FRI303 PRL-R Variants Are Not Only Associated With Prolactinomas But Also With Dopamine Agonist Resistance
Authors: de Castro Moreira Andrea Ramos , Trarbach Ericka Barbosa , Glezer Andrea , Rosa Maciel Gustavo Arantes , Formiga Bueno Cristina Bellotti , Stellfeld Monteiro Anna Louise , Padula Mario , Pajaro Grande Isabella Pacetti , Bronstein Marcello Delano 
Published: October 2023

Abstract
Disclosure: A.R. Moreira: None. E.B. Trarbach: None. A. Glezer: None. G.A. Maciel: None. C.B. Bueno: None. A.S. Monteiro: None. M. Padula: None. I.P. Grande: None. M.D. Bronstein: None.
Introduction: Knockout prolactin receptor gene (PRL-R) mice are animal models for prolactinomas and PRL acts via autocrine/paracrine inhibiting lactotroph proliferation. Recent studies identified variants in PRL-R gene in patients with prolactinoma and two of them Glu400(376)Gln/p.Asn516(492)Ile, were more common in patients compared to controls. Functional analysis of the p.Asn516(492)Ile variant showed an increase in Akt expression and cell proliferation induced by PRL. However, the association between PRL-R variants and response to cabergoline (CAB) treatment has not been investigated. Objective: This study aims to analyze the PRL-R gene in an extensive cohort of patients with sporadic prolactinomas and evaluate its association with clinical, laboratorial and tumor imaging characteristics, as well as CAB treatment resistance. Methods: DNA was extracted from peripheral blood samples of 178 patients with prolactinoma and 146 were classified according to cabergoline response. The PRL-R gene was analyzed by PCR techniques and automated Sanger-type sequencing. Four in silico tools were used for analysis. Results: We found six PRL-R variants: p.Ile100(76)Val (n=18), p.Ile170(146)Leu (n=6), p.Glu400(376)Gln/p.Asn516(492)Ile (n=3), p.Glu470Asp (n =1) and p.Ala591Pro (n=1), the last two described for the first time in prolactinomas´ patients. The variants p.Glu400(376)Gln/p.Asn516(492)Ile and p.Ala591Pro were more frequent amongst patients compared to genomic databases and the p.Asn516(492)Ile showed pathogenic potential using in silico analysis. PRL-R variants were associated with male sex (P=0.015), higher serum PRL levels (P=0.007), larger tumors (P=0.001), higher frequency of macroadenomas (P=0.031) and cabergoline resistance (P&lt;0.001). Considering together only the PRL-R variants classified as pathogenic/probably pathogenic (p.Ile170(146)Leu, p.Glu400(376)Gln/Asn516(492) and p.Ala591Pro) versus the benign variants (p.Ile100(76)Val, p.Glu470Asp and wild type) we also observed a higher levels of serum PRL (P=0.008), largest tumor diameter (P=0.028) and higher frequency of CAB resistance (P=0.048).Conclusion: Our study showed a higher frequency of the PRL-R variants p.Glu400(376)Gln/p.Asn516(492)Ile, and p.Ala591Pro in patients with prolactinomas when compared to Brazilian and international databases, suggesting that these variants could play a role in the prolactinoma tumorigenesis. Patients with PRL-R variants presented male predominance, higher serum PRL levels, larger tumor size at diagnosis and higher frequency of CAB resistance. More studies evaluating germinative and somatic PRL-R variants are needed to clarify the PRL/PRL-R system role in the tumorigenesis and progression of prolactinomas and their interesting association with CAB resistance.
Presentation: Friday, June 16, 2023