A novel hyperplasia-neoplasia sequence in pancreatic endocrine tumors: Glucagon cell adenomatosis

Introduction: Glucagon cell adenomatosis (GCA) was recently recognized by us as a multifocal neoplastic disease of the endocrine pancreas unrelated to MEN1. Multiple micro- and a few macrotumors are found on the background of a hyperplasia of glucagon cells. The disease may cause unspecific abdominal symptoms and only rarely a glucagonoma syndrome. We aimed to investigate the genetic alterations of GCGR gene in patients with GCA.

Material and methods: FFPE pancreatic tissues from six patients showing multiple microadenomas and partly macroadenomas of glucagon cells were macro- or microdissected. Following DNA extraction all exons of the GCGR gene were analysed for mutations by Sanger and deep sequencing. Genotyping for all detected GCGR variants was performed by using Taqman Assay in 2560 healthy individuals.

Results: Sequencing of the GCGR gene revealed germ line mutations in three out of six patients. One patient showed two different heterozygous point mutations in the hyperplastic alpha cells as well as in the non-tumorous tissue leading to two premature stop codons. One patient harboured a homozygous stop mutation. The third patient showed two homozygous missense mutations of the GCGR gene that most likely also led to a dysfunction of the GCGR. These variants were not identified in healthy subjects. In the three other patients no germ line or somatic mutations of the GCGR gene were detected. GCA patients harbouring GCGR mutations showed a more advanced phenotype regarding alpha cell hyperplasia and exclusively developed macrotumors.

Summary: The finding of germ line “loss of function” mutations of the GCGR gene in three of six GCA cases suggests that deficiency in the GCGR signalling causes glucagon cell adenomatosis via glucagon cell hyperplasia. However, there is a second still unrecognized mechanism that leads to GCA in patients with wild type GCGR gene.