Genotype analysis of the human endostatin variant p.D104N in benign and malignant adrenocortical tumors

Abstract

OBJECTIVE:Endostatin is a potent endogenous inhibitor of angiogenesis. It is derived from the proteolytic cleavage of collagen XVIII, which is encoded by the COL18A1 gene. A polymorphic COL18A1 allele encoding the functional polymorphism p.D104N impairs the activity of endostatin, resulting in a decreased ability to inhibit angiogenesis. This polymorphism has been previously analyzed in many types of cancer and has been considered a phenotype modulator in some benign and malignant tumors. However, these data are controversial, and different results have been reported for the same tumor types, such as prostate and breast cancer. The purpose of this study was to genotype the p.D104N variant in a cohort of pediatric and adult patients with adrenocortical tumors and to determine its possible association with the biological behavior of adrenocortical tumors.METHODS:DNA samples were obtained from 38 pediatric and 56 adult patients (0.6–75 yrs) with adrenocortical tumors. The DNA samples were obtained from peripheral blood, frozen tissue or paraffin-embedded tumor blocks when blood samples or fresh frozen tissue samples were unavailable. Restriction fragment length polymorphism analysis was used to genotype the patients and 150 controls. The potential associations of the p.D104N polymorphism with clinical and histopathological features and oncologic outcome (age of onset, tumor size, malignant tumor behavior, and clinical syndrome) were analyzed.RESULTS:Both the patient group and the control group were in Hardy–Weinberg equilibrium. The frequencies of the p.D104N polymorphism in the patient group were 81.9% (DD), 15.9% (DN) and 2.2% (NN). In the controls, these frequencies were 80.6%, 17.3% and 2.0%, respectively. We did not observe any association of this variant with clinical or histopathological features or oncologic outcome in our cohort of pediatric and adult patients with adrenocortical tumors.

Adrenocortical Carcinoma in Childhood: A Systematic Review

“…De Sousa et al showed that expression of DAX1, a stem cell fate regulator, was more frequent in pediatric ACC than in adult ACC at the protein and mRNA levels and revealed a significant positive correlation between DAX1 and SF1 expression, suggesting a potential role in tumorigenesis without relevance for prognosis [ 120 ]. In addition, human endostatin variant p.D104N has been described in DNA analysis to be more common in pediatric ACT (80.6%) [ 130 ]. Unlike in adults, the expression of matrix metalloproteinase 2 or the loss of HLA class II antigens based on immunohistochemical analysis does not discriminate between benign and malignant tumors in children [ 82 ].…”

A high risk of osteosarcoma in individuals who are homozygous for the p.D104N in endostatin

“…Angiogenesis is a discrete event in carcinogenesis that is related to the aggressive potential of a tumor 5 6 . Accumulating evidence suggests that tumor growth is associated with increased angiogenesis and that the formation of new blood vessels is a fundamental step in tumor development and expansion 7 . In addition, studies have suggested that increased angiogenic properties within a tumor are associated with poorer clinical outcomes 8 .…”

Impact of common SNPs in VEGF gene on the susceptibility of osteosarcoma

“…Accumulating evidence suggests that tumor growth is associated with increased angiogenesis and that new blood vessel formation is a fundamental step in tumor development and expansion (Mariani et al, 2012). VEGF is an important promoter of angiogenesis and is encoded by the VEGF gene (Hicklin and Ellis, 2005).…”