本研究旨在明确肝门周围胆管癌 (PCA) 和远端胆管癌 (DCA) 之间的基因组差异，并确定生存的基因组决定因素。对连续患有 ECA 的患者进行分析，并按解剖部位进行分层 (PCA/DCA)。 、疾病程度和治疗。使用 Cox 比例风险回归分析基因组改变、临床病理特征和结果之间的关联以比较生存率。 2004 年至 2022 年期间总共有 224 名患者（n = 127 PCA；n = 97 DCA）符合纳入标准。中位生存期为 29 个月（切除后 43 个月，诊断为不可切除疾病后 17 个月）。与 PCA 相比，DCA 富含 TP53alt（改变；69% vs 33%；Q < 0.01）、表观遗传途径改变（45% vs 29%；Q = 0.041），并且总改变途径较多（中位数 3 v 2；Q < 0.01）。 Q < 0.01）。 PCA (36%) 和 DCA (37%) 之间的 KRASalt 频率相似；然而，DCA 在 KRAS G12D 中富集（19% vs 9%；P = .002）。没有其他临床病理学或基因组变量可以区分亚型。在切除的患者中，没有基因组改变与结果相关。然而，在不可切除的患者中，CDKN2Aalt（风险比[HR]，2.59[1.48至4.52]）和APCalt（HR，5.11[1.96至13.3]）与生存率降低相关。对于整个队列，不可切除性（HR，3.13 [2.25 至 4.36]）、CDKN2Aalt（HR，1.80 [1.80 至 2.68]）和 APCalt（HR，2.00 [1.04 至 3.87]）与较差的生存率相关。CDKN2Aalt 和 APCalt与 ECA 的不良生存率（主要是晚期疾病）相关。由于PCA和DCA在基因上相似，因此在未来的基因组研究中PCA和DCA的共同分析是合理的。

This study aimed to define genomic differences between perihilar cholangiocarcinoma (PCA) and distal cholangiocarcinoma (DCA) and identify genomic determinants of survival.Consecutive patients with ECA with tissue for targeted next-generation sequencing were analyzed, stratified by anatomic site (PCA/DCA), disease extent, and treatment. Associations between genomic alterations, clinicopathologic features, and outcomes were analyzed using Cox proportional hazards regression to compare survival.In total, 224 patients diagnosed between 2004 and 2022 (n = 127 PCA; n = 97 DCA) met inclusion criteria. The median survival was 29 months (43 after resection and 17 from diagnosis for unresectable disease). Compared with PCA, DCA was enriched in TP53alt (alterations; 69% v 33%; Q < 0.01), epigenetic pathway alterations (45% v 29%; Q = 0.041), and had more total altered pathways (median 3 v 2; Q < 0.01). KRASalt frequency was similar between PCA (36%) and DCA (37%); however, DCA was enriched in KRAS G12D (19% v 9%; P = .002). No other clinicopathologic or genomic variables distinguished subtypes. In resected patients, no genomic alterations were associated with outcome. However, in unresectable patients, CDKN2Aalt (hazard ratio [HR], 2.59 [1.48 to 4.52]) and APCalt (HR, 5.11 [1.96 to 13.3]) were associated with reduced survival. For the entire cohort, irresectability (HR, 3.13 [2.25 to 4.36]), CDKN2Aalt (HR, 1.80 [1.80 to 2.68]), and APCalt (HR, 2.00 [1.04 to 3.87]) were associated with poor survival.CDKN2Aalt and APCalt were associated with poor survival in ECA, primarily in advanced disease. As PCA and DCA were genetically similar, coanalysis of PCA and DCA in future genomic studies is reasonable.