Decoding the Molecular and Mutational Ambiguities of Gastroenteropancreatic Neuroendocrine Neoplasm Pathobiology

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), considered a heterogeneous neoplasia, exhibit ill-defined pathobiology and protean symptomatology and are ubiquitous in location. They are difficult to diagnose, challenging to manage, and outcome depends on cell type, secretory product, histopathologic grading, and organ of origin. A morphologic and molecular genomic review of these lesions highlights tumor characteristics that can be used clinically, such as somatostatin-receptor expression, and confirms features that set them outside the standard neoplasia paradigm. Their unique pathobiology is useful for developing diagnostics using somatostatin-receptor targeted imaging or uptake of radiolabeled amino acids specific to secretory products or metabolism. Therapy has evolved via targeting of protein kinase B signaling or somatostatin receptors with drugs or isotopes (peptide-receptor radiotherapy). With DNA sequencing, rarely identified activating mutations confirm that tumor suppressor genes are relevant. Genomic approaches focusing on cancer-associated genes and signaling pathways likely will remain uninformative. Their uniquely dissimilar molecular profiles mean individual tumors are unlikely to be easily or uniformly targeted by therapeutics currently linked to standard cancer genetic paradigms. The prevalence of menin mutations in pancreatic NEN and P27KIP1 mutations in small intestinal NEN represents initial steps to identifying a regulatory commonality in GEP-NEN. Transcriptional profiling and network-based analyses may define the cellular toolkit. Multianalyte diagnostic tools facilitate more accurate molecular pathologic delineations of NEN for assessing prognosis and identifying strategies for individualized patient treatment. GEP-NEN remain unique, poorly understood entities, and insight into their pathobiology and molecular mechanisms of growth and metastasis will help identify the diagnostic and therapeutic weaknesses of this neoplasia.

A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management

“…Despite the promulgation of effective and applicable guidelines (e.g., WHO/ENETs classification of 2010) ( 3 , 4 ) and their regular reassessment, a critical limitation is the dearth of large, randomized prospective trials. The precise delineation of definable strategies is further constrained by the tumor heterogeneity (diverse cell types, disparate molecular regulatory mechanisms and ill-understood oncogenic drivers) ( 5 , 6 ). As a consequence, five-year survival rates diverge widely (15–95%), depending on the primary site, variable tumor biology, disease extent at diagnosis, available therapeutic options and designated centers of care ( 7 , 8 , 9 ).…”

“…The majority of tumors (~95%) do not exhibit germline mutations ( 6 , 38 ). Although genomic studies have revealed a number of sporadic genomic alterations, particularly in pancreatic NENs, the relationship between specific genes and tumor pathobiology remains unclear ( 5 ). Unlike the majority of cancers, activating mutations are infrequent if not largely unknown in GEP-NEN ( 5 ) with most tumors exhibiting mutations (when identified) in tumor suppressor genes.…”

“…Although genomic studies have revealed a number of sporadic genomic alterations, particularly in pancreatic NENs, the relationship between specific genes and tumor pathobiology remains unclear ( 5 ). Unlike the majority of cancers, activating mutations are infrequent if not largely unknown in GEP-NEN ( 5 ) with most tumors exhibiting mutations (when identified) in tumor suppressor genes. Although genomic studies seeking underlying driver mutations have proven disappointing ( 39 , 40 ), transcriptome assessments have been useful in identifying and differentiating the different subtypes of NENs (based on origin e.g., pancreatic vs small intestinal, and aggressiveness e.g., non-progressive vs malignant/metastatic) ( 41 , 42 ) and have demonstrable predictive utility at a tissue level ( 43 ).…”

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

“…NET mutational profiles have been extensively investigated (Jiao et al 2011, Oberg et al 2013, Francis et al 2013, Fernandez-Cuesta et al 2014, Kidd et al 2015a, leading to the observation that they are extremely variable depending on the site. Somatic mutations have also been intensively investigated to possibly predict sensitivity or resistance to mTOR inhibitors.…”

Pathophysiology of Gastric NETs: Role of Gastrin and Menin

“…It was known that gastrin binding to CCKBR activates the gene encoding histidine decarboxylase (HDC), the rate-limiting enzyme for histamine synthesis triggering histamine production. Additionally, genes encoding vesicular monoamine transporter molecule 2 (VMAT2), responsible for the storage of histamine in secretory vesicles and chromogranin A (CgA) secreted with other products into ECL vesicles are also upregulated (36, 37). However, the signaling and molecular events leading up to ECL hyperplasia were not understood.…”