In-silico VHL Gene Mutation Analysis and Prognosis of Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease.

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In-silico VHL Gene Mutation Analysis and Prognosis of Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease.

J Clin Endocrinol Metab. 2017 Dec 26;:

Authors: Tirosh A, Lakis ME, Green P, Nockel P, Patel D, Nilubol N, Gara SK, Keutgen XM, Linehan WM, Kebebew E

Abstract
Context: Patients with vHL disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types.
Objective: To define PNET aggressiveness according to VHL genotype.
Design: A prospective natural history study.
Setting: The NIH clinical center.
Patients: Patients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutation.
Intervention: In silico prediction of VHL mutation using five computational prediction models. Patients with > 80% prediction for disease-causing mutations in all models (high predicted risk (HPR)) were compared with others (low predicted risk (LPR)).
Main Outcome Measure: Rates of metastases, surgical intervention and disease progression.
Results: 69 patients were included: 2 developed metastases, 12 required surgery, and 31 had disease progression during a median follow-up of 60 months (range 13-84). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), HPR group (n=13) had a higher rate of disease progression than the LPR group (n=43) in multivariable analysis (hazard ratio 3.6, 95% CI 1.1-11.9, P = 0.037). The HPR group also had a higher risk of developing metastases (P = 0.015). Among patients with codon 167 hotspot mutations (n = 26), those in the HPR group had a higher risk for disease progression (P = 0.03) compared to other patients.
Conclusions: Computational models for predicting the impact of missense VHL gene mutations may be used as a prognostic factor in patients with PNETs in the context of vHL disease.

PMID: 29294023 [PubMed - as supplied by publisher]

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