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Introduction: This review explores insights provided by next-generation sequencing (NGS) of pituitary tumors and the clinical implications.Areas covered: Although syndromic forms account for just 5% of pituitary tumours, past Sanger sequencing studies pragmatically focused on them. These studies identified mutations in MEN1, CDKN1B, PRKAR1A, GNAS and SDHx causing Multiple Endocrine Neoplasia-1 (MEN1), MEN4, Carney Complex-1, McCune Albright Syndrome and 3P association syndromes, respectively. Furthermore, linkage analysis of single-nucleotide polymorphisms identified AIP mutations in 20% with familial isolated pituitary adenomas (FIPA). NGS has enabled further investigation of sporadic tumours. Thus, mutations of USP8 and CABLES1 were identified in corticotrophinomas, BRAF in papillary craniopharyngiomas and CTNNB1 in adamantinomatous craniopharyngiomas. NGS also revealed that pituitary tumours occur in the DICER1 syndrome, due to DICER1 mutations, and CDH23 mutations occur in FIPA. These discoveries revealed novel therapeutic targets and studies are underway of BRAF inhibitors for papillary craniopharyngiomas, and EGFR and USP8 inhibitors for corticotrophinomas.Expert opinion: It has become apparent that single-nucleotide variants and small insertion/deletion DNA mutations cannot explain all pituitary tumorigenesis. Integrated and improved analyses including whole-genome sequencing, copy number, and structural variation analyses, RNA sequencing and epigenomic analyses, with improved genomic technologies, are likely to further define the genomic landscape.

Somatic GNAS and USP8 mutations have been implicated in sporadic somatotrophinomas and corticotrophinomas, respectively.However, no genes are known to be recurrently mutated in sporadic prolactinomas. The prevalence of copy number variants (CNV), which is emerging as a mechanism of tumorigenesis in sporadic pituitary adenomas in general, is also unclear in prolactinomas. To characterize the genetic events underpinning sporadic prolactinomas, we performed whole exome sequencing of paired tumor and germline DNA from 12 prolactinoma patients. We observed recurrent large-scale CNV, most commonly in the form of copy number gains. We also identified sequence variants of interest in 15 genes. This included the DRD2, PRL, TMEM67, and MLH3 genes with plausible links to prolactinoma formation. Of the 15 genes of interest, CNV was seen at the genelocus in the corresponding tumor in 10 cases, and pituitary expression of eight genes was in the top 10% of tissues. However,none of our shortlisted somatic variants appeared to be classical driver mutations as no variant was found in more than one tumor.Future directions of research include mechanistic studies to investigate how CNV may contribute to prolactinoma formation,larger studies of relevant prolactinoma subsets according to clinical characteristics, and additional genetic investigations for aberrations not captured by whole exome sequencing. Refereed/Peer-reviewed