Higher Risk of Aggressive Pancreatic Neuroendocrine Tumors in MEN1 Patients With MEN1 Mutations Affecting the CHES1 Interacting MENIN Domain

• Published in: The journal of clinical endocrinology and metabolism 2014-11, Vol.99 (11), p.E2387-E2391
• Main Authors: Bartsch, Detlef K, Slater, Emily P, Albers, Max, Knoop, Richard, Chaloupka, Brunhilde, Lopez, Caroline L, Fendrich, Volker, Kann, Peter H, Waldmann, Jens
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Cell Cycle Proteins - genetics; Child; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1 - genetics; Multiple Endocrine Neoplasia Type 1 - pathology; Mutation; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phenotype; Proto-Oncogene Proteins - genetics; Repressor Proteins - genetics; Retrospective Studies; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2013-4432

Context: Sixty to 80% of multiple endocrine neoplasia type 1 (MEN1) patients develop pancreatic neuroendocrine neoplasias (pNENs), which reveal an aggressive behavior in 10%-20% of patients. Causative MEN1 mutations in the interacting domains of the encoded Menin protein directly alter its regulation abilities and may influence the phenotype. Objective: The objective of the study was the evaluation of an association between MEN1 mutations in different interacting domains of Menin and the phenotype of pNENs. Design: This was a retrospective analysis of a prospectively collected cohort of 71 genetically confirmed MEN1 patients at a tertiary referral center. Main Outcome Measures: Analysis of patients' characteristics and clinical phenotype of pNENs regarding the mutation type and its location in Menin interacting domains was measured. Results: Sixty-seven patients (93%) developed pNENs after a median follow-up of 134 months. Patients with mutations leading to loss of interaction (LOI) with the checkpoint kinase 1 (CHES1) interacting domain codons (428–610) compared with patients with mutations resulting in LOI with other domains (eg, JunD, Smad3) had significantly higher rates of functioning pNENs (70% vs 34%), malignant pNENs (59% vs 16%), and aggressive pNENs (37% vs 9%), respectively. Patients with CHES1-LOI also had an increased pNEN-related mortality (20% vs 4.5%). Neither gender, age, nor the ABO blood types were associated with the phenotype of pNENs. Conclusions: MEN1 patients with MEN1 mutations leading to CHES1-LOI have a higher risk of malignant pNENs with an aggressive course of disease and disease-related death.