Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer

0493626 - ÚEM 2019 RIV US eng J - Článek v odborném periodiku
Catalano, C. - da Silva Filho, M.I. - Frank, Ch. - Jirásková, Kateřina - Vymetálková, Veronika - Levý, M. - Liška, V. - Vyčítal, O. - Naccarati, Alessio - Vodičková, Ludmila - Hemminki, K. - Vodička, Pavel - Weber, A.N.R. - Försti, A.
Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer.
PLoS ONE. Roč. 13, č. 2 (2018), č. článku e0192385. ISSN 1932-6203. E-ISSN 1932-6203
Grant CEP: GA MZd(CZ) NV15-26535A; GA MZd(CZ) NV15-27580A
Institucionální podpora: RVO:68378041
Klíčová slova: class-i transactivator * immune evasion * t-cells * expression * colon
Obor OECD: Gastroenterology and hepatology
Impakt faktor: 2.776, rok: 2018

Constitutive activation of interferon signaling pathways has been reported in colorectal cancer leading to a strong CD8+ T cell response through stimulation of NLRC5 expression. Primed CD8+ T cell expansion, however, may be negatively regulated by PD-L1 expression. Additionally, aberrant PD-L1 expression enables cancer cells to escape the immune attack. Our study aimed to select potential regulatory variants in the NLRC5 and PD-L1 genes by using several online in silico tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, microRNA and transcription factor binding site prediction tools and to investigate their influence on colorectal cancer risk in a Czech cohort of 1424 patients and 1114 healthy controls. Logistic regression analysis adjusted for age and gender reported a moderate association between rectal cancer risk and two NLRC5 SNPs, rs1684575 T>G and rs3751710. Given that a combination of genetic variants, rather than a single polymorphism, may explain better the genetic etiology of colorectal cancer, we studied the interplay between the variants within NLRC5, PD-L1 and the previously genotyped IFNGR1 and IFNGR2variants, to evaluate their involvement in the risk of colorectal cancer development. Overall we obtained 18 pair wise interactions within and between the NLRC5ad PD-L1 genes and 6 more when IFNGR variants were added. Our data suggest that not only a single genetic variant but also an interaction between two or more variants within genes involved in immune regulation may play important roles in the onset of colorectal cancer, providing therefore novel biological information, which could eventually improve colorectal cancer risk management but also PD-1-based immunotherapy of colorectal cancer.
Trvalý link: http://hdl.handle.net/11104/0287041