Molecular features of pancreatic neuroendocrine neoplasms

The most relevant distinction in this field exists between well-differentiated pancreatic neuroendocrine tumors (pNETs) and poorly differentiated neuroendocrine carcinomas (pNECs). The latter frequently exhibit mutations in genes such as KRAS, TP53, RB1, APC, and CDKN2A, thus being more similar to pancreatic ductal adenocarcinoma in terms of molecular profiles and also clinical behavior [3–6].

Pancreatic NETs are totally different from pNECs. First, in a non-negligible portion of cases (10%) pNETs are associated with the presence of germline alterations in genes that are responsible for hereditary syndromes, including multiple endocrine neoplasia type 1 (MEN1 gene), von Hippel-Lindau disease (VHL), Neurofibromatosis type 1 (NF1), and Tuberous Sclerosis Complex (TSC1/2), respectively [5,7]. In specific clinical contexts, detecting these molecular alterations represents a critical step in the genetic screening of affected individuals and their relatives.

It is essential to consider that these genes are also involved in a significant proportion of sporadic cases (somatic and not germline alterations); for instance, approximately 30% of sporadic pNENs harbor somatic MEN1 mutations [8]. Additionally, other genes have been identified as crucial genetic drivers for the development of pNETs in the general population. These include MUTYH, PTEN, DAXX/ATRX, and TERT [5]. The pathways affected encompass DNA damage repair, chromatin remodeling, the mTOR signaling pathway, and the alternative lengthening of telomeres [5].

Notably, the assessment of molecular alterations may play an important prognostic role in patients affected by pNETs [9,10]. Indeed, the presence of alterations affecting the chromatin remodelers DAXX or ATRX (mutations in these two genes are mutually exclusive) are particularly significant for identifying patients with a poor prognosis, including earlier tumor progression and higher likelihood of lymph node involvement and distant metastases.