Calatayud, M. (Maria)

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    Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma
    (2023) Leton, R. (Rocío); Maletta, F. (Francesca); Rapizzi, E. (Elena); Honrado, E. (Emiliano); Galvez, M.A. (Maria A.); Calatayud, M. (Maria); Fliedner, S.M.J. (Stephanie M.J.); Palacios, N. (Nuria); López-Fernández, A. (Adrià); Balbin, M. (Milagros); Eisenhofer, G. (Graeme); Lahera, M. (Marcos); Bancos, I. (Irina); Lider, S. (Sofia); Cascon, A. (Alberto); Caleiras, E. (Eduardo); Richter, S. (Susan); Gil, E. (Eduardo); Bechmann, N. (Nicole); Korpershoek, E. (Esther); Matías-Guiu, X. (Xavier); Canu, L. (Letizia); Lim, E.S. (Eugenie S.); Galofre, J.C. (Juan Carlos); Robledo, M. (Mercedes); Herrera-Martínez, A.D. (Aura D.); Mellid, S. (Sandra)
    IntroductionThe percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes. MethodsHerein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development. ResultsAmongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an intermediate signature to suggest that both variants had a pathological role in tumour development. DiscussionIn conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.
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    Autonomous cortisol secretion in patients with primary aldosteronism: prevalence and implications on cardiometabolic profile and on surgical outcomes
    (European Society of Endocrinology, 2023) Díaz-Guardiola, P. (Patricia); Morales, M. (Manuel); Calatayud, M. (Maria); Ferreira, R. (Rui); Sampedro-Nuñez, M.A. (Miguel Antonio); Meneses, D. (Diego); Percovich, J.C. (Juan Carlos); Ruiz-Sanchez, J.G. (Jorge Gabriel); Del-Castillo-Tous, M; Serrano, J. (Joaquín); Manjón, L. (Laura); Picón-César, M.J. (María José); González-Boillos, M. (Marga); Martín-Rojas-Marcos, P. (Patricia); Hanzu, F. (Felicia); Gonzalvo-Diaz, C. (César); Gracia-Gimeno, P. (Paola); Gómez-Hoyos, E. (Emilia); Perdomo, C. (Carolina); García-Sanz, I. (Íñigo); Pla-Peris, B. (Begoña); Michalopoulou, T. (Theodora); Recasens, M. (Mónica); Araujo-Castro, M. (Marta); Pascual-Corrales, E. (Eider); Parra-Ramírez, P. (Paola); García-Centeno, R. (Rogelio); Rebollo-Román, A. (Angel); Escudero-Quesada, V. (Verónica); García-Cano, A.M. (Ana María); Vicente, A. (Almudena); Sanmartín-Sánchez, A. (Alicia); Paja, M. (Miguel); Moya-Mateo, E.M. (Eva María); Barahona-San-Millan, R. (Rebeca); Lamas, C. (Cristina); Furio-Collao, S.A. (Simone Andree); Mena-Ribas, E. (Elena); Guerrero-Vázquez, R. (Raquel); Robles-Lázaro, C. (Cristina)
    Purpose The aim of this study was to evaluate the prevalence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) and its implications on cardiometabolic and surgical outcomes. Methods This is a retrospective multicenter study of PA patients who underwent 1 mg dexamethasone-suppression test (DST) during diagnostic workup in 21 Spanish tertiary hospitals. ACS was defined as a cortisol post-DST >1.8 µg/dL (confirmed ACS if >5 µg/dL and possible ACS if 1.8–5 µg/dL) in the absence of specific clinical features of hypercortisolism. The cardiometabolic profile was compared with a control group with ACS without PA (ACS group) matched for age and DST levels. Results The prevalence of ACS in the global cohort of patients with PA (n = 176) was 29% (ACS–PA; n = 51). Ten patients had confirmed ACS and 41 possible ACS. The cardiometabolic profile of ACS–PA and PA-only patients was similar, except for older age and larger tumor size of the adrenal lesion in the ACS–PA group. When comparing the ACS–PA group (n = 51) and the ACS group (n = 78), the prevalence of hypertension (OR 7.7 (2.64–22.32)) and cardiovascular events (OR 5.0 (2.29–11.07)) was higher in ACS–PA patients than in ACS patients. The coexistence of ACS in patients with PA did not affect the surgical outcomes, the proportion of biochemical cure and clinical cure being similar between ACS–PA and PA-only groups. Conclusion Co-secretion of cortisol and aldosterone affects almost one-third of patients with PA. Its occurrence is more frequent in patients with larger tumors and advanced age. However, the cardiometabolic and surgical outcomes of patients with ACS–PA and PA-only are similar.