Faculty Collaboration Database

In silico VHL Gene Mutation Analysis and Prognosis of Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease. J Clin Endocrinol Metab 2018 Apr 01;103(4):1631-1638

Date

01/03/2018

Pubmed ID

29294023

Pubmed Central ID

PMC6276699

DOI

10.1210/jc.2017-02434

Scopus ID

2-s2.0-85045464322 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

CONTEXT: Patients with von Hippel-Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types.

OBJECTIVE: To define pancreatic neuroendocrine tumor (PNET) aggressiveness according to VHL genotype.

DESIGN: A prospective natural history study.

SETTING: The National Institutes of Health clinical center.

PATIENTS: Patients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutations.

INTERVENTION: In-silico prediction of VHL mutation via 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: Sixty-nine patients were included: 2 developed metastases, 12 needed surgery, and 31 had disease progression during a median follow-up of 60 months (range 13 to 84 months). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), the 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% confidence interval, 1.1 to 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) than 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.

Author List

Tirosh A, El Lakis M, Green P, Nockel P, Patel D, Nilubol N, Gara SK, Keutgen XM, Linehan WM, Kebebew E

MESH terms used to index this publication - Major topics in bold

Adrenal Gland Neoplasms
Adult
Carcinoma, Renal Cell
Computer Simulation
DNA Mutational Analysis
Disease Progression
Female
Hemangioblastoma
Humans
Male
Middle Aged
Mutation
Pancreas
Pancreatic Neoplasms
Pheochromocytoma
Prognosis
Prospective Studies
Reproducibility of Results
Von Hippel-Lindau Tumor Suppressor Protein
von Hippel-Lindau Disease