Association of prolactin receptor (PRLR) variants with prolactinomas

Research output: Contribution to journalArticlepeer-review

Authors

  • Paul J Newey
  • Angela Rogers
  • Victoria Stokes
  • Matt J Neville
  • Kate E Lines
  • Georgia Ntali
  • Peter Lees
  • Patrick J Morrison
  • Panagiotis N Singhellakis
  • Fotini Ch Malandrinou
  • Ashley B Grossman
  • Fredrik Karpe
  • Rajesh V Thakker

Colleges, School and Institutes

External organisations

  • University of Oxford

Abstract

Prolactinomas are the most frequent type of pituitary tumors, which represent 10-20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocyte, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (p<0.0001) in prolactinoma patients than in 60,706 individuals of the Exome Aggregation Consortium cohort and 7,045 individuals of the Oxford Biobank. In vitro analysis of the PRLR variants demonstrated that the Asn492Ile variant, but not Glu376Gln, when compared to wild-type PRLR, increased prolactin-induced pAkt signaling (>1.3-fold, p<0.02) and proliferation (1.4-fold, p<0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to wild-type levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas, and reveal a new aetiology and potential therapeutic approach for these neoplasms.

Bibliographic note

Caroline M Gorvin, Paul J Newey, Angela Rogers, Victoria Stokes, Matt J Neville, Kate E Lines, Georgia Ntali, Peter Lees, Patrick J Morrison, Panagiotis N Singhellakis, Fotini Ch Malandrinou, Niki Karavitaki, Ashley B Grossman, Fredrik Karpe, Rajesh V Thakker; Association of prolactin receptor (PRLR) variants with prolactinomas, Human Molecular Genetics, , ddy396, https://doi.org/10.1093/hmg/ddy396

Details

Original languageEnglish
Number of pages15
JournalHuman Molecular Genetics
Early online date15 Nov 2018
Publication statusE-pub ahead of print - 15 Nov 2018

Keywords

  • signal transduction, pituitary neoplasms, dna, genes, leukocytes, prolactinoma, prolactin receptor, neoplasms, prolactin, everolimus, proto-oncogene proteins c-akt, akt signaling pathway