Abstract
BackgroundGenome-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.MethodsWe 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.ResultsA 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.ConclusionsThese 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.
Highlights
Genome-wide association studies (GWASs) have enriched the fields of genomics and drug development
In order to identify potential genetic modifiers underlying Adrenocortical carcinoma (ACC) development that could improve cancer risk management and treatment, we genotyped a total of 42 TP53 R337H carriers with ACC, divided into a discovery cohort (BRZ1, N = 26) and a validation cohort (BRZ2, N = 16)
History showed that three children were from Li-Fraumeni syndrome (LFS) families, 17 children were from LiFraumeni-Like (LFL) families and 22 with no LFS/LFL family histories (Supplementary Table 1) according to the most stringent criteria.[31]
Summary
Genome-wide association studies (GWASs) have enriched the fields of genomics and drug development. In a large population-based cohort, the penetrance for paediatric ACC is less than 5%, whilst the overall cancer risk among females and males is less than 50% before the seventh decade.[5,7] The frequency of R337H prevalence among paediatric ACC varies from 75–96%, and is nearly 15% among adult ACC in Southern and South-eastern Brazil.[7,9,10] The phenotypic heterogeneity among R337H carriers in terms of cancer risk and the variability in age-of-onset may indicate the involvement of environmental and/or genetic variants that are able to modulate cancer development.[5,7] The enormous heterogeneity in cancer development noted in families carrying the germline R337H mutation[5] has prompted us to gain further insight into potential genetic factors cooperating to modify the agedependent incidence of cancer onset in the adrenal cortex R337H in Southern and South-eastern Brazil showed that this mutation has a frequency of 0.21–0.30%.5–7 This mutation is responsible for the increased incidence of paediatric ACC in Paraná state (3.4 per million before the age 15 years per year compared to 0.3 per million in the USA, or 6.4/million children younger than 10 years per year).[2,5] A hospital-based cohort estimated that the penetrance of this mutation for paediatric ACC is 10%.8 in a large population-based cohort, the penetrance for paediatric ACC is less than 5%, whilst the overall cancer risk among females and males is less than 50% before the seventh decade.[5,7] The frequency of R337H prevalence among paediatric ACC varies from 75–96%, and is nearly 15% among adult ACC in Southern and South-eastern Brazil.[7,9,10] The phenotypic heterogeneity among R337H carriers in terms of cancer risk and the variability in age-of-onset may indicate the involvement of environmental and/or genetic variants that are able to modulate cancer development.[5,7] The enormous heterogeneity in cancer development noted in families carrying the germline R337H mutation[5] has prompted us to gain further insight into potential genetic factors cooperating to modify the agedependent incidence of cancer onset in the adrenal cortex
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