Insights into pituitary tumorigenesis: from Sanger sequencing to next-generation sequencing and beyond

ABSTRACT

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.

KEYWORDS:

• BRAF
• CTNNB1
• USP8
• CABLES1
• DICER1
• CDH23
• epigenetics
• next-generation sequencing
• pituitary tumor

Article highlights

• Prior to the availability of next-generation sequencing (NGS), knowledge of pituitary tumourigenesis was limited to the small proportion of pituitary tumors occurring as part of a genetic syndrome. Using NGS, in particular, whole-exome sequencing (WES), novel mutations have been identified to further explain the pathogenesis of both familial and sporadic forms of pituitary tumors.

• In addition to Multiple Endocrine Neoplasia type 1 and type 4, Carney Complex (CNC) and McCune–Albright Syndrome (MAC), two new syndromes have been described to be associated with pituitary tumors, the DICER syndrome and the 3 P association syndrome (pituitary adenomas associated with paragangliomas/phaeochromocytomas). In these syndromes, the causative mutations were found to affect the DICER1 gene and succinate dehydrogenase complex (SDHx), respectively.

• Linkage analysis has led to the discovery of germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations in approximately 20% of patients with familial isolated pituitary adenomas (FIPA). Disease penetrance is approximately 30% in FIPA patients, associated tumors are typically macroadenomas and treatment resistance is common. Furthermore, WES has revealed CDH23 mutations in other patients with FIPA.

• WES studies of sporadic corticotrophinomas have identified somatic USP8 gene mutations in 30–45% and CABLES1 gene mutations in 2% of tumors. Tumors with USP8 mutations are more frequently observed in young females and disease relapse is common.

• Somatic GNAS mutations have been identified in 30–40% of sporadic somatotrophinomas. These tumors are typically small and treatment responses appear similar to tumors without GNAS mutations. In contrast, patients with McCune–Albright syndrome exhibit somatic mosaicism due to post-zygotic GNAS mutations and these patients typically develop somatotroph hyperplasia rather than discrete somatotrophinomas.

• WES studies of lactotrophinomas, thyrotrophinomas and silent gonadotrophinomas have not identified any pathogenic gene mutations to date. Null cell pituitary tumors do not exhibit immunoreactivity for either pituitary transcription factors or pituitary hormones and WES of these tumors are yet to be performed.

• Craniopharyngiomas are epithelial tumors affecting the sellar region and BRAF mutations have been found in more than 90% of papillary subtypes, while CTNNB1 (β-catenin) mutations have been observed in 60–70% of adamantinomatous subtypes.

• NGS has revealed potential new therapeutic targets. As a consequence, two patients with papillary craniopharyngiomas have been treated with BRAF inhibitors with good clinical response. EGFR inhibitors are being trialed in patients with corticotrophinomas and USP8 inhibitors are being developed as a potential novel therapy for the treatment of corticotrophinomas.

• X-linked acrogigantism (X-LAG) results from micro-duplication of Xq26.3 and affects approximately 7–8% of patients with gigantism. Somatic mosaicism is seen in affected males. Patients typically develop symptoms of growth hormone excess from infancy. Associated tumors are typically macroadenomas and treatment resistance is common.

• Through NGS studies of pituitary tumors, it has become apparent that tumor agonistic DNA mutational events are rarely observed in sporadic pituitary tumors and cell-specific changes, such as chromosome structural alterations and copy number variations, DNA methylation, histone modification, microRNAs and long noncoding RNAs, contribute to the complex process of pituitary tumorigenesis.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.