Abstract
Pulmonary metastases are the major cause of death of osteosarcoma (OS) patients. Endothelin-1 (ET-1) reportedly plays an important role in OS metastasis. In the present study, we for the first time explored the association of ET-1 SNPs with the risk of pulmonary metastatic OS. We genotyped three SNPs (rs1800541, rs2070699 and rs5370) in the ET-1 gene in a case-control study, using 260 pairs of age-, sex-, residence area- and tumor location-matched subjects. Patients with pulmonary metastatic OS and patients with localized high-grade (stage IIB) OS were enrolled as cases and controls, respectively. The G allele at rs1800541 was found associated with reduced risk of pulmonary metastatic OS after adjustment for body mass index, systolic blood pressure, diastolic blood pressure and the plasma ET-1 level (P=10-4; adjusted OR, 0.55; 95% CI, 0.42-0.70), while the G allele at rs2070699 was not significantly associated with the risk of pulmonary metastatic OS (P=0.15; adjusted OR, 1.15; 95% CI, 0.87-1.50). The mRNA and the secreted protein levels of ET-1 in primary OS cell cultures (POCCs) established from surgically resected primary OS in the rs1800541 TT homozygotes were higher than those from the TG heterozygotes (P<0.05), who in turn showed higher ET-1 mRNA and secreted ET-1 levels than the GG homozygotes (P<0.05). In the control subjects, the rs1800541 TT homozygotes showed an 18.4% relapse rate, significantly higher than that of the GG homozygotes (0%) (P<0.01). On the other hand, the GG homozygotes showed a 71.4% complete recovery rate, significantly higher than that of the TG heterozygotes (7.3%) and the TT homozygotes (0%) (P<0.01). This study provides the first evidence of an association between the ET-1 gene SNPs and the risk of pulmonary metastatic OS.
Highlights
Osteosarcoma (OS) is the most frequent malignant bone tumor in children and adolescents [1]
ET-1 reportedly plays an important role in OS metastasis [8,9,10]
We for the first time report that a Single nucleotide polymorphisms (SNPs) at polymorphic site rs1800541 in the ET-1 gene is associated with increased risk of pulmonary metastatic OS
Summary
Osteosarcoma (OS) is the most frequent malignant bone tumor in children and adolescents [1]. OS is a devastating disease, characterized by high local aggressiveness and a tendency to metastasize to the lungs and distant bones. In spite of the use of neoadjuvant chemotherapy and improvement in surgical technology that have increased the survival rate to 65-75%, pulmonary metastasis occurs in approximately 40%-50% of OS patients and remains a major cause of fatal outcome [2,3,4]. The cure rate of OS is approximately 65% for patients with localized diseases. When presenting with metastases at the time of diagnosis, the survival rate is 25% [5,6]. There have been many studies on its genetics, biology, pathology and clinical aspects, the etiology of osteosarcoma is not well understood
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