Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts
Cancers, 2021
Sainz J., García-Verdejo F., Martínez-Bueno M., Kumar A., Sánchez-Maldonado J., Díez-Villanueva A., Vodičková L., Vymetálková V., Martin Sánchez V., Da Silva Filho M., Sampaio-Marques B., Brezina S., Butterbach K., ter Horst R., Hoffmeister M., Ludovico P., Jurado M., Li Y., Sánchez-Rovira P., Netea M., Gsur A., Vodička P., Moreno V., Hemminki K., Brenner H., Chang-Claude J., Försti A.
Disease area | Application area | Sample type | Products |
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Oncology | Pathophysiology | Serum | Olink Target 96 |
Abstract
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.