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

Surakhy, M and Wallace, M and Bond, E and Grochola, L F and Perez, H and Di Giovannantonio, M and Zhang, P and Malkin, D and Carter, H and Parise, I Z S and Zambetti, G and Komechen, H and Paraizo, M M and Pagadala, M S and Pinto, E M and Lalli, E and Figueiredo, B C and Bond, G L (2020) A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence. British Journal of Cancer, 122 (8). pp. 1231-1241. ISSN 0007-0920

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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.

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