Yu Zhou1, Bo Liu, Min Wang, Jiangdong Ni. 1. Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Abstract
BACKGROUND: Osteosarcoma (OS) is the most common childhood bone cancer. Chemoresistance is the principal reason for poor survival and disease recurrence in OS patients, and ET-1 reportedly plays an important role in the development of chemoresistance in OS cells. In the present study, we for the first time explored the association of endothelin-1 (ET-1) SNPs and haplotypes with the risk of chemoresistant pediatric OS. PROCEDURE: We genotyped three SNPs (rs1800541, rs2070699, and rs5370) in the ET-1 gene in a case-control study, using 350 pairs of age, sex, and tumor location and stage matched pediatric patients with OS. Patients who showed <90% tumor necrosis after neochemotherapy were defined as poor responders (cases), and those who showed ≥90% tumor necrosis were defined as good responders (controls). RESULTS: The G allele at rs1800541 and the G allele at rs2070699 were associated with reduced and increased risk of chemoresistant OS, respectively. The rs1800541-rs2070699 haplotypes TG and GT were respectively associated with increased (P = 0.012; adjusted OR, 1.82; 95% CI, 1.10-5.65) and reduced (P = 0.009; adjusted OR, 0.25; 95% CI, 0.14-0.84) risk of chemoresistant OS. The TG and the GT haplotypes have a gene-dosage effect on increasing and decreasing the ET-1 expression in primary OS tumor cells from chemoresistant pediatric OS subjects, respectively. CONCLUSIONS: This study provides the first evidence of an association between the ET-1 gene SNPs and haplotypes and the risk of chemoresistant pediatric OS, potentially adding new insights into the pathophysiology and treatment of chemoresistant OS.
BACKGROUND:Osteosarcoma (OS) is the most common childhood bone cancer. Chemoresistance is the principal reason for poor survival and disease recurrence in OS patients, and ET-1 reportedly plays an important role in the development of chemoresistance in OS cells. In the present study, we for the first time explored the association of endothelin-1 (ET-1) SNPs and haplotypes with the risk of chemoresistant pediatric OS. PROCEDURE: We genotyped three SNPs (rs1800541, rs2070699, and rs5370) in the ET-1 gene in a case-control study, using 350 pairs of age, sex, and tumor location and stage matched pediatric patients with OS. Patients who showed <90% tumor necrosis after neochemotherapy were defined as poor responders (cases), and those who showed ≥90% tumor necrosis were defined as good responders (controls). RESULTS: The G allele at rs1800541 and the G allele at rs2070699 were associated with reduced and increased risk of chemoresistant OS, respectively. The rs1800541-rs2070699 haplotypes TG and GT were respectively associated with increased (P = 0.012; adjusted OR, 1.82; 95% CI, 1.10-5.65) and reduced (P = 0.009; adjusted OR, 0.25; 95% CI, 0.14-0.84) risk of chemoresistant OS. The TG and the GT haplotypes have a gene-dosage effect on increasing and decreasing the ET-1 expression in primary OS tumor cells from chemoresistant pediatric OS subjects, respectively. CONCLUSIONS: This study provides the first evidence of an association between the ET-1 gene SNPs and haplotypes and the risk of chemoresistant pediatric OS, potentially adding new insights into the pathophysiology and treatment of chemoresistant OS.