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 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.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 Programme, Generalitat de Catalunya for institutional support

An investigation of DNA damage and DNA repair in chemical carcinogenesis triggered by small-molecule xenobiotics and in cancer: Thirty years with the comet assay

In the present review we addressed the determination of DNA damage induced by small-molecule carcinogens, considered their persistence in DNA and mutagenicity in in vitro and in vivo systems over a period of 30 years. The review spans from the investigation of the role of DNA damage in the cascade of chemical carcinogenesis. In the nineties, this concept evolved into the biomonitoring studies comprising multiple biomarkers that not only reflected DNA/chromosomal damage, but also the potential of the organism for biotransformation/elimination of various xenobiotics. Since first years of the new millennium, dynamic system of DNA repair and host susceptibility factors started to appear in studies and a considerable knowledge has been accumulated on carcinogens and their role in carcinogenesis. It was understood that the final biological links bridging the arising DNA damage and cancer onset remain to be elucidated. In further years the community of scientists learnt that cancer is a multifactorial disease evolving over several decades of individual´s life. Moreover, DNA damage and DNA repair are inseparable players also in treatment of malignant diseases, but affect substantially other processes, such as degeneration. Functional monitoring of DNA repair pathways and DNA damage response may cast some light on above aspects. Very little is currently known about the relationship between telomere homeostasis and DNA damage formation and repair. DNA damage/repair in genomic and mitochondrial DNA and crosstalk between these two entities emerge as a new interesting topic