Whole-genome sequencing of a multiple endocrine neoplasia type 1 proband identifies gross deletion in MEN1

Abstract BackgroundMultiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome with neuroendocrine tumorigenesis of the parathyroid and pituitary glands and pancreatic islet cells. This hereditary cancer is caused by germline mutations in the MEN1, located on chromosome 11q13. Among the approximately 3,000 cancer patients, in which multi-omics analysis was performed, we had a patient with multiple tumors including pancreatic neuroendocrine tumor, thymic carcinoid and adenoma parathyroid, who showed no family history of MEN1.MethodsWe performed whole genome sequencing (WGS) of peripheral blood samples and three isolated tumor tissues (pancreas, thymus, and parathyroid). Sanger sequencing was used to validate MEN1 mutations; meanwhile, MEN1 mRNA levels on tumor samples were obtained by microarrays. MEN1 copy numbers and protein expression levels were determined by real-time PCR, and immunohistochemistry, respectively.ResultsMEN1 mRNA levels of pancreas and parathyroid tissues from patient-derived tumor samples were remarkably reduced, compared to those of 3,095 tumor and normal tissue samples. WGS data indicated the thymus sample with MEN1 nonsense mutation (W203*), while no MEN1 mutations were observed in the other two samples. WGS also identified MEN1 gross deletion of 18.5 kbp (chr11:64569322 – chr11:64587796; GRCh37/hg19 assembly) in peripheral blood samples and all the three tumor tissues. In addition, no MEN1 copy numbers on pancreas and parathyroid tumors were detected, whereas peripheral blood and the thymic carcinoid had one copy. Immunostaining of all the tissues detected very low levels of the MEN1 protein, Menin.ConclusionWe detected a hemizygous MEN1 germline deletion in blood sample of the MEN1 proband. All the three tumor samples had second hit with a deleterious mutation or normal alleles lacked to generate loss of heterozygosity at the MEN1 locus, suggesting loss of tumor suppressive function for MEN1.