Somatic VHL Mutation in a Patient With MEN1-Associated Metastatic Pancreatic Neuroendocrine Tumor Responding to Sunitinib Treatment: A Case Report

Abstract

Multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) are autosomal-dominant diseases caused by germline mutations in tumor-suppressor genes. A patient with a germline MEN1 mutation and a somatic VHL mutation in the tumor has not been reported. Herein, we report on a patient with MEN1 and a metastatic nonfunctioning pancreatic neuroendocrine tumor (PNET) with a somatic VHL mutation. This patient underwent a pancreaticoduodenectomy for a grade 2 PNET obstructing her pancreatic duct. The patient developed liver and regional lymph node metastases as well as growth of a PNET in the remnant pancreas. As part of a clinical trial for mutation-targeted therapy, a biopsy of the metastatic tumor was obtained. The clinical diagnosis, confirmed by OncoVAR-NET and molecular profiling analysis, revealed MEN1 with a germline deletion in exon 2 and a c.402 deletion C, p.Phe134LeufsX51. In addition, a somatic mutation in the VHL gene—a nonsense mutation, c.529A>T, p.Arg177Ter—was identified by hybrid capture sequencing. The mutations were confirmed by Sanger sequencing. Comparative genomic hybridization showed loss of heterozygosity in both the MEN1 and VHL genes. The patient was treated with sunitinib and had a partial response to treatment. This case illustrates not only that a second hit occurs in tumor suppressor genes but that somatic mutations are also possible in additional tumor suppressor genes. This suggests that targeted therapy selection should include analysis of somatic mutations even when the susceptibility gene is known.

Tumor-to-tumor metastasis of clear cell renal cell carcinoma to contralateral synchronous pheochromocytoma: A case report

“…A VHL -associated CCRCC case in which a deletion of c.530-536 resulted in an Arg177Thr change has also been reported[ 23 ]. In addition, one study reported a rare VHL somatic c.529A>T mutation in a MEN1-associated metastatic pancreatic neuroendocrine tumor[ 24 ].…”

<p>Sunitinib-and-Chinese herbal medicine-based systematic treatment clinically cured a patient with multiple metastatic primary clear cell carcinoma of the liver: a case report</p>

“…However, in the current setting where there are not much treatment methods available and high-level evidence-based research is difficult to achieve, our study is a very worthwhile approach. Of course, it is worthy of recommendation if we can identify the degree of angiogenesis by immunohistochemistry before treatment or whether gene sequencing can determine the associated VHL gene and other genes for individualized precise treatment 22…”

DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment

“…In one MEN1-related PanNET (WHO grade 2), a high methylation percentage of the VHL promoter was found together with loss of VHL protein expression. It has been reported that somatic VHL mutations and LOH of chromosomal locus 3p (with the site of VHL) may be involved in PanNET development and/or progression in MEN1 (38,39). DNA promoter hypermethylation of VHL has previously been described in 6% of sporadic PanNETs (40).…”