RESUMO
Cushing's disease (CD) is caused by pituitary corticotroph adenomas that secrete excess adrenocorticotropic hormone (ACTH). In these tumors, somatic mutations in the gene USP8 have been identified as recurrent and pathogenic and are the sole known molecular driver for CD. Although other somatic mutations were reported in these studies, their contribution to the pathogenesis of CD remains unexplored. No molecular drivers have been established for a large proportion of CD cases and tumor heterogeneity has not yet been investigated using genomics methods. Also, even in USP8-mutant tumors, a possibility may exist of additional contributing mutations, following a paradigm from other neoplasm types where multiple somatic alterations contribute to neoplastic transformation. The current study utilizes whole-exome discovery sequencing on the Illumina platform, followed by targeted amplicon-validation sequencing on the Pacific Biosciences platform, to interrogate the somatic mutation landscape in a corticotroph adenoma resected from a CD patient. In this USP8-mutated tumor, we identified an interesting somatic mutation in the gene RASD1, which is a component of the corticotropin-releasing hormone receptor signaling system. This finding may provide insight into a novel mechanism involving loss of feedback control to the corticotropin-releasing hormone receptor and subsequent deregulation of ACTH production in corticotroph tumors.
Assuntos
Adenoma Hipofisário Secretor de ACT/genética , Proteínas ras/genética , Adenoma/genética , Hormônio Adrenocorticotrópico/genética , Adulto , Corticotrofos/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Feminino , Humanos , Mutação , Hipersecreção Hipofisária de ACTH/genética , Neoplasias Hipofisárias/genética , Receptores de Hormônio Liberador da Corticotropina/genética , Análise de Sequência de DNA , Ubiquitina Tiolesterase/genéticaRESUMO
OBJECTIVES: To review the responses of advance directives signed by Jehovah's Witness patients prior to undergoing surgery at a gynecologic oncology service. STUDY DESIGN: A retrospective chart review of gynecologic oncology patients undergoing surgery at a bloodless surgery center from 1998-2007 was conducted. Demographic, pathologic, and clinical data were recorded. The proportion of patients who accepted and refused various blood-derived products was determined and was compared to previously published results from a similar study of labor and delivery unit patients. RESULTS: No gynecologic oncology patients agreed to accept transfusions of whole blood, red cells, white cells, platelets, or plasma under any circumstance, whereas 9.8% of pregnant patients accepted transfusion (P=0.0385). However, 98% of gynecologic oncology patients agreed to accept some blood products, including fractions such as albumin, immunoglobulins, and clotting factors, while only 39% of pregnant patients agreed (P<0.0001). In addition, all gynecologic oncology patients (100%) accepted intraoperative hemodilution, compared to 55% of pregnant patients (P<0.0001). CONCLUSION: Our results confirm the commonly held belief that the majority of Jehovah's Witness patients refuse to accept major blood components. However, Jehovah's Witness patients at a gynecologic oncology service will accept a variety of blood-derived products (minor fractions) and interventions designed to optimize outcomes when undergoing transfusion-free surgery. Patients presenting to a gynecologic oncology service respond differently to advanced directives related to bloodless surgery, as compared to patients from an obstetrical service.