ECEESPE2025 Poster Presentations Pituitary, Neuroendocrinology and Puberty (162 abstracts)
Aggressive prolactinomas: unveiling mechanisms of dopamine agonist resistance through exomic, tanscriptomic, and metabolic strategies
Florencia Martinez-Mendoza 1,2 , Daniel Marrero-Rodríguez 1 , Sergio Andonegui-Elguera 1 , Ernesto Sosa-Eroza 3 , Silvia Hinojosa-Alvarez 4 , Jesús Hernandez-Perez 4 , Roció A. Chavez-Santoscoy 4 , Estibeyesbo Said Plascencia-Nieto 2 , Pilar Ortiz-Vilchis 5 , Rocio L. Arreola-Rosales 6 , Blas E. Lopez-Felix 7 , Alberto Moscona-Nissan 1 , Sophia Mercado-Medrez 1 , Keiko Taniguchi-Ponciano 1 & Moisés Mercado 1
1Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico; 2Sección de Estudios de Posgrado e investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico city, Mexico; 3Servicio de endocrinología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México., Mexico City, Mexico; 4Tecnológico de Monterrey, Monterrey, México., Escuela de ingeniería y ciencias, Monterrey N.L, Mexico; 5SEPI–ESM, Instituto Politécnico Nacional, Mexico City, Mexico; 6Departamento de patología, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico; 7Servicio de neurocirugía, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
JOINT311
Background/Aims: Pituitary tumors are the second most common intracranial neoplasm, of these, prolactinomas are the most frequent functioning subtype. For this type of tumor, dopamine agonists (DA) constitute the treatment of choice. However, a subset of patients (30-50%) exhibits resistance to DA treatment. This resistance may involve different molecular mechanisms, which remain largely unclear and not fully understood. The aim of this project is to characterize the allelic variants and transcriptomic profile of aggressive, treatment-resistant prolactinomas through whole-exome and whole transcriptome analysis.
Methods: We evaluated 12 patients with DA-resistant lactotroph tumors and 6 non-tumoral pituitaries by whole exome sequencing (WES) and whole transcriptomic sequencing (WTS). Nine of the 12 tumors were categorized as totally unresponsive whereas three were considered partially resistant.
Results: WES identified approximately 18,000 variants, of which only two (TP53 c.C817T p. R273C and one in SF3B1 c.C1873T p. R625C) were considered pathogenic. These variants are known to play a pathogenic role in other tumors and are associated with tumorigenesis. The most frequent mutational signature was SBS5 which is associated with normal cellular damage of DNA processes. The tumor mutational burden (TMB) was similar in both the partially and the totally resistant tumors. In the WTS analysis, prolactinomas showed different degrees of transcriptomic heterogeneity between partial and null responses. Interestingly, the null response group exhibited molecular events related to metabolism, which were linked to antifolate resistance, fatty acid degradation, and sphingolipid metabolism. Furthermore, metabolic characterization revealed high heterogeneity, mainly in pathways associated with lipid metabolism.
Conclusions: We conclude that prolactinomas are genomically stable, which could indicate that mechanisms other than somatic mutations are involved in lactotrophic tumorigenesis and that differences in response to DA treatment may result from transcriptomically heterogeneous clones.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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