cGAS-STING 通路相关的遗传变异可预测转移性结直肠癌患者的预后：FIRE-3 和 TRIBE 试验的数据。
Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials.
机构信息
Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing 100142, China; Center of Evidence-based Medicine, Fudan University, Shanghai, China.
Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, USA.
出版信息
Eur J Cancer. 2022 Sep;172:22-30. doi: 10.1016/j.ejca.2022.05.016. Epub 2022 Jun 21.
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 cGAS-STING 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.
背景
干扰素基因刺激物（STING）的激活被报道可以增强西妥昔单抗介导的自然杀伤细胞激活和树突状细胞成熟。环鸟苷酸-腺苷酸合酶（cGAS）-STING 通路中的基因多态性可能会影响先天免疫反应。因此，我们假设 cGAS-STING 通路中的遗传变异可能预测转移性结直肠癌患者基于西妥昔单抗的治疗效果。
方法
FIRE-3（西妥昔单抗组，n=129；贝伐珠单抗组，n=107）和 TRIBE（贝伐珠单抗组，n=215）患者的血液样本中的基因组 DNA 使用 OncoArray-500K 珠芯片组进行基因分型。对 3 个基因（cGAS、STING 和干扰素 B1（IFNB1）中的 7 个选定的单核苷酸多态性进行分析，以研究其与总生存期和无进展生存期的相关性。
结果
在西妥昔单抗组中，与携带 C/C 的患者相比，携带 STING rs1131769 任何 T 等位基因的患者总生存期明显缩短（36.3 个月 vs 56.1 个月），无论是在单变量分析 [风险比（HR）=2.08；95%置信区间（CI）：1.06-4.07；P=0.03] 还是多变量分析（HR=2.98；95%CI：1.35-6.6；P=0.0085）中均如此；携带 IFNB1 rs1051922 G/A 和 A/A 基因型的患者无进展生存期明显短于携带 G/G 等位基因的患者，无论是在单变量分析（G/A 与 G/G，10.2 个月 vs 14.1 个月，HR=1.84；95%CI 1.23-2.76；A/A 与 G/G，10.7 个月 vs 14.1 个月，HR=2.19；95%CI 0.97-4.96；P=0.0077）还是多变量分析（G/A 与 G/G，HR=2；95%CI 1.22-3.3；A/A 与 G/G，HR=2.19，95%CI 0.92-5.26，P=0.02）中均如此。这些关联在 FIRE-3 或 TRIBE 的贝伐珠单抗组中均未观察到。
结论
这些结果首次表明，STING 和 IFNB1 基因的种系多态性可能预测转移性结直肠癌患者基于西妥昔单抗的治疗结局。
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