Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts

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.

Colorectal Cancer Study of Austria (CORSA): A Population-Based Multicenter Study

“…Therefore, CORSA represents an active and leading player in cooperation, support actions, and consortia. So far, CORSA contributed to multiple international consortia such as Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], COlorectal cancer GENeTics (COGENT) and COnsortium of METabolomics Studies (COMETS) [ 13 ]. Furthermore, CORSA was a partner in two ERANET-TRANSCAN-funded projects: MetaboCCC [ 11 , 12 , 44 , 45 , 46 , 50 , 51 ], and “Biomarkers related to folate-dependent metabolism in colorectal cancer recurrence and survival” (FOCUS) [ 35 , 36 ].…”

Inflammasomes Are Influenced by Epigenetic and Autophagy Mechanisms in Colorectal Cancer Signaling

“…The results of a recent meta-analysis of four large cohorts indicate that the polymorphisms in DAPK2 and ATG5 autophagy-related genes have an impact on the risk of developing sporadic CRC. This influence is partially due to their effect on IL1β production [ 82 ]. IRGM, a risk factor for Crohn’s disease, has been found to restrict the activation of the NLRP3 inflammasome by hindering its assembly and facilitating its selective autophagy [ 83 ].…”

Death‐associated protein kinases and intestinal epithelial homeostasis

“…Polymorphisms within the DAPK2 allele were identified by GWAS and shown to influence the risk of developing CRC, likely through its association with host immune responses (Sainz et al, 2021). Additional evidence links DAPK2 to cell cycle arrest and apoptosis of CRC patient‐derived cancer stem cells.…”