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1.
N Engl J Med ; 369(22): 2105-14, 2013 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-24283224

RESUMEN

BACKGROUND: Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing's syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition. METHODS: We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models. RESULTS: The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival. CONCLUSIONS: Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.).


Asunto(s)
Síndrome de Cushing/genética , Genes Supresores de Tumor , Proteínas Supresoras de Tumor , Glándulas Suprarrenales/patología , Adulto , Anciano , Proteínas del Dominio Armadillo , Síndrome de Cushing/complicaciones , Síndrome de Cushing/patología , Femenino , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Transcriptoma
2.
NPJ Syst Biol Appl ; 9(1): 37, 2023 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-37524705

RESUMEN

Lung adenocarcinoma (LUAD) is associated with a low survival rate at advanced stages. Although the development of targeted therapies has improved outcomes in LUAD patients with identified and specific genetic alterations, such as activating mutations on the epidermal growth factor receptor gene (EGFR), the emergence of tumor resistance eventually occurs in all patients and this is driving the development of new therapies. In this paper, we present the In Silico EGFR-mutant LUAD (ISELA) model that links LUAD patients' individual characteristics, including tumor genetic heterogeneity, to tumor size evolution and tumor progression over time under first generation EGFR tyrosine kinase inhibitor gefitinib. This translational mechanistic model gathers extensive knowledge on LUAD and was calibrated on multiple scales, including in vitro, human tumor xenograft mouse and human, reproducing more than 90% of the experimental data identified. Moreover, with 98.5% coverage and 99.4% negative logrank tests, the model accurately reproduced the time to progression from the Lux-Lung 7 clinical trial, which was unused in calibration, thus supporting the model high predictive value. This knowledge-based mechanistic model could be a valuable tool in the development of new therapies targeting EGFR-mutant LUAD as a foundation for the generation of synthetic control arms.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Animales , Ratones , Gefitinib/farmacología , Gefitinib/uso terapéutico , Genes erbB-1 , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/farmacología , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Progresión de la Enfermedad
3.
Open Forum Infect Dis ; 7(12): ofaa567, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33409332

RESUMEN

BACKGROUND: Ritonavir-boosted darunavir (DRV/r) is a protease inhibitor (PI) indicated for the treatment of naïve and pretreated HIV-infected patients since 2007. Our study aims to describe DRV/r-treated patients experiencing virological failure (VF) documented with HIV resistance testing. METHODS: Data from patients belonging to the ANRS CO3 Aquitaine Cohort treated with a regimen including DRV/r between February 2007 and December 2015 were analyzed. Baseline characteristics of patients experiencing VF (defined by 2 consecutive plasma viral loads >50 copies/mL) were compared with those without VF. We then described factors associated with VF as emergence of IAS DRV resistance-associated mutations (RAMs). RESULTS: Among the 1458 patients treated at least once with a DRV/r-based regimen, 270 (18.5%) patients experienced VF during follow-up, including 240 with at least 1 genotype resistance test (GRT). DRV RAMs were detected in 29 patients (12%). Among them, 25/29 patients had ≥2 DRV RAMs before DRV/r initiation, all of whom had experienced VF during previous PI treatments. For 18/29, DRV/r was maintained after VF, and controlled viremia was restored after modification of DRV-associated antiretroviral molecules or increased DRV dose. Finally, only 6/29 patients selected new DRV RAMs after DRV/r initiation. All of these experienced previous VFs while on other PIs. CONCLUSIONS: These results highlight the efficacy and robustness of DRV/r, as the emergence of DRV RAMs appeared in <0.4% of patients receiving a DRV/r-based regimen in our large cohort.

4.
Compr Physiol ; 5(1): 293-326, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25589272

RESUMEN

The adrenal gland consists of two distinct parts, the cortex and the medulla. Molecular mechanisms controlling differentiation and growth of the adrenal gland have been studied in detail using mouse models. Knowledge also came from investigations of genetic disorders altering adrenal development and/or function. During embryonic development, the adrenal cortex acquires a structural and functional zonation in which the adrenal cortex is divided into three different steroidogenic zones. Significant progress has been made in understanding adrenal zonation. Recent lineage tracing experiments have accumulated evidence for a centripetal differentiation of adrenocortical cells from the subcapsular area to the inner part of the adrenal cortex. Understanding of the mechanism of adrenocortical cancer (ACC) development was stimulated by knowledge of adrenal gland development. ACC is a rare cancer with a very poor overall prognosis. Abnormal activation of the Wnt/ß-catenin as well as the IGF2 signaling plays an important role in ACC development. Studies examining rare genetic syndromes responsible for familial ACT have played an important role in identifying genetic alterations in these tumors (like TP53 or CTNNB1 mutations as well as IGF2 overexpression). Recently, genomic analyses of ACT have shown gene expression profiles associated with malignancy as well as chromosomal and methylation alterations in ACT and exome sequencing allowed to describe the mutational landscape of these tumors. This progress leads to a new classification of these tumors, opening new perspectives for the diagnosis and prognostication of ACT. This review summarizes current knowledge of adrenocortical development, growth, and tumorigenesis.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Corteza Suprarrenal/crecimiento & desarrollo , Corteza Suprarrenal/embriología , Corteza Suprarrenal/fisiología , Neoplasias de la Corteza Suprarrenal/diagnóstico , Animales , Biomarcadores de Tumor/metabolismo , Desarrollo Fetal/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Humanos , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Regeneración/fisiología
5.
Artículo en Inglés | MEDLINE | ID: mdl-26106367

RESUMEN

Adrenocortical tumors (ACTs) are typically unilateral and can be classified as benign adrenocortical adenomas (ACAs) or malignant adrenocortical cancers (ACCs). In rare cases, tumors may occur in both adrenal glands as micronodular hyperplasia (primary pigmented nodular adrenal dysplasia) or as macronodular hyperplasia (primary bilateral macronodular adrenal hyperplasia, PBMAH). The study of certain tumor predisposition syndromes has improved our understanding of sporadic ACTs. Most ACAs are associated with abnormalities of the cAMP signaling pathway, whereas most ACCs are linked to alterations in IGF2, TP53, or the Wnt/ßcatenin pathways. Over the past year, single-nucleotide polymorphism array technology and next-generation sequencing have identified novel genetic alterations in ACTs that shed new light on the molecular mechanisms of oncogenesis. Among these are somatic mutations of PKA catalytic subunit alpha gene (PRKACA) in ACA, germline, and somatic mutations of armadillo repeat containing 5 gene (ARMC5) in primary bilateral macronodular adrenal hyperplasia and somatic alterations of the E3 ubiquitin ligase gene ZNRF3 in ACC. This review focuses on the recent discoveries and their diagnostic, prognostic, and therapeutic implications.

6.
PLoS One ; 8(2): e55743, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23409032

RESUMEN

CONTEXT: Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine neoplasm, with limited therapeutic options. Activating ß-catenin somatic mutations are found in ACC and have been associated with a poor clinical outcome. In fact, activation of the Wnt/ß-catenin signaling pathway seems to play a major role in ACC aggressiveness, and might, thus, represent a promising therapeutic target. OBJECTIVE: Similar to patient tumor specimen the H295 cell line derived from an ACC harbors a natural activating ß-catenin mutation. We herein assess the in vitro and in vivo effect of ß-catenin inactivation using a doxycyclin (dox) inducible shRNA plasmid in H295R adrenocortical cancer cells line (clone named shß). RESULTS: Following dox treatment a profound reduction in ß-catenin expression was detectable in shß clones in comparison to control clones (Ctr). Accordingly, we observed a decrease in Wnt/ßcatenin-dependent luciferase reporter activity as well as a decreased expression of AXIN2 representing an endogenous ß-catenin target gene. Concomitantly, ß-catenin silencing resulted in a decreased cell proliferation, cell cycle alterations with cell accumulation in the G1 phase and increased apoptosis in vitro. In vivo, on established tumor xenografts in athymic nude mice, 9 days of ß-catenin silencing resulted in a significant reduction of CTNNB1 and AXIN2 expression. Moreover, continous ß-catenin silencing, starting 3 days after tumor cell inoculation, was associated with a complete absence of tumor growth in the shß group while tumors were present in all animals of the control group. CONCLUSION: In summary, these experiments provide evidences that Wnt/ß-catenin pathway inhibition in ACC is a promising therapeutic target.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Apoptosis/genética , Silenciador del Gen , Mutación , beta Catenina/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/metabolismo , Animales , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Interferencia de ARN , Transducción de Señal , Factores de Transcripción TCF/metabolismo , Transcripción Genética , Trasplante Heterólogo , Proteínas Wnt/metabolismo
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