Abstract
The D104N polymorphism (p.D104N) in endostatin has been previously identified in many types of cancer, and this polymorphism is believed to be a phenotypic modulator in some tumors. However, it is unknown whether endostatin p.D104N affects the risk and progression of osteosarcoma (OS). Here, we analyzed the p.D104N endostatin variant in 236 patients with OS and 418 healthy individuals. Similar frequencies of wild type and heterozygous p.104DN endostatin were observed in controls and OS patients. Interestingly, the frequency of the homozygous p.D104N (p.104NN) genotype was higher in OS patients group compared to control group, suggesting that individuals with p.104NN endostatin have a significantly increased risk for OS. In addition, OS patients with p.104NN endostatin had a shorter survival time and a higher rate of metastasis than OS patients with wild type endostatin. Animal experiments revealed that overexpression of p.104NN endostatin did not significantly inhibit OS lung metastasis. Interestingly, administration of endostatin dramatically inhibited OS lung metastasis in the p.104NN endostatin xenograft model. Together, these results suggest that p.104NN of endostatin is associated with the risk of OS and demonstrates predictive significance for clinical outcome in OS patients. In addition, endostatin therapy may be necessary for OS patients harboring p.104NN endostatin.
Highlights
Osteosarcoma (OS) is the most common primary malignant tumor in children[1], and 30% of children diagnosed with OS will not survive for more than 5 years[2,3]
The D104N polymorphism in endostatin has been previously reported in many types of cancer, and this polymorphism is believed to be a phenotypic modulator in some benign and malignant tumors[21]
Studies have shown that the heterozygous p.D104N of endostatin is associated with an increased risk of prostate cancer[27] and invasive breast cancer[15] and with worse clinical outcomes for gastric cancer[22], whereas no associations were observed between the heterozygous p.D104N genotype and the risk of multiple myeloma[28] and lung cancer[29]
Summary
Osteosarcoma (OS) is the most common primary malignant tumor in children[1], and 30% of children diagnosed with OS will not survive for more than 5 years[2,3] Treatment of this disease often fails due to the development of metastasis[4]. Studies in breast cancer showed that endostatin p.D104N is associated with invasive breast cancer[15], and patients carrying this polymorphism exhibited shorter progression-free survival and overall survival compared to those with wild type endostatin[22]. It is not known whether this polymorphism in endostatin affects the risk and progression of OS. We aimed to determine the frequency of the wild type, heterozygous p.D104N (p.104DN), and homozygous p.D104N (p.104NN) endostatin genotypes in patients with OS and to determine the influence of this polymorphism on OS risk, biological features and clinical outcomes
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