Germline and somatic genetic changes in multicentric tumors obtained from a patient with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome caused by germline mutations of the MEN1 gene located in chromosome 11q13. In patients with MEN1, multicentric tumors develop in the involved organs; however, precise evaluation of genetic changes in these multicentric tumors has not been performed. In the present study, using whole-exome sequencing, we analyzed germline and somatic genetic changes in blood cells, two pancreatic endocrine tumors and one duodenal tumor obtained from a patient with MEN1 gastrinoma. We found that this patient possessed a novel germline mutation of the MEN1 gene [NM_137099.2:c.1505dupA (p.Lys502Lysfs); the localization was Chr11:64572134 on Assembly GRCh37], in which an adenine insertion in codon 502 of the MEN1 gene resulted in a frame shift and a premature stop codon. In terms of heterozygosity, the mutated allele was heterozygous in blood cells, hemizygous in the two pancreatic tumors and homozygous in the duodenal tumor. Immunohistochemical staining confirmed that only truncated menin protein accumulated in the nucleus of the tumor tissues. Further evaluation of tumor-specific somatic mutations in two pancreatic tumors did not detect single-nucleotide variations (SNVs) in 609 cancer-associated genes designated by the COSMIC cancer gene census, suggesting that the germline MEN1 mutation and resultant loss of heterozygosity played a major role in tumorigenesis. In the duodenal tumor, in addition to the germline MEN1 mutation, single-nucleotide variations in two cancer-associated genes were found. Further studies are required to clarify the role of these somatic single-nucleotide variations in the progression of MEN1 tumors.