Genetic Testing in Pituitary Adenomas: Consensus Statement

Genetic testing of patients with pituitary adenomas enables delivery of genotype-based precision care. Germline testing might identify variants predisposing to formation of pituitary adenomas and, potentially, other neoplasms. These include loss-of-function variants in AIP, MEN1, CDKN1B, PRKAR1A, SDHA, SDHB, SDHC, SDHD and MAX; GPR101-containing Xq26.3 microduplications; and postzygotic gain-of-function GNAS variants. Somatic testing might help identify and manage aggressive pituitary adenoma types and very rarely encountered pituitary carcinomas. This Pituitary Society Consensus Statement provides evidence-based guidance on the clinical application of these genetic tests, focusing on germline genetic testing, with recommendations regarding genes for inclusion in panel testing, test indications, pre-test counselling, test methodologies, and the interpretation and follow-up of results. As somatic genetic testing is gradually becoming available in clinical practice, recommendations are provided regarding clinical scenarios in which somatic testing might be considered and which genes to test. The consensus group concluded that genetic testing is an increasingly valuable adjunct in the assessment and management of people with pituitary adenomas. When indicated, genetic testing should ideally be undertaken within a multidisciplinary team comprising endocrine, genetic and laboratory expertise to ensure high-quality testing and safe and effective result interpretation and follow-up.

Germline Testing Recommendations

The Pituitary Society recommends germline genetic testing for individuals with pituitary adenomas who meet specific criteria, including young patients aged 18-30 years with early-onset somatotroph or lactotroph macroadenomas. Variants in AIP and MEN1 are the most common germline causes, accounting for most familial cases. Other genes such as CDKN1B, PRKAR1A, SDHx genes, MAX, and GPR101 are also associated with hereditary syndromes. Testing should be considered for those with a family history of pituitary adenomas or related endocrine syndromes. Pre-test counselling is essential to discuss potential outcomes and implications.

Somatic Testing Considerations

Somatic testing of adenoma tissue is emerging as an adjunctive assessment, particularly for aggressive or recurrent pituitary adenomas and carcinomas. Activating GNAS variants, occurring either as postzygotic mosaic alterations causing McCune-Albright syndrome or as tumour-restricted somatic variants, lead to constitutive cAMP signalling in a subset of somatotroph adenomas. USP8 variants enhance epidermal growth factor receptor expression in some corticotroph adenomas. SF3B1 variants have been linked to prolactinomas with aggressive features. Together with other, less frequent somatic variants, chromosomal instability and epigenetic deregulation, these alterations might influence the phenotype, endocrine activity and therapeutic responses.

Testing Methods and Multidisciplinary Approach

Advances in next-generation sequencing (NGS) now allow efficient and accessible simultaneous detection of germline and somatic variants across multiple genes, enabling comprehensive genomic profiling during diagnostic workflows. The Pituitary Society recommends that genetic testing be undertaken within a multidisciplinary team comprising endocrine, genetic and laboratory expertise to ensure high-quality testing and safe and effective result interpretation and follow-up. Testing practices are inconsistent across health systems, in part reflecting differences in cost, infrastructure availability and clinical expertise.

Conclusion

The Pituitary Society Consensus Statement establishes an integrated, evidence-based framework that translates complex biological insights into clinical utility, aiming to harmonize optimal clinical practice worldwide and ensure that genomic advances underlying pituitary adenoma pathogenesis translate to maximal benefits for patients and their families.