Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts
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Colorectal cancerAutophagyGenetic variantsGenetic susceptibility
Sainz, J.; García-Verdejo, F.J.; Martínez-Bueno, M.; Kumar, A.; Sánchez-Maldonado, J.M.; Díez-Villanueva, A.; Vodiˇcková, L.; Vymetálková, V.; Martin Sánchez, V.; Da Silva Filho, M.I.; et al. Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts. Cancers 2021, 13, 1258. [https://doi.org/10.3390/cancers13061258]
SponsorshipInstituto de Salud Carlos III (Madrid, Spain; PI12/02688 and PI17/02256); CORSA was funded by the Austrian Research Promotion Agency (FFG); BRIDGE grant (no. 829675, to Andrea Gsur); Czech Republic CCS was funded by GACR grants (18–09709S, 19–10543S and 20–03997S), ProgresQ28/1.LF and UNCE/MED/006 grants; COST Action CA17118, supported by COST (European Cooperation in Science and Technology); A.K. is a recipient of a Ramalingaswami Re-Retry Faculty Fellowship (Grant; BT/RLF/Re-entry/38/2017) from the Department of Biotechnology (DBT), Government of India (GOI); Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723, the Instituto de Salud Carlos III, co-funded by FEDER funds–a way to build Europe–grants PI14-00613, PI17-00092 and the Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MORE.; European Union Horizon 2020 grant No. 856620; CERCA Programme, Generalitat de Catalunya for institutional support
The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, DAPK2 (p = 2.19 × 10−5) and ATG5 (p = 6.28 × 10−4) were associated with the risk of CRC. Mechanistically, the DAPK2rs11631973G allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with Staphylococcus aureus (p = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (p = 0.0038) and serum levels of en-RAGE (p = 0.0068). ATG5rs546456T allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (p = 0.0088 and p = 0.0076, respectively), CD14+CD16− cell levels in blood (p = 0.0068) and serum levels of CCL19 and cortisol (p = 0.0052 and p = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the DAPK2 and ATG5 loci in the pathogenesis of CRC, likely through the modulation of host immune responses.