PO.PS01.07 · 人群科学
肝细胞癌中生存相关种系变异的鉴定
Identification of survival-associated germline variants in hepatocellular carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：肝细胞癌（HCC）仍是全球癌症相关死亡的主要原因之一。HCC的预后模型主要依赖肿瘤负荷和肝功能，对遗传因素在生存差异中的贡献考虑有限。鉴定与生存相关的种系变异有助于完善预后判断并揭示疾病进展的生物学机制。
方法：我们对来自M.D. Anderson癌症中心队列的864例HCC患者的总生存期进行了全基因组关联研究（GWAS）。基因分型、质量控制和填补流程遵循先前所述方案（PMID: 38381705）。使用对年龄、性别及前五个主成分进行校正的Cox比例风险模型评估遗传变异与总生存期之间的关联。全基因组显著性定义为P<5×10⁻⁸。采用功能注释和通路富集分析（MAGMA）以探究所鉴定位点的生物学相关性。
结果：经质量控制后，共分析了8,525,017个单核苷酸多态性（SNP）。我们鉴定出7个在全基因组显著性水平上与HCC生存相关的新位点。7个位点中有5个与人体测量性状和血液学测量性状相关，反映了代谢、造血、免疫功能和炎症。位于STX7 3′非翻译区（UTR3）的一个变异显示出与总生存期的全基因组显著关联（HR=3.23；P=2.56×10⁻⁸）。携带风险等位基因者的生存时间显著短于非携带者。通路分析揭示了生物学相关过程的富集，包括肝脏生长和再生（生长激素及白介素-6（IL-6）信号通路），提示肝细胞增殖和IL-6/STAT3介导的炎症信号。免疫相关通路，如T细胞活化调控和髓样白细胞迁移，凸显了种系变异在免疫监视中的作用。此外，调控血管重塑和代谢应激反应的通路（如JAK活化、线粒体动力学）提示微环境结构和肝细胞韧性的遗传决定因素影响患者结局。
结论：本项HCC生存的种系GWAS鉴定出7个新的全基因组显著位点，并提示参与肝脏再生、炎症和组织重塑的通路。这些发现支持遗传变异在塑造HCC预后中的作用，并凸显将种系遗传学整合入预后建模和治疗靶点发现的潜力。
查看英文原文 English abstract
Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Prognostic models for HCC primarily rely on tumor burden and liver function, with limited consideration of inherited genetic contributions to survival variability. Identifying germline variants associated with survival could refine prognosis and reveal biological mechanisms underlying disease progression.
Methods: We conducted a genome-wide association study (GWAS) of overall survival among 864 patients with HCC from the M.D. Anderson Cancer Center cohort. Genotyping, quality control, and imputation procedures followed previously described protocols (PMID: 38381705). Associations between genetic variants and overall survival were assessed using Cox proportional hazards models adjusted for age, sex, and the first five principal components. Genome-wide significance was defined as P < 5×10 -8 . Functional annotation and pathway enrichment analyses (MAGMA) were employed to investigate the biological relevance of the identified loci.
Results: After quality control, 8,525,017 single-nucleotide polymorphisms (SNPs) were analyzed. We identified seven new loci associated with HCC survival at the genome-wide significance level. Five out of seven loci are associated with anthropometric traits and hematological measurement traits, reflecting metabolism, hematopoiesis, immune function, and inflammation. A variant in the 3′ untranslated region (UTR3) of STX7 showed a genome-wide significant association with overall survival (HR = 3.23; P = 2.56 ×10⁻⁸). Carriers of the risk allele had significantly shorter survival times compared with noncarriers. Pathway analysis revealed enrichment in biologically relevant processes, including liver growth and regeneration (growth hormone and Interleukin-6 (IL-6) signaling pathway), implicating hepatocyte proliferation and IL-6/STAT3-mediated inflammatory signaling. Immune-related pathways, such as regulation of T cell activation and myeloid leukocyte migration, highlight the role of germline variation in immune surveillance. Moreover, pathways governing vascular remodeling and metabolic stress response (e.g., JAK activation, mitochondrial dynamics) suggest that inherited determinants of microenvironmental structure and hepatocyte resilience influence patient outcomes.
Conclusion: This germline GWAS of HCC survival identifies seven new genome-wide significant loci and implicates pathways involved in liver regeneration, inflammation, and tissue remodeling. These findings support a role for inherited genetic variation in shaping HCC prognosis and underscore the potential of integrating germline genetics into prognostic modelling and therapeutic target discovery.
利益披露 Disclosure
Y. Han, None..
J. Byun, None..
C. I. Amos, None.