Journal
GENETICS IN MEDICINE
Volume 20, Issue 10, Pages 1266-1273Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2017.261
Keywords
genotype-phenotype; protein binding site; survival; tumor risk; von Hippel-Lindau disease
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Funding
- National Natural Science Foundation of China [81572506]
- Special Health Development Research Project of Capital [2016-2-4074]
- Beijing Municipal Science and Technology Commission [Z151100003915126]
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Purpose: Von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL). Methods: VHL patients (n = 339) were recruited and grouped based on mutation types: HIF-alpha binding site missense (HM) mutations, non-HIF-alpha binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared. Results: Missense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p < 0.001) and lower risks of central nervous system hemangioblastoma (CHB) (HR = 0.700, p = 0.045), renal cell carcinoma (HR = 0.610, p = 0.024), and pancreatic tumor (HR = 0.382, p < 0.001) than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival (HR = 0.345, p = 0.005) and CHB-specific survival (HR = 0.129, p = 0.005) than HMTR mutations. Conclusion: The modified genotype-phenotype correlation links VHL gene mutation, substrate binding site, and phenotypic diversity (penetrance and survival), and provides more accurate information for genetic counseling and pathogenesis studies.
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