Abstract
Despite the knowledge of many genetic alterations present in osteosarcoma, the complexity of this disease precludes placing its biology into a simple conceptual framework. Lysyl oxidase (LOX) catalyzes the cross-linking of elastin and collagen, which is essential for the structural integrity and function of bone tissue. In the current study, we performed genomic sequencing on all seven exons -including the intron-exon splice sites, and the putative promoter region of LOX gene - followed by luciferase reporter assay to analyze the function of newly identified polymorphisms. Associations between LOX polymorphisms and osteosarcoma were then evaluated. Our sequencing data revealed three polymorphisms (−22G/C, 225C/G, and 473G/A) in the exons and promoter region of LOX. The −22G/C polymorphism lies in the downstream core promoter element (DPE) region and caused a decrease in promoter activity of LOX. The prevalence of the −22C allele and 473A allele were significantly increased in osteosarcoma patients compared to controls (odds ratio [OR] = 3.88, 95% confidence interval [CI] = 1.94−7.78, p = 4.18×10−5, and OR = 1.38, 95%CI = 1.07−1.78, p = 0.013; p 0.0167 was considered significant after Bonferroni correction). Analyzing haplotype showed that the frequency of CCG haplotype (−22, 225, 473) was significantly higher in osteosarcoma cases than in healthy controls after Bonferroni correction (p = 4.46×10−4). These results indicate that the −22G/C polymorphism may affect the expression of LOX, and that −22G/C and 473G/A polymorphisms may be new risk factors for osteosarcoma. These findings reveal a potential new pathway by which genetic polymorphisms may affect human diseases.
Highlights
Osteosarcoma is the most common pediatric bone malignancy in the world [1]
Polymorphisms in Lysyl oxidase (LOX) Gene Genomic DNA sequencing analysis was performed on all 7 exons, all exon/intron splice sites, and 850 bp upstream including the predicted promoter region of LOX, in 30 control subjects and 15 osteosarcoma patients
The 225C/G single nucleotide polymorphism (SNP) lies in exon 3 and is a silent polymorphism with both alleles coding for alanine
Summary
Osteosarcoma is the most common pediatric bone malignancy in the world [1]. Fifty years ago, surgery was the only available treatment, and survival was abysmal at less than 20% [2]. Treatment of patients with osteosarcoma was transformed in the 1980s and 1990s with advances in chemotherapy and orthopedic surgical techniques, leading to long-term survival rates that approach 70% [2,3]. Further increases in survival have not occurred in the last decade despite numerous trials targeting increased intensities of chemotherapy treatments and use of new chemotherapeutic agents [3]. Lysyl oxidase (proteinlysine 6-oxidase, LOX) is a copper-dependent enzyme that initiates cross-linking of collagen and elastin by catalyzing oxidative deamination of e-amino groups of lysine and hydroxylysine residues [6]. Pyridinolines and deoxypyridinolines are the primary cross-links of mature type I collagen that provide mechanical integrity, rigidity, and strength [10,11]. Diminished LOX enzyme activity results in an increased risk of bone deformities and fractures [12,13]
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