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Genet Med. 2018 Oct;20(10):1266-1273. doi: 10.1038/gim.2017.261. Epub 2018 Mar 29.

Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein.

Liu SJ1,2,3, Wang JY1,2,3, Peng SH1,2,3, Li T1,2,3, Ning XH1,2,3, Hong BA1,2,3, Liu JY1,2,3, Wu PJ4, Zhou BW1,2,3, Zhou JC1,2,3, Qi NN1,2,3, Peng X1,2,3, Zhang JF1,2,3, Ma KF1,2,3, Cai L5,6,7, Gong K5,6,7.

Author information

1
Department of Urology, Peking University First Hospital, Beijing, P.R. China.
2
Institute of Urology, Peking University, Beijing, P.R. China.
3
National Urological Cancer Center, Beijing, P.R. China.
4
Department of Urology, Beijing Hospital, Beijing, P.R. China.
5
Department of Urology, Peking University First Hospital, Beijing, P.R. China. drcailin@163.com.
6
Institute of Urology, Peking University, Beijing, P.R. China. drcailin@163.com.
7
National Urological Cancer Center, Beijing, P.R. China. drcailin@163.com.

Abstract

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-α binding site missense (HM) mutations, non-HIF-α 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.

KEYWORDS:

genotype–phenotype; protein binding site; survival; tumor risk; von Hippel–Lindau disease

PMID:
29595810
DOI:
10.1038/gim.2017.261
[Indexed for MEDLINE]

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