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. 2020 Dec 10:11:532588.
doi: 10.3389/fgene.2020.532588. eCollection 2020.

The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population

Jianhui Qiu  1   2   3 , Kenan Zhang  1   2   3 , Kaifang Ma  1   2   3 , Jingcheng Zhou  1   2   3 , Yanqing Gong  1   2   3 , Lin Cai  1   2   3 , Kan Gong  1   2   3
Affiliations

The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population

Jianhui Qiu et al. Front Genet. .

Abstract

Purpose: Von Hippel-Lindau (VHL) disease is a hereditary kidney cancer syndrome, with which patients are more likely to get affected by renal cell carcinoma (RCC), pancreatic cyst or tumor (PCT), central nervous system hemangioblastoma (CHB), retinal angiomas (RA), and pheochromocytoma (PHEO). Mutations of VHL gene located in 3p25 may impair the function of the VHL protein and lead to the disease. It's unclear why obvious phenotype varieties exist among VHL patients. Here we aimed to ascertain whether the mutation types and locations affect the phenotype.

Methods: We enrolled 577 Chinese VHL patients from 211 families and divided them into three groups and six subgroups according to their mutation types and locations. Cox survival analysis and Kaplan-Meier analysis were used to compare intergroup age-related tumor risks.

Results: Patients with nonsense or frameshift mutations that were located before residues 117 of VHL protein (NoF1 subgroup) hold lower age-related risks of VHL associated tumors (HR = 0.638, 95%CI 0.461-0.883, p = 0.007), CHB (HR = 0.596, 95%CI 0.409-0.868, p = 0.007) or PCT (HR = 0.595, 95%CI 0.368-0.961, p = 0.034) than patients whose mutations were located after residues 117 (NoF2 subgroup). Patients in NoF1 subgroup still had lower age-related risks of CHB (HR = 0.652, 95%CI 0.476-0.893, p = 0.008) and PCT (HR = 0.605, 95%CI 0.398-0.918, p = 0.018) compared with those in combined NoF2 subgroup and other truncating mutation patients. NoF1 subgroup correspondingly had a longer estimated median lifespan (64 vs. 55 year, p = 0.037) than NoF2 subgroup. Among patients with missense mutations of VHL, only a small minority (23 of 286 missense mutations carriers) carried mutations involving neither HIF-α binding region nor elongin C binding region, who were grouped in MO subgroup. MO subgroup seemed to have a higher age-related risk of PHEO. In the whole cohort (n = 577), PHEO was an independent protective factor for CHB (p = 0.001) and survival (p = 0.005). RA and CHB failed to predict the age-related risk of each other.

Conclusion: The mutation types and locations of VHL gene are associated with phenotypes. Genetic counselors could predict phenotypes more accurately based on more detailed genotype-phenotype correlations. Further genotype-phenotype studies should focus on the prediction of tumor recurrence, progression, and metastasis. The deep molecular mechanism of genotype-phenotype correlation is worth further exploring.

Keywords: Von Hippel-Lindau disease; elongin C; genotype-phenotype; hypoxia-inducible factor α; tumor risk.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) The structure of the VHL gene. (B) The number of cases and families with missense mutations on each residues of pVHL.
FIGURE 2
FIGURE 2
Comparison of age-related risks in NoF1 and NoF2 subgroup. (A) All the five VHL-associated tumors, (B) CHB, (C) RA, (D) RCC, (E) PCT, (F) PHEO. NoF1, nonsense or frameshift mutations before residue 117 of VHL protein; NoF2, nonsense or frameshift mutations after residue 117 of VHL protein; CHB, central nervous system hemangioblastoma; RA, retinal angiomas; RCC, renal cell carcinoma; PCT, pancreatic cyst or tumor; PHEO, pheochromocytoma.
FIGURE 3
FIGURE 3
Comparison of age-related risks of PHEO between MO subgroup and MH subgroup (A), MO subgroup and ME subgroup (B), MH subgroup and those in combination with MO and ME subgroups (C), those in combined with MO and ME subgroups and all other VHL patients (D). PHEO, pheochromocytoma; MH, missense mutations in HIF-α binding site; ME, missense mutations in elongin C binding site; MO, missense mutations subgroup in other sites.
FIGURE 4
FIGURE 4
Comparison of survival in patients with different mutation groups. (A) Comparison of survival in patients from NoF1 and NoF2 subgroups. (B) Comparison of survival in type 1 and type 2 patients. (C) Comparison of CHB-specific survival in patients with MH and ME mutations. (D) Comparison of RCC-specific survival in patients with MH and ME mutations. (E) Comparison of CHB-specific survival in patients with NoF1 and NoF2 mutations. (F) Comparison of RCC-specific survival in patients with NoF1 and NoF2 mutations. NoF1, nonsense or frameshift mutations before residue 117 of VHL protein; NoF2, nonsense or frameshift mutations after residue 117 of VHL protein; CHB, central nervous system hemangioblastoma; MH, missense mutations in HIF-α binding site; ME, missense mutations in elongin C binding site; RCC, renal cell carcinoma.
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