Evaluation of the molecular pathogenesis of adrenocortical tumors by functional genomics

点击翻译按钮获取中文摘要

Adrenocortical tumors comprise benign adenomas and malignant carcinomas. Adrenocortical adenomas are among the most prevalent human neoplasias and can be hormonally active or endocrinologically silent. On the other side, adrenocortical carcinoma is a rare cancer with very poor prognosis and limited treatment options. Despite recent advances, the pathogenic mechanisms underlying autonomous steroid secretion (e.g. adrenal Cushing Syndrome) and adrenocortical tumorigenesis still remain largely obscure. Using single nucleotide polymorphism (SNP) arrays and next generation exome-sequencing we have identified key alterations affecting genes or pathways that could represent potential drivers for autonomous steroid secretion (i.e. somatic mutations in the PRKACA gene) and early tumorigenesis (i.e. activation of the Notch signalling pathway). The aim of the proposed project is to identify additional relevant genomic variants and molecular alterations that may be involved in the pathogenesis of adrenocortical neoplasias. Therefore, we will extend our research, utilizing now a combination of modern genetic analyses such as whole-genome sequencing and RNA-sequencing. In the first part of the study, we will investigate snap-frozen adrenal adenoma samples, in which exome sequencing did not identify any "Driver" mutation, as well as adrenocortical carcinomas in early tumor stages. We thereby aim to investigate so far unexplored genetic alterations (for instance in gene-regulatory regions) and their causal link with changes in gene expression and clinical phenotype. In the second part, we will perform for the first time molecular analysis at the single-cell level in both normal adrenal glands and adrenocortical tumors. This novel approach will allow investigating cellular subpopulations, intra-tumoral molecular heterogeneity and clonal complexity to gain fundamental new insights in the molecular and cellular architecture. This will lead to a better understanding of autonomous steroid secretion and early adrenocortical tumorigenesis in order to facilitate in the future the development new therapeutic options.