tretinoin and Adrenocortical-Carcinoma

Genome-wide association studies (GWASs) have enriched the fields of genomics and drug development. Adrenocortical carcinoma (ACC) is a rare cancer with a bimodal age distribution and inadequate treatment options. Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation. The heterogeneous risk among carriers suggests other genetic modifiers could exist.. We analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients. We restricted our analyses to single nucleotide polymorphisms (SNPs) previously identified in GWASs to associate with disease or human traits.. A SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts. Patients homozygous for the minor allele were diagnosed up to 16 years earlier. This SNP resides in a gene involved in the retinoic acid (RA) pathway and patients with differing levels of RA pathway gene expression in their tumours associate with differential ACC progression.. These results identify a novel genetic component to ACC development that resides in the retinoic acid pathway, thereby informing strategies to develop management, preventive and therapeutic treatments for ACC.

Topics: Adolescent; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Age Factors; Age of Onset; Alcohol Dehydrogenase; Child; Child, Preschool; Female; Genes, p53; Genome-Wide Association Study; Humans; Incidence; Infant; Male; Polymorphism, Single Nucleotide; Tretinoin

Bone morphogenetic proteins (BMP) have been shown to affect tumorigenesis in a variety of tumors. Quantitative PCR analysis revealed down-regulation of BMP2 and BMP5 in tissue samples from adrenocortical carcinoma and adrenocortical tumor cell lines compared with normal adrenal glands. Integrity of BMP-dependent pathways in these cell lines could be shown by activation of the Smad1/5/8 pathway with subsequent increase of ID protein expression upon incubation with BMP2 or BMP5. On a functional level, BMP treatment resulted in inhibition of cell proliferation and viability in a dose- and time-dependent manner. This growth inhibitory effect was associated with BMP-dependent reduction of AKT phosphorylation under baseline conditions and under insulin-like growth factor costimulation. Furthermore, steroidogenic function, including melanocortin-2 receptor and steroidogenic enzyme expressions, was profoundly reduced. In vitro demethylation treatment and overexpression of GATA6 resulted in reactivation of BMP-dependent pathways with concomitant modulation of steroidogenesis. Taken together, we show that loss of expression of members of the BMP family of ligands is a common finding in adrenocortical tumors and we provide evidence that BMP-dependent pathways are likely to be involved in the modulation of the malignant and functional phenotype of adrenocortical cancer cells.

Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Aldosterone; Blotting, Western; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 5; Bone Morphogenetic Protein Receptors; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colforsin; Dose-Response Relationship, Drug; Down-Regulation; GATA6 Transcription Factor; Humans; Hydrocortisone; Insulin-Like Growth Factor I; Phosphorylation; Proto-Oncogene Proteins c-akt; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Steroid 17-alpha-Hydroxylase; Time Factors; Tretinoin; Tumor Cells, Cultured