Association of prolactin receptor (PRLR) variants with prolactinomas

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

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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.
Original languageEnglish
Article numberddy396
JournalHuman Molecular Genetics
Early online date15 Nov 2018
DOIs
Publication statusE-pub ahead of print - 15 Nov 2018

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Prolactin Receptors
Prolactinoma
STAT5 Transcription Factor
Janus Kinase 2
Cytokine Receptors
1-Phosphatidylinositol 4-Kinase
Linkage Disequilibrium
Pituitary Neoplasms
Brain Neoplasms
Neoplasms
Leukocytes
DNA
Therapeutics
Genes

Cite this

Gorvin, C. M., Newey, P. J., Rogers, A., Stokes, V., Neville, M. J., Lines, K. E., ... Thakker, R. V. (2018). Association of prolactin receptor (PRLR) variants with prolactinomas. Human Molecular Genetics, [ddy396]. https://doi.org/10.1093/hmg/ddy396
Gorvin, Caroline M ; Newey, Paul J ; Rogers, Angela ; Stokes, Victoria ; Neville, Matt J ; Lines, Kate E ; Ntali, Georgia ; Lees, Peter ; Morrison, Patrick J ; Singhellakis, Panagiotis N ; Malandrinou, Fotini Ch ; Karavitaki, Niki ; Grossman, Ashley B ; Karpe, Fredrik ; Thakker, Rajesh V. / Association of prolactin receptor (PRLR) variants with prolactinomas. In: Human Molecular Genetics. 2018.
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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.",
author = "Gorvin, {Caroline M} and Newey, {Paul J} and Angela Rogers and Victoria Stokes and Neville, {Matt J} and Lines, {Kate E} and Georgia Ntali and Peter Lees and Morrison, {Patrick J} and Singhellakis, {Panagiotis N} and Malandrinou, {Fotini Ch} and Niki Karavitaki and Grossman, {Ashley B} and Fredrik Karpe and Thakker, {Rajesh V}",
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Gorvin, CM, Newey, PJ, Rogers, A, Stokes, V, Neville, MJ, Lines, KE, Ntali, G, Lees, P, Morrison, PJ, Singhellakis, PN, Malandrinou, FC, Karavitaki, N, Grossman, AB, Karpe, F & Thakker, RV 2018, 'Association of prolactin receptor (PRLR) variants with prolactinomas', Human Molecular Genetics. https://doi.org/10.1093/hmg/ddy396

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

In: Human Molecular Genetics, 15.11.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association of prolactin receptor (PRLR) variants with prolactinomas

AU - Gorvin, Caroline M

AU - Newey, Paul J

AU - Rogers, Angela

AU - Stokes, Victoria

AU - Neville, Matt J

AU - Lines, Kate E

AU - Ntali, Georgia

AU - Lees, Peter

AU - Morrison, Patrick J

AU - Singhellakis, Panagiotis N

AU - Malandrinou, Fotini Ch

AU - Karavitaki, Niki

AU - Grossman, Ashley B

AU - Karpe, Fredrik

AU - Thakker, Rajesh V

PY - 2018/11/15

Y1 - 2018/11/15

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddy396

DO - 10.1093/hmg/ddy396

M3 - Article

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

M1 - ddy396

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