von Hippel–Lindau Methylation Status in Patients with Multiple Myeloma: A Potential Predictive Factor for the Development of Bone Disease

Abstract

It has been suggested that during multiple myeloma (MM) progression, a proangiogenesis stress response occurs, but the mechanistic basis of this has not been established. It is an attractive hypothesis that loss of expression of the von Hippel—Lindau (VHL) gene, resulting in constitutive activation of hypoxia-inducible factor—1α (HIF-1α), contributes to increased angiogenesis in MM. Because aberrant methylation in the VHL CpG island could cause downregulation of VHL transcription, we prospectively studied the methylation status of the VHL CpG island in 45 individuals with multiple myeloma (MM; 25 men, 20 women; mean age, 66.4 years) and in 10 individuals with borderline thrombocytopenia, who were proven to have no malignancy and served as controls. Methylation was found in 15 of 45 patients with MM at diagnosis (33.3%). The presence of methylation in the VHL CpG island was significantly associated with the development of bone disease (odds ratio, 7.5; P = .018). Patients with bone disease had an increased risk of death compared with those with no bone lytic lesions (hazard ratio [HR], 5.1; P = .13). VHL methylation was not a predictor of excess mortality (HR, 0.92; P = .91). Our data imply that methylation in the VHL CpG island is a frequent event in patients with MM and might be a potential biomarker of bone disease. Methylation in the VHL CpG island, leading to transcriptional silencing and hence decreased HIF-1α proteolysis, could be a possible mechanism of increased angiogenesis and altered bone marrow microenvironment that is more supportive for survival and growth of MM cells, contributing to MM bone disease. Whether it represents an early or late event of the disease merits additional study. Additional studies regarding the serum levels of HIF-1α and vascular endothelial growth factor would be mechanistically interesting.