Genetic testing considerations for hereditary duodenopancreatic neuroendocrine tumors

Abstract The incidence of duodenal and pancreatic neuroendocrine tumors (dpNETs) has increased substantially in recent years. These tumors may be due to syndromic hereditary predisposition syndromes: multiple endocrine neoplasia type 1 (MEN1) or 4 (MEN4), Von Hippel–Lindau disease (VHL), neurofibromatosis type 1 (NF1), or tuberous sclerosis complex (TSC). Because a dpNET may be the first MEN1 sign, recent guidelines recommend MEN1 genetic testing in selected patients with an isolated dpNET. Whether similar genetic testing strategies should be extended to other hereditary syndromes remains unknown. We conducted a retrospective analysis of the genetic and clinical data of patients who underwent genetic testing for isolated or syndromic dpNETs. We assessed the presence of (likely) pathogenic variants ((L)PVs) in MEN1 , NF1 , VHL , CDKN1B , TSC1 , and TSC2 . 410 patients were included: 301 with isolated (=non syndromic) dpNETs and 109 with syndromic dpNETs. Among them, 38 carried a (L)PV, most frequently in MEN1 ( n = 27 patients), followed by NF1 ( n = 8) and VHL ( n = 3). No TSC1 , TSC2 , or CDKN1B (L)PVs were found. Patients with syndromic dpNETs exhibited significantly higher positive rates (29.4%) compared to isolated dpNETs (<2%). We confirm that MEN1 is the predominant gene underlying predisposition to dpNETs. The low diagnostic yield in isolated dpNETs supports a clinically stratified genetic testing strategy. Clinical evaluation should systematically assess for signs of MEN1, MEN4, VHL, NF1, or TSC to inform appropriate genetic testing and maximize diagnostic yield. Concerning MEN1, we propose limiting extended genetic testing in patients with isolated dpNETs to those with (i) gastrinoma, (ii) multiple dpNETs, or (iii) diagnosis before 40 years of age.