Uncovering the heterogeneous genetic variations in two insulin-expressing tumors in a patient with MEN1

Multiple endocrine neoplasia type 1 (MEN1) is associated with a heterozygous inherited mutation of the menin 1 (MEN1) gene; however, the molecular pathogenesis remains to be fully elucidated. In the present study, whole exome sequencing was performed on two pancreatic neuroendocrine tumors (PNETs), termed T1 and T2, peri-tumoral tissue (PT) and a blood sample obtained from a patient with MEN1. The cells in T1 and T2, but not PT, showed loss of chromosome 11 where MEN1 was located, confirming that the loss of heterozygosity (LOH) of MEN1 was a crucial event in tumorigenesis. PT exhibited chromosome copy number variations (CNVs), suggesting that CNVs may occur ahead of MEN1-associated tumorigenesis. The ploidy, CNVs and somatic point mutations were completely different in T1 and T2, showing the first evidence that multiple PNETs in patients with MEN1 are heterogeneous and arise from polyclonal origins. With the except of one recurrent and possibly benign mutation, no other suspicious driver mutations were identified in the tumors. By contrast, accompanying several chromosome losses, germline heterozygous mutations in the tumor suppressor genes, mucin 6, oligomeric mucus/gel-forming (MUC6), and G protein-coupled receptor 17 (GPR17) showed loss of heterozygosity in the two tumors, or in T2, respectively. These data demonstrated that chromosome instability may aggravate inherited mutations other than MEN1, thus contributing to the tumorigenesis in MEN1-associated PNETs.