hanneke I. Vos , Marieke J.H. Coenen , Hans Gelderblom , Tahar van der Straaten , Eveline S.J.M de Bont , Winette T.A. Van Der Graaf , H.W.B. Schreuder , Frank N. van Leeuwen , Henk-jan Guchelaar , Dunja Maroeska W.M. Te Loo
Background: Despite multiagent chemotherapeutic treatment, osteosarcoma patients relapse frequently and survival has reached a plateau in the past decades. A poor response to chemotherapy seems to be the predominant risk factor for an unfavorable outcome. We have previously identified several genetic polymorphisms in genes in the metabolic pathways of cisplatin and doxorubicin which might be used for risk stratification of patients in relation to treatment response. However, as the complex metabolism of drugs used in the treatment of osteosarcoma involves a broader range of genes, we have performed a DMET analysis including 1,936 genetic variants in 231 genes known to be involved in drug metabolism and transport. Methods: We used a two-stage design, including 135 osteosarcoma patients in the discovery stage. Germline DNA was genotyped using the DMET Plus array. Associations between the presence of genetic variants and histological response (HR) to preoperative cisplatin and doxorubicin based chemotherapy, 5-year Disease Free Survival (DFS) and ototoxicity (SIOP grade 1-3) were assessed by logistic regression models in PLINK. In the replication cohort 185 osteosarcoma patients will be included. Results: 734 markers and 131 patients passed quality control (call rates > 0.9, minor allele frequency > 0.01) in the discovery cohort. A total of 21 markers showed association (p < 0.05) with HR and 20 markers with 5-year DFS, with overlap of associated markers in the transporter SLCO4A1 and Phase I enzyme CYP8B1 genes. In addition, 21 markers were significantly associated with ototoxicity, the majority was located in cytochrome p450 genes. Conclusions: To the best of our knowledge, the present pharmacogenetic study is the first in osteosarcoma patients using the DMET analysis. Significant associations of treatment response and ototoxicity with genes previously unknown to impact cisplatin and doxorubicin metabolism and transport were explored. Following replication and validation in functional studies and in larger prospective studies, these markers are of potential interest for the development of new treatment strategies and optimizing current therapy.
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