Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location

作者：Jodi K. Maranchie, Anoushka M. Afonso, Paul S. Albert, Sivaram Kalyandrug, John L. Phillips, Shubo Zhou, James Peterson, Β. Michael Ghadimi, Katheen Hurley, Joseph Riss, James R. Vasselli, Thomas Ried, Berton Zbar, Peter L. Choyke, McClellan M. Walther, Richard D. Klausner, W. Marston Linehan · 发表于：Human Mutation · 年份：2003 · DOI：10.1002/humu.10302 · 被引用次数：99 · 研究领域：MRI in cancer diagnosis、Cancer, Hypoxia, and Metabolism、Genetic and Kidney Cyst Diseases

von Hippel Lindau disease (VHL) is an autosomal dominant familial cancer syndrome linked to alteration of the VHL tumor suppressor gene. Affected patients are predisposed to develop pheochromocytomas and cystic and solid tumors of the kidney, CNS, pancreas, retina, and epididymis. However, organ involvement varies considerably among families and has been shown to correlate with the underlying germline alteration. Clinically, we observed a paradoxically lower prevalence of renal cell carcinoma (RCC) in patients with complete germline deletion of VHL. To determine if a relationship existed between the type of VHL deletion and disease, we retrospectively evaluated 123 patients from 55 families with large germline VHL deletions, including 42 intragenic partial deletions and 13 complete VHL deletions, by history and radiographic imaging. Each individual and family was scored for cystic or solid involvement of CNS, pancreas, and kidney, and for pheochromocytoma. Germline deletions were mapped using a combination of fluorescent in situ hybridization (FISH) and quantitative Southern and Southern blot analysis. An age-adjusted comparison demonstrated a higher prevalence of RCC in patients with partial germline VHL deletions relative to complete deletions (48.9 vs. 22.6%, p=0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p=0.22), pancreas (p=0.72), or pheochromocytoma (p=0.34). Deletion mapping revealed that development of RCC had an even gr...