RESUMEN
Background: Meningiomas are the most common primary tumor of the central nervous system. The relationship between meningioma and progestins is frequently mentioned but has not been elucidated. Patients and methods: We identified 40 female patients operated for a meningioma after long-term progestin therapy and performed targeted next generation sequencing to decipher the mutational landscape of hormone-related meningiomas. A published cohort of 530 meningiomas in women was used as a reference population. Results: Compared with the control population of meningiomas in women, progestin-associated meningiomas were more frequently multiple meningiomas [19/40 (48%) versus 25/530 (5%), P < 10-12] and located at the skull base [46/72 (64%) versus 241/481 (50%), P = 0.03]. We found a higher frequency of PIK3CA mutations [14/40 (35%) versus 18/530 (3%), P < 10-8] and TRAF7 mutations [16/40 (40%) versus 140/530 (26%), P < 0.001] and a lower frequency of NF2-related tumors compared with the control population of meningiomas [3/40 (7.5%) versus 169/530 (32%), P < 0.001]. Conclusion: This shift in mutational landscape indicates the vulnerability of certain meningeal cells and mutations to hormone-induced tumorigenesis. While the relationship between PIK3CA mutation frequency and hormone-related cancers such as breast and endometrial cancer is well-known, this hormonally induced mutational shift is a unique feature in molecular oncology.
Asunto(s)
Neoplasias Meníngeas/genética , Meningioma/genética , Congéneres de la Progesterona/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Acetato de Clormadinona/efectos adversos , Fosfatidilinositol 3-Quinasa Clase I/genética , Acetato de Ciproterona/efectos adversos , Análisis Mutacional de ADN , Femenino , Humanos , Acetato de Megestrol/efectos adversos , Neoplasias Meníngeas/patología , Meningioma/patología , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Adulto JovenRESUMEN
Insulinomas are rare causes of hypoglycemia. After having ruled out non insulinomatous causes of hypoglycemia in a patient in whom Whipple's triad is documented, hyperinsulinism must be demonstrated biochemically, either during a spontaneous hypoglycemic episode or, more often, during a supervised fast which may be prolonged up to 72 h. A mixed-meal test may also help to diagnose the very rare cases of postprandial hypoglycemia related to non insulinoma pancreatogenic hypoglycemic syndrome (NIPHS) or to some rare insulinomas. Only when diagnosis of hypoglycemic hyperinsulinism is made, the tumor localization process may be initiated. This may be difficult due to the small size of insulinomas (generally < 1 cm). Multimodal approach is necessary. The association of endoscopic ultrasound and CT-scan or MRI seems optimal. Octreoscan will be also performed. First results with a very new technique, the GLP-1 receptor imaging, are promising for localizing very small tumors. This localization aims to allow a sparing surgery; enucleation of benign tumors, if possible, allows a pancreatic tissue preservation in patients with quite normal survival.
Asunto(s)
Hipoglucemia/etiología , Insulinoma/complicaciones , Neoplasias Pancreáticas/complicaciones , Antineoplásicos/uso terapéutico , Diagnóstico Diferencial , Humanos , Hipoglucemia/diagnóstico , Hipoglucemia/terapia , Insulinoma/tratamiento farmacológico , Insulinoma/cirugía , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugíaRESUMEN
OBJECTIVE: The cAMP/protein kinase A (PKA) pathway plays an important role in endocrine tumorigenesis. PKA is a heterotetramer with two regulatory subunits (four genes: PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B) and two catalytic subunits. Inactivating PRKAR1A mutations have been observed in Carney complex and a subset of adrenocortical tumors (ACT). This study was designed to search for other alterations of PKA in ACT, and to establish their correlation with the clinical characteristics. METHODS: In this study, 35 ACT (10 non-secreting adrenocortical adenomas (ACA-NS), 13 cortisol-secreting adenomas (ACA-S), and 12 malignant s (ACC)) were studied. PKA subunits were studied by western blot and RT-qPCR. The PKA activity was measured. RESULTS: A subgroup of ACA-S with a 96% R2B protein decrease by comparison with normal adrenal (4.1%+/-4 vs 100%+/-19, P<0.001) was identified, ACA-S2 (6/13). By contrast, no differences were observed in ACC and ACA-NS. The level of R1A mRNA was decreased in ACA-S (P<0.001), but not the level of R2B mRNA. No mutation of the R2B gene was detected in ACA-S2. The ACA-S2 group with loss of R2B protein showed a threefold higher basal PKA activity than the ACA with normal R2B protein (3.37+/-0.31 vs 1.00+/-0.20, P<0.0001). The ACA-S2 tumors with the loss of the R2B protein presented a homogenous phenotype and were all small benign cortisol-secreting tumors. CONCLUSION: This loss of PRKAR2B protein due to a post-transcriptional mechanism in ACA-S is a new mechanism of cAMP pathway dysregulation in adrenocortical tumorigenesis. It defines a new subtype of secreting adenomas with high basal PKA activity presenting a homogenous clinical phenotype.