Abstract
The tissue-specific incidence of cancers and their genetic basis are poorly understood. Although prior studies have shown global correlation across tissues for cancer risk single-nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWAS), any shared functional regulation of gene expression on a per SNP basis has not been well characterized. We set to quantify cis-mediated gene regulation and tissue sharing for SNPs associated with eight common cancers. We identify significant tissue sharing for individual SNPs and global enrichment for breast, colorectal, and Hodgkin lymphoma cancer risk SNPs in multiple tissues. In addition, we observe increasing tissue sharing for cancer risk SNPs overlapping with super-enhancers for breast cancer and Hodgkin lymphoma providing further evidence of tissue specificity. Finally, for genes under cis-regulation by breast cancer SNPs, we identify a phenotype characterized by low expression of tumor suppressors and negative regulators of the WNT pathway associated with worse freedom from progression and overall survival in patients who eventually develop breast cancer. Our results introduce a paradigm for functionally annotating individual cancer risk SNPs and will inform the design of future translational studies aimed to personalize assessment of inherited cancer risk across tissues.
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All data are publicly available via GTEx (https://www.gtexportal.org/home/datasets) and TCGA databases (https://dcc.icgc.org/).
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AS: conceptualization, data curation, formal analysis, validation, investigation, visualization, methodology, writing—original draft, writing—review and editing. BS: data curation, investigation, writing—original draft, writing—review and editing. EJM: investigation, writing—original draft, writing—review and editing. MSB: conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, writing—original draft, writing—review and editing.
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Subramanian, A., Su, S., Moding, E.J. et al. Investigating the tissue specificity and prognostic impact of cis-regulatory cancer risk variants. Hum. Genet. 142, 1395–1405 (2023). https://doi.org/10.1007/s00439-023-02586-6
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DOI: https://doi.org/10.1007/s00439-023-02586-6