Pathobiology and genetics of adrenocortical carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence worldwide of 0.7-2.0 cases/million/year. Initial staging is the most important factor in determining prognosis. If diagnosed early, surgical resection +/- adjuvant treatment can lead to five-year survival of up to 80%. However, often it is diagnosed late and in advanced disease five-year survival is <15% with a high recurrence rate even after radical surgery. The mainstay of adjuvant treatment is with the drug mitotane. Mitotane has a specific cytotoxic effect on steroidogenic cells of the adrenal cortex but despite this progression through treatment is common. Developments in genetic analysis in the form of next-generation sequencing, aided by bioinformatics, have enabled high-throughput molecular characterisation of these tumours. This, in addition to a better appreciation of the processes of physiological, homeostatic self-renewal of the adrenal cortex has furthered our understanding of the pathogenesis of this malignancy. In this review, we have detailed the pathobiology and genetic alterations in adrenocortical carcinoma through integrating current understanding of homeostasis and self-renewal in the normal adrenal cortex with molecular profiling of tumours from recent genetic analyses. Improved understanding of the mechanisms involved in self-renewal and stem cell hierarchy in normal human adrenal cortices, together with the identification of cell populations likely to be co-opted by oncogenic mutations, will enable further progress in the definition of the molecular pathways involved in the pathogenesis of ACC. The combination of these advances eventually will lead to the development of novel, effective and personalised strategies to eradicate molecularly annotated ACCs.

Identification of Novel Hub Genes Through Expression Profiles Analysis in Adrenocortical Carcinoma

“…3). Since the staging system in ACC is the most important factor in the prediction of prognosis, we analyzed the expression pro le of four novel hub genes in different stages of ACC and found that TPX2 and RACGAP1 were positively correlated with the staging, indicating a promising role of such genes in the strati cation and the prediction of prognosis in ACC [11]. Interestingly, co-expression analysis revealed that the association between TPX2 and RACGAP1 was the strongest among all contrast groups and that the expression of HOXA5 was almost completely independent of that of RACGAP1 and TPX2 (Fig.…”

“…Even though these markers serve as relatively good prognostic tools, the outcome of ACC remains rather variable owing to its nature of heterogeneity even within the same disease stage or the same resection margin status [10]. Importantly, the initial staging of ACC has become the foremost factor in the determination of prognosis, with a ve-year survival of 81% for stage I and of only 13% for stage IV [3,6,11]. Unfortunately, early diagnosis of ACC serves as a vast roadblock due to the lack of speci c symptoms and the rarity of this malignancy [10,12].…”

“…Currently, limited treatment options are another Gordian knot in ACC. While surgical resection is the last straw of curative treatment for ACC, recurrence, and progression are common events, even in patients undergoing R0 resection [11]. Adjuvant therapies, including the only formally approved drug Mitotane and radiotherapy, have shown certain improvements on the recurrence-free survival in ACC, but not on the overall survival [3,[13][14][15].…”

“…Even though the management of ACC remains challenging because of the heterogeneity and unpredictability, the advances in gene analysis with the help of bioinformatics have bene ted the identi cation of promising targets and established novel approaches for research, to improve our understanding of ACC [5,11]. Therefore, we aimed to identify novel hub genes that may play essential roles in ACC using public datasets to elucidate the development and the prediction of prognosis of ACC in this study.…”

The underlying molecular mechanism and drugs for treatment in adrenal cortical carcinoma

“…ACC-specific literature is plenty of demonstrations that the above cited genetic alterations portend a poorer survival. Furthermore, more recent comprehensive genomic analyses of ACC [7][8][9][10][11] have gained significant improvements in our knowledge of this disease. In particular, the ACC-TCGA sub-project which represents the base of the present works [12].…”