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. 2021 Mar 12;13(6):1258.
doi: 10.3390/cancers13061258.

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

Juan Sainz  1   2   3   4 , Francisco José García-Verdejo  5 , Manuel Martínez-Bueno  6 , Abhishek Kumar  7   8   9 , José Manuel Sánchez-Maldonado  1   2   3 , Anna Díez-Villanueva  10 , Ludmila Vodičková  11   12   13 , Veronika Vymetálková  11   12   13 , Vicente Martin Sánchez  14   15 , Miguel Inacio Da Silva Filho  7 , Belém Sampaio-Marques  16   17 , Stefanie Brezina  18 , Katja Butterbach  19 , Rob Ter Horst  20 , Michael Hoffmeister  21 , Paula Ludovico  16   17 , Manuel Jurado  1   2   3 , Yang Li  20   22 , Pedro Sánchez-Rovira  5 , Mihai G Netea  20   23 , Andrea Gsur  18 , Pavel Vodička  11   12   13 , Víctor Moreno  10 , Kari Hemminki  7   24   25 , Hermann Brenner  19   26   27 , Jenny Chang-Claude  28   29 , Asta Försti  7   30   31
Affiliations

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

Juan Sainz et al. Cancers (Basel). .

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.

Keywords: autophagy; colorectal cancer; genetic variants; susceptibility.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow diagram of the study.
Figure 2
Figure 2
Functional characterisation of the DAPK2 variant. NS, not significant. (A) PBMCs were stimulated with S. Aureus. (B) en-RAGE levels were measured in serum of 343 healthy subjects. (C) Percentage of CD24+CD38+CD27+IgM+ transient B cells were quantified considering CD3-CD19+ B cells as grandparent cell population (cell populations from which this population was isolated). CD3-CD19+ B cells were used to normalize the analysis in order to avoid inter-experimental bias and to increase statistical power. Results remain very similar when CD24+CD38+ B cells were used as parent cell population for normalization (p = 0.0073).
Figure 3
Figure 3
Functional characterisation of the ATG5rs546456 variant. NS, not significant. (A,B) PBMCs were stimulated with LPS. (C) Percentages of CD14+CD16− cells were quantified considering monocytes CD14+ as the grandparent cell population. (D) Serum levels of CCL19 and (E) cortisol were measured in the sera of 343 healthy subjects.
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