Differences in the clinical and hormonal presentation of patients with familial and sporadic primary aldosteronism

Purpose: To compare the clinical and hormonal characteristics of patients with familial hyperaldosteronism (FH) and sporadic primary aldosteronism (PA). Methods: A systematic review of the literature was performed for the identification of FH patients. The SPAIN-ALDO registry cohort of patients with no suspicion of FH was chosen as the comparator group (sporadic group). Results: A total of 360 FH (246 FH type I, 73 type II, 29 type III, and 12 type IV) cases and 830 sporadic PA patients were included. Patients with FH-I were younger than sporadic cases, and women were more commonly affected (P = 0.003). In addition, the plasma aldosterone concentration (PAC) was lower, plasma renin activity (PRA) higher, and hypokalemia (P < 0.001) less frequent than in sporadic cases. Except for a younger age (P < 0.001) and higher diastolic blood pressure (P = 0.006), the clinical and hormonal profiles of FH-II and sporadic cases were similar. FH-III had a distinct phenotype, with higher PAC and higher frequency of hypokalemia (P < 0.001), and presented 45 years before sporadic cases. Nevertheless, the clinical and hormonal phenotypes of FH-IV and sporadic cases were similar, with the former being younger and having lower serum potassium levels. Conclusion: In addition to being younger and having a family history of PA, FH-I and III share other typical characteristics. In this regard, FH-I is characterized by a low prevalence of hypokalemia and FH-III by a severe aldosterone excess causing hypokalemia in more than 85% of patients. The clinical and hormonal phenotype of type II and IV is similar to the sporadic case

Autonomous cortisol secretion in patients with primary aldosteronism: prevalence and implications on cardiometabolic profile and on surgical outcomes

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 spe cific 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 simil ar, 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 patien ts 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-thi rd 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

Aportación de la secuenciación masiva de nueva generación en el diagnóstico del síndrome de cáncer de mama y ovario hereditario mediante el uso de un panel de genes

La incorporación de la secuenciación de nueva generación, en el Laboratorio de Genómica del Servicio de Análisis Clínicos del Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), ha permitido estudiar el Síndrome de Cáncer de Mama y Ovario Hereditario (SCMOH) mediante la realización de un panel de 26 genes, en el que se incluyeron genes de alta y moderada penetrancia. Sin embargo, este aumento de información, con respecto al estudio genético de solo BRCA1 y BRCA2, debe ir acompañado de una correcta interpretación de la misma. Por lo tanto, fue necesario evaluar la utilidad clínica de los estudios genéticos mediante paneles de genes en la población estudiada. Teniendo en cuenta este objetivo general se abordaron también otros objetivos secundarios como: determinar el rendimiento diagnóstico del análisis mediante paneles de genes en la población estudiada y con un test previo de BRCA1 y BRCA2 no informativo, evaluar los criterios de selección, caracterizar las variantes genéticas encontradas desde el punto de vista molecular y clínico, evaluar la frecuencia mutacional de los distintos genes estudiados, llevar a cabo un estudio de correlación genotipo-fenotipo en aquellas variantes clínicamente relevantes y describir la incidencia de variantes de significado clínico desconocido (VUS) obtenidas, así como de las VUS priorizadas. En la presente tesis se partió de una población de 138 familias con estudio previo no informativo para BRCA1 y BRCA2, procedentes de las consultas de consejo genético de los servicios de Oncología del HCUVA y del Hospital General Universitario Morales Meseguer, las cuales habían sido incluidas por cumplir criterios adicionales de selección a los propuestos por la Sociedad Española de Oncología Médica (SEOM). Tras la aplicación del panel de genes BRCA Hereditary MasterTM Plus de Agilent®, se procedió a categorizar las variantes halladas desde el punto de vista molecular y clínico con la ayuda de diferentes herramientas informáticas, bases de datos, publicaciones y programas in silico. Utilizando esta metodología se desarrolló un algoritmo de priorizaron de variantes de significado clínico desconocido. Posteriormente, mediante secuenciación Sanger, se realizó la comprobación de aquellas variantes con relevancia clínica (patogénicas y probablemente patogénicas), cuyo estudio fue ampliado a los familiares, obteniéndose información entre el genotipo y el fenotipo. Finalmente, para comprobar el efecto fundador de la variante c.8251_8254del en ATM se realizó un estudio de microsatélites en las familias afectadas y en población control. Tras la aplicación del panel de genes descrito se ha conseguido mejorar el rendimiento diagnóstico en un 8% en la población estudiada, resultado similar a lo descrito previamente en la bibliografía. Para ello, la aplicación de criterios adicionales de selección de familias no ha contribuido de manera significativa a aumentar el rendimiento diagnóstico con respecto a los criterios de selección propuestos por la SEOM. Con respecto a la categorización de variantes a nivel clínico y molecular, se han detectado un gran número de variantes missense que, en la mayoría de los casos se categorizaron clínicamente como variantes de significado clínico desconocido, mientras que la mayoría de las variantes clasificadas como patogénicas y probablemente patogénicas fueron de tipo nonsense o frameshift. Gracias a la incorporación de un algoritmo de priorización de variantes VUS se consiguió reducir el porcentaje de familias portadoras de este tipo de variantes de un 52% a un 20%, por lo que sería recomendable la utilización de esta herramienta en el análisis de los estudios genéticos. Este estudio también ha aportado la identificación de 14 variantes (4 clínicamente relevantes y 10 VUS) previamente no descritas. Así mismo, destacar que la incidencia de mutaciones en el gen ATM (4,35%) ha sido la más alta descrita hasta la actualidad, y la aportación al rendimiento diagnóstico de la variante 8251_8254del en ATM, presente en dos familias del estudio, provenientes probablemente de un ancestro común de la Región de Murcia. En relación a los estudios de correlación genotipo-fenotipo en los portadores de variantes patogénicas en los genes no BRCA destaca el cáncer de mama unilateral como el fenotipo más frecuente, seguido del cáncer de ovario. En cuanto a las características histopatológicas de los casos cáncer de mama, todos fueron positivos para receptores hormonales, excepto en la portadora de la variante patogénica en TP53. Este resultado es similar a los comunicados en otros estudios.The incorporation of next generation sequencing in Genomics Laboratory in Clinical Analysis Service of University Hospital Virgen de la Arrixaca (HCUVA) has allowed the study of Hereditary Breast and Ovarian Cancer (HBOC) through the performance of 26 genes panel, in which high and moderate penetrance genes were included. However, the increase of information in comparison with the genetic study of only BRCA1 and BRCA2 must be accompanied of a correct interpretation of this information. Therefore, it was necessary to evaluate the clinical utility of genetic studies through multigene pane testing in the studied population. Taking this general objective into account, also the following secondary objectives were addressed: establishing the diagnostic yield of multigene panel testing analysis in the studied population with a previous uninformative test for BRCA1 and BRCA2, evaluating the selection criteria, characterizing molecularly and clinically the variants encountered, evaluating the mutation rate of the studied genes, performing genotype-phenotype correlation study in those clinically relevant variants and describing the incidence of variants of uncertain significance variants (VUS) as well as prioritized VUS. In this thesis the study population were 138 families with a previous uninformative test for BRCA1 and BRCA2 from Genetic Counselling Units from Medical Oncology Services of HCUVA and University Hospital Morales Meseguer, which had been included for meeting additional criteria to those proposed by Spanish Society of Medical Oncology (SEOM). After the analysis through the multigene panel BRCA Hereditary MasterTM Plus (Agilent®), the found variants were classified molecularly and clinically by using different bioinformatics tools, databases, bibliography and in silico studies. With this methodology an algorithm for prioritizing VUS was stablished. Subsequently, the verification of clinically variants (pathogenic and likely pathogenic) found and the extension of study to family members were performed by Sanger sequencing, so information of genotype and phenotype was obtained. Finally, to probe the founder effect of the variant c.8251_8254del in ATM a microsatellite analysis in families affected a control population was carried out. The use of the multigene panel described above increased the diagnostic yield by 8% in the studied population, as described in bibliography. To that end, the implementation of additional criteria of selection did not contribute significantly to increase the diagnostic yield in comparison with those proposed by SEOM. With regard to the molecular and clinical characterization of multigene panel generated a great number of missense variants which, in most cases, were classified clinically as variants with uncertain significance. However, most of pathogenic and probably pathogenic variants were nonsense or frameshift. Thanks to the incorporation of a VUS prioritizing algorithm, the percentage of families that carried this type of variants was reduced from 52% to 20%, so it is recommendable to use this tool in the analysis of genetic studies. This study also contributed to the identification of 14 previously non described variants (4 clinically relevant and 10 with unknown significance). Likewise, it is worth noting that prevalence of mutations in the ATM (4.35%) has been the highest described until now as well as the contribution to the detection rate of the variant c8251_8254del in ATM, found in two families of the study, and which has a common origin in Murcia. With respect to the genotype-phenotype correlation studies performed in carriers of pathogenic variants in non BRCA genes the most common cancer was unilateral breast cancer, followed by ovarian cancer. In respect of the histopathologic features of breast cancer cases, all of them were positive for hormonal receptors, except he carrier of a pathogenic variant in TP53. This result is similar to the found in other studies

Antitumoral Effects of Tricyclic Antidepressants: Beyond Neuropathic Pain Treatment

Growing evidence shows that nerves play an active role in cancer development and progression by altering crucial molecular pathways and cell functions. Conversely, the use of neurotropic drugs, such as tricyclic antidepressants (TCAs), may modulate these molecular signals with a therapeutic purpose based on a direct antitumoral effect and beyond the TCA use to treat neuropathic pain in oncology patients. In this review, we discuss the TCAs’ safety and their central effects against neuropathic pain in cancer, and the antitumoral effects of TCAs in in vitro and preclinical studies, as well as in the clinical setting. The current evidence points out that TCAs are safe and beneficial to treat neuropathic pain associated with cancer and chemotherapy, and they block different molecular pathways used by cancer cells from different locations for tumor growth and promotion. Likewise, ongoing clinical trials evaluating the antineoplastic effects of TCAs are discussed. TCAs are very biologically active compounds, and their repurposing as antitumoral drugs is a promising and straightforward approach to treat specific cancer subtypes and to further define their molecular targets, as well as an interesting starting point to design analogues with increased antitumoral activity

New insights into the performance of multigene panel testing: two novel nonsense variants in BRIP1 and TP53 in a young woman with breast cancer

© 2018 Elsevier Inc. All rights reserved. This document is the Published version of a Published Work that appeared in final form in Cancer Genetics. To access the final edited and published work see https://doi.org/10.1016/j.cancergen.2018.06.002Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the tumour suppressor gene TP53. Here we report the case of a family whose index case was a woman diagnosed with bilateral breast cancer at the age of 18 and who had a non-informative result after BRCA1 and BRCA2 testing. After extending the study through multigene panel testing, two clinically relevant variants in the TP53 and BRIP1 genes, respectively, were found. Afterwards, the patient developed a glioblastoma. Both tumours were consistent with Li-Fraumeni syndrome. Thanks to the possibility of studying different genes related with hereditary breast and ovarian cancer, it was possible to find out the gene variant that caused the early onset cancers in the patient. Furthermore, genetic counselling was provided to the index case and her family

Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain)

© 2018 Elsevier Masson SAS. All rights reserved. This document is the Published version of a Published Work that appeared in final form in European Journal of Medical Genetics. To access the final edited and published work see https://doi.org/10.1016/j.ejmg.2018.01.015RAD51C and RAD51D have been defined as susceptibility genes for hereditary breast and ovarian cancer syndrome in several studies. In the present study, a mutation analysis of these genes was performed on non BRCA1/2 families. RAD51C and RAD51D genes were analyzed in 141 and 77 families, respectively. The analysis included direct sequencing and multiple ligation probe analysis. The RAD51C pathogenic variant c.404G > A was identified in a breast and ovarian cancer family (0.7%), while the RAD51D pathogenic variant c.694C > T was described in an ovarian cancer family (1.3%). Moreover, three unknown clinical significance variants were detected: c.307T > G in RAD51C, and c.413A > G and c.715C > T in RAD51D. No large genomic rearrangements (LGRs) were found. RAD51D carriers suffered from premenopausal ovarian tumors. These results increase our knowledge about the RAD51C and RAD51D mutation spectrum and support the notion that these genes should be included in the gene panel testing performed on patients with hereditary breast and ovarian cancer syndrome

Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance

© 2022 Elsevier Masson SAS. All rights reserved. This document is the Published version of a Published Work that appeared in final form in European Journal of Medical Genetics. To access the final edited and published work see https://doi.org/10.1016/j.ejmg.2022.104468Introduction: BRCA1 and BRCA2 are the two main genes causing hereditary breast and ovarian cancer (HBOC). However, thanks to the development of Next Generation Sequencing (NGS), other genes linked to this syndrome (CHEK2, BRIP1, ATM and PALB2 among others) can be analysed. Material and methods: an analysis by multigene panel testing was performed in 138 index cases (ICs) from HBOC Spanish families with a previous non-informative result for BRCA1/2. The BRCA Hereditary Cancer Master™ Plus kit, including 26 actionable and candidate genes related to HBOC was employed. Once classified, an algorithm was employed to prioritized those variants of unknown significance with a higher risk of having a deleterious effect. Moreover, a mRNA splicing assay was performed for the prioritized VUS c.3402+3A > C in ATM, located at intron 23. Results: A total of 82 variants were found: 70 VUS and 12 pathogenic or probably pathogenic variants. The diagnostic yield in actionable genes non-BRCA was 7.97% of the total tested ICs. Overall, 19 VUS were prioritized, which meant 27% of the 70 total VUS. RNA analysis of the variant 3402+3A > C confirmed a deleterious impact on splicing. Discussion: The implementation of a multigene panel in HBOC studied families improved the diagnostic yield, concordant with results obtained in previous publications. Due to the important number of VUS obtained in NGS, the application of a prioritization algorithm is needed in order to select those variants in which it is necessary to conduct further studies

Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical–pathological features in BRCA carriers and non-carriers

© Springer Science+Business Media Dordrecht 2017. This document is the Published version of a Published Work that appeared in final form in Familial Cancer. To access the final edited and published work see https://doi.org/10.1007/s10689-017-9985-xThis is the first study performed in Murcia (south-eastern Spain) in which 592 families with hereditary breast and ovarian cancer were identified thanks to Genetic Counselling Units from this area over 6 years. Diagnostic performance was 18.1% and 194 different genetic variants were obtained. Variants with uncertain significance accounted for only 5.6% of the total number of reports, so our population has been well characterised. In BRCA1 gene, two novel variants were found (c.1859delT and c.3205C > T) and the most frequently detected mutations were c.68_69delAG, c.212 + 1G > A, c.5123C > A, c.211A > G and c.1918C > T, which together represented 56.67% of total pathogenic mutations. In BRCA2 gene, four recurrent variants were described (deletion of entire exon 2, c.9117G > A, c.3264dupT and c.3455T > G) representing 43.5% of the mutations in this gene. Mutation c.68_69delAG and deletion of entire exon 2 in BRCA1 and BRCA2 genes respectively were the most prevalent variants in our population. Regarding the genotype-phenotype relation, mutation c.212 + 1G > A appeared in an important percentage of breast and ovarian cancer cases, c.5123C > A in bilateral breast cancer and c.9117G > A in bilateral breast cancer and ovarian cancer. With respect to clinical–pathological characteristic, BRCA1/BRCA2 mutation carriers showed earlier onset age of breast tumour and higher risk of developing contra lateral breast cancer than non-informative cases. Moreover, association between either molecular subtype triple negative breast cancer or ovarian cancer and BRCA1 carriers was obtained