Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials

Wang, Jingyuan; Xiao, Yi; Loupakis, Fotios; Stintzing, Sebastian; Yang, Yan; Arai, Hiroyuki; Battaglin, Francesca; Kawanishi, Natsuko; Jayachandran, Priya; Soni, Shivani; Zhang, Wu; Mancao, Christoph; Cremolini, Chiara; Liu, Tianshu; Heinemann, Volker; Falcone, Alfredo; Shen, Lin; Millstein, Joshua und Lenz, Heinz-Josef (2022): Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials. In: European Journal of Cancer, Bd. 172: S. 22-30

Abstract

Background: The activation of stimulator of interferon genes (STING) was reported to enhance cetuximab-mediated natural killer cell activation and dendritic cell maturation. Polymorphisms in genes in the cyclic GMP-AMP synthase (cGAS)-STING pathway may affect innate immune response. Therefore, we hypothesised that genetic variants in the cGASSTING pathway may predict the efficacy of cetuximab-based treatment in patients with metastatic colorectal cancer.Methods: Genomic DNA from blood samples of patients enrolled in FIRE-3 (cetuximab arm, n = 129;bevacizumab arm, n = 107) and TRIBE (bevacizumab arm, n = 215) was genotyped using the OncoArray-500K bead chip panel. Seven selected single nucleotide polymorphisms in 3 genes (cGAS, STING and interferon B1 (IFNB1)) were analysed for the association with overall survival and progression-free survival.Results: In the cetuximab cohort, patients with STING rs1131769 any T allele showed significantly shorter overall survival (36.3 versus 56.1 months) than carriers of C/C in both univariate [hazard ratio (HR) = 2.08;95% confidence interval (CI): 1.06-4.07;P = 0.03] and multivariate (HR = 2.98;95% CI: 1.35-6.6;P = 0.0085) analyses;patients carrying IFNB1 rs1051922 G/A and A/A genotype showed a significantly shorter progression-free survival than carriers of G/G allele in both univariate (G/A versus G/G, 10.2 versus 14.1 months, HR = 1.84;95% CI 1.23-2.76;A/A versus G/G, 10.7 versus 14.1 months, HR = 2.19;95% CI 0.97-4.96;P = 0.0077) and multivariate analyses (G/A versus G/G, HR = 2;95% CI 1.22-3.3;A/A versus G/G, HR = 2.19, 95% CI 0.92-5.26, P = 0.02). These associations were not observed in the bevacizumab arm of FIRE-3 or TRIBE.Conclusion: These results suggest for the first time that germline polymorphisms in STING and IFNB1 genes may predict the outcomes of cetuximab-based treatment in patients with metastatic colorectal cancer. 2022 Elsevier Ltd. All rights reserved.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0959-8049
• Sprache: Englisch