Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts

• Published in: Cancers 2021-03, Vol.13 (6), p.1-16
• Main Authors: Sainz, Juan, García-Verdejo, Francisco José, Martínez-Bueno, Manuel, Kumar, Abhishek, Sánchez-Maldonado, José Manuel, Díez-Villanueva, Anna, Vodičková, Ludmila, Vymetálková, Veronika, Marques, Maria Belém Sousa Sampaio, Ludovico, Paula
• Format: Article
• Language: English
• Subjects: Alleles; Autophagy; Cancer; CCL19 protein; CD14 antigen; CD16 antigen; CD27 antigen; CD38 antigen; Colorectal cancer; Colorectal carcinoma; Cortisol; Genetic diversity; Genetic variants; Genome-wide association studies; Genomes; Genomics; Gram-positive bacteria; Immunoglobulin M; Immunomodulation; Interleukin 1; Leukocytes (mononuclear); Lipopolysaccharides; Meta-analysis; Molecular modelling; Nonsteroidal anti-inflammatory drugs; Patients; Peripheral blood mononuclear cells; Phagocytosis; Quality control; Science & Technology; Serum levels; Susceptibility; Tumor necrosis factor
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13061258

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 DAPK2 rs11631973G 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). ATG5 rs546456T 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. This work was partially supported by grants from the Instituto 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), the “Herzfelder’sche Familienstiftung” (grant 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. This article is based upon work from 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). V.M. received funding from the 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. K.H. was supported by European Union Horizon 2020 grant No. 856620. We thank the CERCA