Types of pancreatic lesions and the mutational landscape of the VHL gene in patients with von Hippel-Lindau disease.
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BACKGROUND: Von Hippel-Lindau (VHL) disease is a heritable syndrome with multiorgan involvement. In this study, we describe the phenotype of pancreatic lesions and the genetic mutational profile of patients with VHL. METHODS: We included 90 patients with VHL who were treated at a single center. Their clinical profile and types of pancreatic lesions were studied. In addition, genetic testing for mutations in the VHL gene was conducted using Sanger sequencing, covering all three exons and splicing sites of VHL. One patient with insulinoma underwent whole-exome sequencing (WES) and whole-genome sequencing (WGS). RESULTS: Of the 90 patients, 55 (61.1 %) had VHL disease-related pancreatic lesions (male: female, 29:26; mean age at diagnosis, 34 years). The lesions included simple cysts (n = 31, 56.4 %), serous cystadenoma (n = 4, 7.3 %), and neuroendocrine tumors (NETs) (n = 32, 58.2 %). Among the 32 NETs, one was an insulinoma, and the others were nonfunctional tumors. Of the 55 patients, 44 patients with pancreatic lesions underwent genetic testing for the VHL gene. Mutations were missense in 38 cases, nonsense in 2 cases, deletion in 3 cases, and a splicing site mutation in 1 case. 23 patients had mutations in either codon 161 or 167. NETs were statistically more frequent in patients with missense mutations in codons 161 and 167 compared to mutations in the rest of the VHL gene (21/23 vs. 7/15; P = 0.006). An amplification pattern of copy-number variation was found on the WGS in the insulinoma patient. CONCLUSION: Pancreatic lesions are common in VHL disease. Mutations in codons 161 and 167 are hotspots in patients with pancreatic lesions, particularly NETs.