ABSTRACT
BACKGROUND: Pituitary adenomas (PA) are the second most common tumor in the central nervous system and have low counts of mutated genes. Splicing occurs in 95% of the coding RNA. There is scarce information about the spliceosome and mRNA-isoforms in PA, and therefore we carried out proteomic and transcriptomic analysis to identify spliceosome components and mRNA isoforms in PA. METHODS: Proteomic profile analysis was carried out by nano-HPLC and mass spectrometry with a quadrupole time-of-flight mass spectrometer. The mRNA isoforms and transcriptomic profiles were carried out by microarray technology. With proteins and mRNA information we carried out Gene Ontology and exon level analysis to identify splicing-related events. RESULTS: Approximately 2000 proteins were identified in pituitary tumors. Spliceosome proteins such as SRSF1, U2AF1 and RBM42 among others were found in PA. These results were validated at mRNA level, which showed up-regulation of spliceosome genes in PA. Spliceosome-related genes segregate and categorize PA tumor subtypes. The PA showed alterations in CDK18 and THY1 mRNA isoforms which could be tumor specific. CONCLUSIONS: Spliceosome components are significant constituents of the PA molecular machinery and could be used as molecular markers and therapeutic targets. Splicing-related genes and mRNA-isoforms profiles characterize tumor subtypes.
Subject(s)
Adenoma/metabolism , Pituitary Neoplasms/metabolism , Proteome , Spliceosomes , Steroidogenic Factor 1/genetics , Transcription Factor Pit-1/genetics , Transcriptome , Adenoma/genetics , Adenoma/pathology , Alternative Splicing , Biomarkers, Tumor , Cell Lineage , Chromatography, High Pressure Liquid , Exons/genetics , Gene Ontology , Hormones/analysis , Humans , Nanotechnology , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Oligonucleotide Array Sequence Analysis , Pituitary Neoplasms/genetics , Pituitary Neoplasms/pathology , Principal Component Analysis , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , Tandem Mass Spectrometry , Transcription Factors/analysisABSTRACT
BACKGROUND AND PURPOSE: Conformal, fractionated radiation therapy (XRT) is variably used as a treatment alternative for active acromegaly patients, usually, after failed pituitary surgery. Our objective was to evaluate the long-term efficacy and safety of XRT using strict criteria of biochemical control. SETTING, DESIGN, PATIENTS, AND METHODS: Retrospective cohort study of 94 patients (73 women, mean age at radiation 53.16 ± 12.9 years) attending a specialized multidisciplinary clinic between 1998 and 2014 with a mean duration of follow-up of 12.9 ± 7.3 years. RESULTS: A basal growth hormone < 1 ng/mL and an IGF-1 < 1.2 × the upper limit of normal was achieved by 41% and 50.8%, respectively, at 5 years of follow-up, and by 44% and 66%, respectively, 10 years after XRT. Median tumor volume decreased significantly from 904 mm3 at baseline to 424 mm3 upon last follow-up (p = 0.01). The prevalence of central hypogonadism, central hypocortisolism, and central hypothyroidism increased from 18%, 35%, and 35% at baseline, to 38%, 53%, and 64%, respectively, after 10 years of follow-up. One patient was diagnosed with a meningioma and another one developed optic neuritis. No cerebrovascular events were recorded, and all patients are currently alive. CONCLUSION: XRT is an effective and reasonably safe means of controlling acromegalic activity. Its main disadvantages are the time required to achieve biochemical control and the development of anterior pituitary hormone deficiencies.