Molecular pathogenesis of adrenocortical cancer
Adrenocortical carcinoma is a rare heterogeneous neoplasm with a poor prognosis. Most patients present with symptoms related to steroid hormone excess or presence of an abdominal mass, while less frequently they are diagnosed incidentally during clinical exploration for other causes. In children, adrenocortical tumors are most commonly found associated with mutations of the TP53 tumor suppressor gene and have the highest incidence in southern Brazil. Several clinical and pathological features distinguish children from adult adrenocortical tumors.
Much progress has been made recently in our understanding of the pathogenesis of adrenocortical cancer, with an important contribution from genomic studies. A relevant role is played by loss of heterozygosity of the 11p15 chromosomal region, with consequent deregulation of the expression of the IGF2 growth factor and other genes. Clinical studies and mouse models also demonstrated the important role for overexpression of the SF-1 transcription factor and beta-catenin activation in triggering tumorigenesis. mRNA expression profiling of adult adrenocortical tumors allowed their molecular classification and the identification of predictors of malignancy and survival, while reliable markers of clinical outcome are still lacking for childhood tumors. Expression of a distinct set of miRNAs, affecting the function of crucial intracellular signalling pathways, is also deregulated in adrenocortical tumors and may be exploited in the future to identify circulating markers of malignancy. Furthermore, studies of tumor genomes have shown the presence of recurrent chromosomal alterations and suggested that distinct oncogenic routes may exist in adrenocortical tumors. Finally, preclinical studies have shown the efficacy of drugs targeting the most important signaling pathways deregulated in adrenocortical tumors to slow down tumor cell proliferation in vitro and in vivo. Those drugs represent promising novel therapeutic tools to be associated to current chemotherapeutic protocols.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.