Genetic and epigenetic features of the uterine smooth muscle tumors: identification of molecular markers

Abstract

Uterine smooth muscle tumors (USMT) arise from the myometrium and are classified according to their biological and clinical presentation as benignant, intermediary and malignant tumors. Leiomyomas (LM) are the most common benignant tumors that occurs in women at reproductive age (~70%) and their histological variants (the unconventional LM - LMU), although rare, presents clinical and morphological features that difficult the initial diagnosis. Although the LM can be asymptomatic, in Brazil, they are the major cause for hysterectomies and can lead to infertility. On the other hand, the leiomyosarcoma (LMS), although uncommon, is the most frequent malignant USMT. It shows high rates of metastasis and relapse, even when early diagnosed, and its overall survival is up to 50%. Even with the same cell pattern of differentiation, USMT have very diverse clinical outcome, and there are no specific molecular markers and treatment for them. Additionally, there are controversies about these tumors origin and their possible malignant risk. While some researchers believe that a LMS can be arising from a degenerated LM, others argue that is an improbable hypothesis. Thus, the knowledge of the USMT genetic and epigenetic profiles can help to identify specific molecular markers for differential diagnosis, prognosis, treatment prediction, as well in the development of specific alternative therapies. The present project aims: 1) To assess the nucleotide sequence of 409 genes whose genetic alterations are associated with the carcinogenesis process; 2) To verify the global methylation profile of the samples; 3) To analyze the expression profile of miRNA involved in tumors development; 4) To evaluate the effects of molecular changes observed in the previous analyses, in the protein expression. The study will include a total of 80 samples from patients with LMS, 80 LM, 20 LMU and 20 MM. Genetic alterations and methylation profile will be assessed by New Generation Sequencing (NGS) assay. miRNA expression profile will be assessed by Real Time PCR analysis and the effects of genetic and epigenetic events on protein expression profile will be analyzed by Immunohistochemistry. All results will be submitted to statistical analyses. (AU)