BERKELEY, CA (UroToday.com) - Kidney cancer is one of the most common urological malignancies in the United States and one of the few that continues to increase in incidence year after year. The main gene involved in renal cell carcinoma, von-Hippel Lindau (VHL), has been subject to multiple genetic and promoter-based epigenetic studies. What is known is that silencing of the VHL gene plays an integral part in RCC tumorigenesis through a damaged hypoxia-inducible factor pathway, leading to upregulation of various growth and pro-angiogenic factors.
At the 2014 annual meeting of the American Urological Association in Orlando, FL, we presented data on VHL showing a pattern of genetic methylation that had yet to be discussed in the current literature. In our abstract and poster presentation, we illustrated a new assay for the detection of DNA methylation in the VHL gene, specifically in exons 1 and 2. With the MALDI-TOF assay technique, we confidently identified the methylation status of individual CpG sites with great robustness and repeatability.
We also discussed data showing that VHL methylation is not just present in the promoter region of the gene, but is also observed in the exonic regions as well. This observation leads us to believe that methylation of exonic regions in VHL presents an as of yet undetermined significance in the manifestation of kidney cancer, especially in clear cell renal cell carcinoma. Moreover, we provided data illustrating that in our sample cohort of RCC specimens, all samples had methylation present in exon 2 of VHL, demonstrating that methylation of this exon is likely of little to no significance in the function of the VHL gene.
It is probable that exonic methylation of VHL represents a unique downregulation pathway separate from that of promoter methylation, gene deletion, and exonic DNA mutation. Indeed, it can be seen that in certain RCC samples that lack promoter methylation or DNA mutations, they contain exonic methylation. Furthermore, there have been recent studies that have shown exonic methylation of genes to have an even stronger downregulation effect than that of gene mutations and promoter methylation. This supports our theory that exon 1 methylation of VHL not only may downregulate VHL protein expression, but also may lead to tumorigenesis and the path toward kidney cancer. Given that VHL expression abnormalities are seen in a vast number of kidney tumors, especially clear cell RCC tumors, it is expected that research into mechanisms of methylation of VHL will yield greater insights into this urologic disease.
Written by:
Fei Lian,1 and John A. Petros2, 3, 4, 5 as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
1Emory University School of Medicine, Atlanta, GA USA
2Department of Urology, Emory University School of Medicine, Atlanta, GA USA
3Department of Urology, Atlanta VA Medical Center, Atlanta, GA USA
4Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA USA
5Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA USA
Von Hippel-Lindau exonic methylation analysis using MALDI-TOF mass spectrometry - Abstract