Journal article
A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence
- Abstract:
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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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 1.9MB, Terms of use)
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- Publisher copy:
- 10.1038/s41416-020-0764-3
Authors
- Publisher:
- Springer Nature
- Journal:
- British Journal of Cancer More from this journal
- Volume:
- 122
- Pages:
- 1231–1241
- Publication date:
- 2020-03-09
- Acceptance date:
- 2019-12-20
- DOI:
- EISSN:
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1532-1827
- ISSN:
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0007-0920
- Language:
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English
- Keywords:
- Pubs id:
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pubs:1081432
- UUID:
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uuid:08e5c4c8-8fa1-436d-b15d-e07a861bc638
- Local pid:
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pubs:1081432
- Source identifiers:
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1081432
- Deposit date:
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2020-01-09
Terms of use
- Copyright holder:
- Surakhy et al.
- Copyright date:
- 2020
- Rights statement:
- Copyright © 2020 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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