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

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 t...

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Hauptverfasser: Sainz, Juan (VerfasserIn) , García-Verdejo, Francisco José (VerfasserIn) , Martínez-Bueno, Manuel (VerfasserIn) , Kumar, Abhishek (VerfasserIn) , Sánchez-Maldonado, José Manuel (VerfasserIn) , Díez-Villanueva, Anna (VerfasserIn) , Vodičková, Ludmila (VerfasserIn) , Vymetálková, Veronika (VerfasserIn) , Martin Sánchez, Vicente (VerfasserIn) , Silva Filho, Miguel Inacio da (VerfasserIn) , Sampaio-Marques, Belém (VerfasserIn) , Brezina, Stefanie (VerfasserIn) , Butterbach, Katja (VerfasserIn) , ter Horst, Rob (VerfasserIn) , Hoffmeister, Michael (VerfasserIn) , Ludovico, Paula (VerfasserIn) , Jurado, Manuel (VerfasserIn) , Li, Yang (VerfasserIn) , Sánchez-Rovira, Pedro (VerfasserIn) , Netea, Mihai G. (VerfasserIn) , Gsur, Andrea (VerfasserIn) , Vodička, Pavel (VerfasserIn) , Moreno, Víctor (VerfasserIn) , Hemminki, Kari (VerfasserIn) , Brenner, Hermann (VerfasserIn) , Chang-Claude, Jenny (VerfasserIn) , Försti, Asta (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2 March 2021
In: Cancers
Year: 2021, Jahrgang: 13, Heft: 6, Pages: 1-16
ISSN:2072-6694
DOI:10.3390/cancers13061258
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cancers13061258
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2072-6694/13/6/1258
Volltext
Verfasserangaben:Juan Sainz, Francisco José García-Verdejo, Manuel Martínez-Bueno, Abhishek Kumar, José Manuel Sánchez-Maldonado, Anna Díez-Villanueva, Ludmila Vodičková, Veronika Vymetálková, Vicente Martin Sánchez, Miguel Inacio Da Silva Filho, Belém Sampaio-Marques, Stefanie Brezina, Katja Butterbach, Rob ter Horst, Michael Hoffmeister, Paula Ludovico, Manuel Jurado, Yang Li, Pedro Sánchez-Rovira, Mihai G. Netea, Andrea Gsur, Pavel Vodička, Víctor Moreno, Kari Hemminki, Hermann Brenner, Jenny Chang-Claude and Asta Försti

MARC

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520 |a 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. 
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