Molecular Genetic Studies of Pancreatic Neuroendocrine Tumors: New Therapeutic Approaches.

Pancreatic neuroendocrine tumors (PNETs) arise sporadically or as part of familial syndromes. Genetic studies of hereditary syndromes and whole exome sequencing analysis of sporadic NETs have revealed the roles of some genes involved in PNET tumorigenesis. The multiple endocrine neoplasia type 1 (MEN1) gene is most commonly mutated. Its encoded protein, menin, has roles in transcriptional regulation, genome stability, DNA repair, protein degradation, cell motility and adhesion, microRNA biogenesis, cell division, cell cycle control, and epigenetic regulation. Therapies targeting epigenetic regulation and MEN1 gene replacement have been reported to be effective in preclinical models.

Stevenson M ，Lines KE ，Thakker RV 《-》

Pancreatic Neuroendocrine Neoplasms in Multiple Endocrine Neoplasia Type 1.

Marini F ，Giusti F ，Tonelli F ，Brandi ML ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Well-differentiated G1 and G2 pancreatic neuroendocrine tumors: a meta-analysis of published expanded DNA sequencing data.

Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic, but PNETs also occur in hereditary syndromes, primarily multiple endocrine neoplasia type 1 (MEN1). The Knudson hypothesis stated a second, somatic hit in MEN1 as the cause of PNETs of MEN1 syndrome. In the recent years, reports on genetic somatic events in both sporadic and hereditary PNETs have emerged, providing a basis for a more detailed molecular understanding of the pathophysiology. In this systematic review and meta-analysis, we made a collation and statistical analysis of aggregated frequent genetic alterations and potential driver events in human grade G1/G2 PNETs. A systematic search was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines of 2020. A search in Pubmed for published studies using whole exome, whole genome, or targeted gene panel (+400 genes) sequencing of human G1/G2 PNETs was conducted at the 25th of September 2023. Fourteen datasets from published studies were included with data on 221 patients and 225 G1/G2 PNETs, which were divided into sporadic tumors, and hereditary tumors with pre-disposing germline variants, and tumors with unknown germline status. Further, non-functioning and functioning PNETs were distinguished into two groups for pathway evaluation. The collated genetical analyses were conducted using the 'maftools' R-package. Sporadic PNETs accounted 72.0% (162/225), hereditary PNETs 13.3% (30/225), unknown germline status 14.7% (33/225). The most frequently altered gene was MEN1, with somatic variants and copy number variations in overall 42% (95/225); hereditary PNETs (germline variations in MEN1, VHL, CHEK2, BRCA2, PTEN, CDKN1B, and/or MUTYH) 57% (16/30); sporadic PNETs 36% (58/162); unknown germline status 64% (21/33). The MEN1 point mutations/indels were distributed throughout MEN1. Overall, DAXX (16%, 37/225) and ATRX-variants (12%, 27/225) were also abundant with missense mutations clustered in mutational hotspots associated with histone binding, and translocase activity, respectively. DAXX mutations occurred more frequently in PNETs with MEN1 mutations, p<0.05. While functioning PNETs shared few variated genes, non-functioning PNETs had more recurrent variations in genes associated with the Phosphoinositide 3-kinase, Wnt, NOTCH, and Receptor Tyrosine Kinase-Ras signaling onco-pathways. The somatic genetic alterations in G1/G2 PNETs are diverse, but with distinct differences between sporadic vs. hereditary, and functional vs. non-functional PNETs. Increased understanding of the genetic alterations may lead to identification of more drivers and driver hotspots in the tumorigenesis in well-differentiated PNETs, potentially giving a basis for the identification of new drug targets. (Funded by Novo Nordisk Foundation, grant number NNF19OC0057915).

Andersen KØ ，Detlefsen S ，Brusgaard K ，Christesen HT ... -  《Frontiers in Endocrinology》

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis.

Pieterman CR ，Conemans EB ，Dreijerink KM ，de Laat JM ，Timmers HT ，Vriens MR ，Valk GD ... -  《-》

Multiple Endocrine Neoplasia Type 1 Syndrome Pancreatic Neuroendocrine Tumor Genotype/Phenotype: Is There Any Advance on Predicting or Preventing?

Multiple endocrine neoplasia type 1 syndrome (MEN1) is a disease caused by mutations in the MEN1 tumor suppressor gene leading to hyperparathyroidism, pituitary adenomas, and entero-pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors (PNETs) are a major cause of mortality in patients with MEN1. Identification of consistent genotype-phenotype correlations has remained elusive, but MEN1 mutations in exons 2, 9, and 10 may be associated with metastatic PNETs; patients with these mutations may benefit from more intensive surveillance and aggressive treatment. In addition, epigenetic differences between MEN1-associated PNETs and sporadic PNETs are beginning to emerge, but further investigation is required to establish clear phenotypic associations.

Ramamoorthy B ，Nilubol N 《-》