Hotspots of Somatic Genetic Variation in Pituitary Neuroendocrine Tumors

Simple Summary Mutational hotspots have gained importance as oncological biomarkers in recent years because of their potential as predictors of clinical outcomes and/or therapeutic targets. In addition, they are easily detectable in clinical samples via Sanger or next-generation sequencing (NGS). The role of these genetic defects is less clear in pituitary neuroendocrine tumors (PitNETs), even though the most common genetic drivers of these neoplasms are located within mutational hotspots. Indeed, hotspots in six different genes are of particular importance in this context. Two of them, USP48 and SF3B1, represent very recent and infrequent genetic associations; thus, their clinical relevance remains unclear. For two other genes, GNAS and USP8, discrepancies exist among studies regarding their associated phenotypes. Finally, the phenotypes associated with BRAF and DICER1 are well defined in other settings, but not yet in sporadic PitNETs. Additional studies are required to assess the potential of these molecular alterations as druggable targets in PitNETs.Abstract The most common genetic drivers of pituitary neuroendocrine tumors (PitNETs) lie within mutational hotspots, which are genomic regions where variants tend to cluster. Some of these hotspot defects are unique to PitNETs, while others are associated with additional neoplasms. Hotspot variants in GNAS and USP8 are the most common genetic causes of acromegaly and Cushing's disease, respectively. Although it has been proposed that these genetic defects could define specific clinical phenotypes, results are highly variable among studies. In contrast, DICER1 hotspot variants are associated with a familial syndrome of cancer predisposition, and only exceptionally occur as somatic changes. A small number of non-USP8-driven corticotropinomas are due to somatic hotspot variants in USP48 or BRAF; the latter is a well-known mutational hotspot in cancer. Finally, somatic variants affecting a hotspot in SF3B1 have been associated with multiple cancers and, more recently, with prolactinomas. Since the associations of BRAF, USP48, and SF3B1 hotspot variants with PitNETs are very recent, their effects on clinical phenotypes are still unknown. Further research is required to fully define the role of these genetic defects as disease biomarkers and therapeutic targets.