A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Identification of Four Novel Prognostic Biomarkers and Construction of Two Nomograms in Adrenocortical Carcinoma: A Multi-Omics Data Study via Bioinformatics and Machine Learning Methods

“…Then two datasets including GSE75415 ( West et al, 2007 ) and GSE12368 ( Soon et al, 2009 ) were included. Then four datasets including GSE76021 ( Pinto et al, 2016 ), GSE19750 ( Demeure et al, 2013 ), GSE10927 ( Giordano et al, 2009 ), and GSE76019 ( Surakhy et al, 2020 ) from this database were collected and used in the present study, because of the complete clinical and survival information they contained. Moreover, we retrieved microarray data of ACC (TCGA-ACC data) and the related clinical information via The Cancer Genome Atlas (TCGA) database ( https://genome-cancer.…”

Adrenocortical carcinoma: Pediatric aspects (Review)

“…In addition, the association of 11p15 or TP53 genes with abnormal activity of phosphodiesterases has been reported (45). Genome-wide association studies (GWAS) based on single nucleotide polymorphism (SNP) assays identified retinoic acid pathway anomalies in adrenocortical carcinoma (46). MEN type 1 syndrome caused by MEN1 gene mutation, which is associated with pituitary tumors or gastrointestinal and pancreatic neuroendocrine neoplasia has been reported to be present in adrenal tumors (47)(48)(49).…”

Molecular genotyping of adrenocortical carcinoma: a systematic analysis of published literature 2019–2021

“…In one study variants of Epidermal Growth Factor Receptor (EGFR) were identified at higher incidence in children and young adults ACC [ 32 ]. Polymorphisms of selected genes could have influence on ACC incidence (retinoic acid pathway genes) [ 33 ], ACC tumorigenesis (phosphodiesterases genes) [ 34 ] or response to mitotane treatment (P450 cytochrome genes) [ 35 ]. Twelve single case reports expanded the catalog of single or multiple variants described in ACC.…”