Very low frequency of germline GPR101 genetic variation and no biallelic defects with AIP in a large cohort of patients with sporadic pituitary adenomas.

CONTEXT: Recently, germline and somatic GPR101 p.(E308D) mutation was found in patients with isolated acromegaly. It is not known whether GPR101 point mutations are associated with other histological types of pituitary adenoma.

OBJECTIVE: We sought germline GPR101 mutations in patients with sporadic pituitary adenomas, and compared the phenotypes of GPR101 mutation carriers and AIP mutation carriers.

DESIGN: An observational cohort study performed between 2007 and 2014 in a single referral center.

PARTICIPANTS: This prospective study involved 766 unselected patients (413 women) with sporadic pituitary adenomas of all histotypes.

METHODS: Entire GPR101 and AIP coding sequence were screened for germline mutations.

RESULTS: Twelve patients (1.6%) were found to carry the GPR101 p.(E308D) mutation or rare GPR101 variants. The minor allele frequency of the GPR101 mutation and variants was higher in patients with pituitary adenomas than in unaffected individuals included in the Exome Aggregation Consortium database. Three of the six patients with the GPR101 p.(E308D) mutation had adult-onset acromegaly, two had adrenocorticotropin-secreting adenomas, and one had a nonfunctioning macroadenoma. Six patients carried rare GPR101 variants. Germline AIP mutations or rare AIP variants were identified in 32 patients (4.2%). AIP mutation carriers were younger at diagnosis than GPR101 mutation carriers and non carriers. None of the patients harbored mutations in both the GPR101 and AIP genes.

CONCLUSION: Germline GPR101 mutations are very rare in patients with sporadic pituitary adenomas of various histotypes. No digenism with AIP was identified. Further studies are required to establish whether and how genetic variation in GPR101 gene contributes to pituitary tumorigenesis.