RAS通路参与了增殖和细胞分裂过程的级联反应，活化的RAS通路可能导致肿瘤发生，包括肝细胞癌（HCC）。然而，很少有研究探讨RAS通路相关基因的遗传变异对HBV相关HCC患者生存的影响。在本研究中，我们评估了62个RAS通路基因中的11,658个单核苷酸多态性（SNP）与866个HBV相关HCC个体的总生存（OS）之间的关联，这些个体被随机分为发现和验证数据集（1：1）。结果，基于多变量Cox比例风险回归分析，确定了三个潜在的功能性SNP，分别是SOS Ras/Rho guanine核苷酸交换因子2（SOS2，rs4632055 A>G）、Ras蛋白特异性鸟嘌呤核苷酸释放因子2（RASGRF2，rs26418 A>G）和丝裂原活化蛋白激酶1（MAP2K1，rs57120695 C>T），这些SNP与HBV相关HCC患者的OS显著、独立地相关（分别为调整后危险比（HR）为1.42、1.32和1.50，95%置信区间（CI）分别为1.14至1.76、1.15至1.53和1.15至1.97，P值分别为0.001、<0.001和0.003）。此外，这三个SNP的不利基因型联合效应与HCC的差生存有显著关联（趋势性检验P<0.001）。表达定量位点（eQTL）分析进一步揭示了rs4632055 G等位基因和rs26418 A等位基因分别与SOS2和RASGRF2 mRNA表达水平降低有关。综上所述，这些潜在的具有功能性的RASGRF2、SOS2和M2PAK1的SNP可能成为HBV相关HCC肝切除术后的潜在预后生物标志物。©2023。作者在Springer-Verlag GmbH Germany，Springer Nature的独家许可下发表。

The RAS pathway participates in the cascade of proliferation and cell division process, and the activated RAS pathway can lead to tumorigenesis including hepatocellular carcinoma (HCC). However, few studies have explored the effects of genetic variants in the RAS pathway-related genes on the survival of patients with HBV-related HCC. In the present study, we assessed the associations between 11,658 single-nucleotide polymorphisms (SNPs) in 62 RAS pathway genes and the overall survival (OS) of 866 HBV-related HCC individuals, which were randomly split (1:1) into discovery and validation datasets. As a result, three potentially functional SNPs were identified, based on multivariable cox proportional hazards regression analyses, in SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2, rs4632055 A > G), Ras protein-specific guanine nucleotide releasing factor 2 (RASGRF2, rs26418A > G) and mitogen-activated protein kinase 1 (MAP2K1,rs57120695 C > T), which were significantly and independently associated with OS of HBV-related HCC patients [adjusted hazards ratios (HRs) of 1.42, 1.32 and 1.50, respectively; 95% confidence intervals (CI), 1.14 to 1.76, 1.15 to 1.53 and 1.15 to 1.97, respectively; P = 0.001, < 0.001 and 0.003, respectively]. Additionally, the joint effects as the unfavorable genotypes of these three SNPs showed a significant association with the poor survival of HCC (trend test P < 0.001). The expression quantitative trait loci (eQTL) analysis further revealed that the rs4632055 G allele and the rs26418 A allele were associated with lower mRNA expression levels of SOS2 and RASGRF2, respectively. Collectively, these potentially functional SNPs of RASGRF2, SOS2 and M2PAK1 may become potential prognostic biomarkers for HBV-related HCC after hepatectomy.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.