A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence
Menée à partir de données cliniques et génétiques portant sur des patients adultes atteints d'un carcinome corticosurrénalien et sur des patients pédiatriques porteurs de la mutation constitutionnelle R337H et atteints de cette maladie, cette étude met en évidence une association entre un polymorphisme à simple nucléotide au niveau du gène de l'alcool déshydrogénase 7 (un gène impliqué dans la voie de l'acide rétinoïque) et le développement précoce d'un carcinome corticosurrénalien
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.