Avaliação da expressão gênica de VDAC2 e TERT e alterações moleculares em seu promotor nos tumores neuroendócrinos da hipófise (PitNETs)

Abstract

Introduction: The pituitary neuroendocrine tumors (PitNETs) are neoplasms originating from the pituitary and correspond to about 10 to 15% of intracranial tumors. Such tumors can be classified into functioning and nonfunctioning, according to whether they produce enough hormones to induce clinical manifestations. Recently, changes in the expression levels of TERT and VDAC2 genes have suggested an important role of these genes in the development of endocrine neoplasms, and they may also be involved in the oncogenesis of PitNETs. The molecular pathogenesis of PitNETs is still poorly understood and, therefore, further studies on this topic in different populations is needed. Objective: to evaluate the gene expression of VDAC2 and TERT and molecular alterations in its promoter in patients with PitNETs treated in the state of Maranhão. Methodology: 89 samples of PitNETs from patients undergoing surgery at the University Hospital of the Federal University of Maranhão - HUUFMA were analyzed. Nucleic acids were extracted and cDNA synthesis was performed from the collected biological material, and then real-time PCR was performed to evaluate TERT and VDAC2 gene expression. DNA sequencing was performed to analyze mutations in the TERT promoter (positions C228T and C250T). Results: most cases were female (59/89 - 66.3%) and were between 51 and 60 years old (25/89 - 28.1%). Considering the tumor characteristics, 64 cases (71.9%) were classified as non-functional and 59 tumors (66.3%) presented as macrotumors. Regarding the molecular analyses, although the acromegalic patients had a higher expression index (IE) of TERT (IE=1.67), no significant differences were observed between tumor types. In addition, no mutations were detected at positions C228T and C250T of the TERT promoter. Regarding VDAC2, when compared to normal pituitary tissue, an increased expression of this gene was found in carriers of non-functioning tumors (3.01-fold), Acromegaly (3.08-fold) and Cushing's disease (6.83-fold). A significant correlation between TERT and VDAC2 expression was also found in our sample (rs= 0.278; p=0.01). Conclusion: In the present study, the higher expression of VDAC2 in tumor samples suggests a possible participation of this gene in the oncogenesis of PitNETs. In addition, the correlation between VDAC2 and TERT may point to a joint action of both signaling pathways, raising the possibility of new therapeutic targets.