ECE2024 Poster Presentations Pituitary and Neuroendocrinology (120 abstracts)
The pathogenic RET val804met variant in acromegaly: a new clinical phenotype?
Sabrina Chiloiro 1 , Ettore Domenico Capoluongo 2 , Flavia Costanza 1,3 , Angelo Minucci 4 , Antonella Giampietro 1 , Amato Infante 5 , Domenico Milardi 1 , Claudio Ricciardi Tenore 4 , Maria De Bonis 4 , Simona Gaudino 5 , Guido Rindi 6 , Alessandro Olivi 7 , Laura De Marinis 1 , Alfredo Pontecorvi 1 , Francesco Doglietto 7 & Antonio Bianchi 1
1Catholic University of Sacred Heart, Endocrinology and Diabetology, Rome, Italy; 2Federico II University, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy; 3Catholic University of Sacred Heart, Department of Endocrinology and Diabetology, Rome, Italy; 4Catholic University of Sacred Heart, Unit of Molecular Diagnostics and Genomics, Department of Laboratory sciences and infectious diseases, Rome, Italy; 5Fondazione Policlinico Universitario A. Gemelli, Department of Imaging, Radiation Therapy and Hematology, Università Cattolica del Sacro Cuore, Fonda-zione Policlinico Universitario Agostino Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; 6Catholic University of Sacred Heart, Section of Anatomic Pathology, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy; 7Catholic University of Sacred Heart, Neurosurgery, Rome, Italy
Genetic discoveries improved the understanding of the etiology and pathogenesis of several diseases, including acromegaly. Germline mutations involving AIP, MEN1, CDKN1B, GPR101, PRKAR1A, and GNAS genes have been described in GH-secreting PitNETs, but realistically many genetic alterations have not been identified yet. Nowadays, RET mutations have not been reported in acromegaly, if not exclusively in the context of a multiple endocrine neoplasia (MEN). A 48-year-old patient was affected by a cavernous sinus and bone-invasive somatotropinoma, resistant to first- and second-line medical therapies. The patient was also diagnosed with left breast cancer and right breast fibroadenoma. According to the somatotropinoma aggressive behavior and cancer history, a genetic study for germline mutations was performed through a specific panel designed for Pit-NETs. To our knowledge, we describe the first acromegalic patient with the RET gene pathogenic variant (PV) (Class 5): c.2410G>A; p.Val804Met; rs79658334. The presence of RET fusions is well documented in breast cancers, but RET germline PVs have never been reported in breast cancer. After excluding all the other possible RET-associated pathologies, including MEN, we speculated that our patient could be affected by Hereditary Cancer-Predisposing Syndrome (HCPS) since the association with this PV is known in the literature. The patient’s first-degree relatives underwent genetic screening for the same RET PV, resulting positive in heterozygosity in the patient’s father and daughter. Clinical, hormonal, and imaging assessment ruled out abnormalities until now, but the 25-year-old daughter was also diagnosed with right breast fibroadenoma. This finding supported the hypothesis that RET c.2410G>A PV may cause HCPS. The RET mutation may have induced constitutive activation of tyrosine kinase expressed also in the pituitary, enhancing GH production and somatotroph cell proliferation, according to the invasive growth and the poor response to treatments of the proband. Furthermore, the occurrence of breast tumors, in addition to the early onset in the young daughter, in the absence of other variants strongly associated with familial cancers, hints at the possibility that the RET PV may contribute to tumor susceptibility. In conclusion, our clinical case describes a new phenotype associated with RET PV, represented by an acromegalic woman with breast carcinoma, suggesting that also pituitary tumors should be considered in the landscape of HCPS. RET mutations may be considered for screening if NGS for well-established PitNET-associated gene mutations renders negative, in patients with aggressive tumors and suggestive clinical history.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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