- 90 例经 WES + 全转录组测序的 iCCA，FGFR2/3 改变 25 例（27.8%），以 FGFR2 融合为主（12 种伙伴基因），另有 FGFR3::TACC3 及 FGFR2 C382R/Y375C。
- 形态线索：FGFR2/3 改变型 100% 为小胆管型，84% 不产黏液，高分化比例更高；BAP1 突变更多，TP53 更少，ARID1A/KRAS 均野生型。
- DSS 单因素分析更好（HR 0.29），多因素分析不显著；作者认为生存优势来自伴随的临床病理与分子特征，而非 FGFR2/3 改变本身。
收录范围：PubMed 英文摘要及中文翻译（abstract-only）。原文为订阅制（Unpaywall：closed），出版社页对本站仅显示摘要，未采集全文、图表。
摘要
肝内胆管癌（iCCA）是一种侵袭性强、预后差的肿瘤。成纤维细胞生长因子受体（FGFR）已成为治疗靶点；然而，FGFR 改变型 iCCA 的临床病理、分子及预后特征仍未完全明确。为此，我们开展了一项为期 5 年的回顾性研究，对采用全外显子组与全转录组双重测序进行基因组分析的 iCCA，按 FGFR2/3 改变状态分层，考察其临床病理特征、生物标志物表达、分子谱，以及对总生存（OS）、无转移生存（MFS）、无进展生存（PFS）和疾病特异生存（DSS）的预后意义。共识别出 90 例 iCCA（25 例 [27.8%] 为 FGFR2/3 改变型，65 例 [72.2%] 为 FGFR2/3 野生型）。FGFR2/3 改变型 iCCA 包括 FGFR2 融合（伙伴基因 BICC1、AHCYL1、CREB5、NOL4、NRAP、PAH、POC1B、SH3GLB1、BAIAP2L1、FKBP15、LRRFIP2 和 TNS3）、FGFR3::TACC3 融合及 FGFR2 突变（C382R 和 Y375C）。FGFR2/3 改变型 iCCA 患者显著更年轻（中位 61.0 岁对 68.0 岁；p = 0.014），肿瘤更大（中位 9.6 cm 对 6.4 cm；p = 0.002），更多为高分化（24.0% 对 1.5%；p < 0.001）、不产黏液（84.0% 对 3.1%；p < 0.001）及小胆管型肿瘤（100% 对 32.3%；p < 0.001），BAP1 突变更多（36.0% 对 12.3%；p = 0.016），TP53 突变更少（4.0% 对 26.2%；p = 0.019），且 ARID1A/KRAS 均为野生型（0.0% 和 0.0% 对 20% 和 13.8%；p = 0.016 和 0.058）。FGFR2/3 野生型 iCCA 富集 TP53/KRAS 突变，并携带少见融合（ST7::MET、NRG1::RBPMS 和 RAB3GAP2::BRAF）。FGFR2/3 改变型 iCCA 患者的 1、2、3 年 DSS 显著更高（95.8%、79.1% 和 79.1% 对 68.4%、48.2% 和 43.8%；单因素分析：HR 0.29；95% CI 0.09–0.95；p = 0.041），但多因素分析中差异不显著（HR 2.52；95% CI 0.14–45.07；p = 0.530）。在小胆管型 iCCA 中，FGFR2/3 改变型 iCCA 的 DSS 仍显著高于野生型（95.8%、79.1% 和 79.1% 对 60.5%、32.3% 和 32.3%；HR 0.24；95% CI 0.06–0.90；p = 0.022），表明生存改善归因于小胆管亚型以外的因素。独立预后因素包括肿瘤多灶性（MFS 较低）、CEA >2.5 ng/mL（PFS 较低）、TP53 突变（OS 较低）、KRAS 突变（OS 和 DSS 较低）、放疗（OS 较高）及手术切除（OS、MFS 和 DSS 较高）。FGFR2/3 改变型 iCCA 是一个与 DSS 改善相关的独特亚型，其驱动因素是内在的临床病理及伴随分子特征，而非单纯 FGFR2/3 改变状态。基因组分析拓展了 iCCA 的分子图谱，可细化预后判断，并为靶向治疗的患者选择提供依据。
- 90 iCCAs profiled by WES + whole-transcriptome sequencing; 25 (27.8%) FGFR2/3-altered, mainly FGFR2 fusions (12 partners), plus FGFR3::TACC3 and FGFR2 C382R/Y375C.
- Morphological clues: FGFR2/3-altered tumours were 100% small duct type, 84% non-mucin-producing and more often well differentiated; more BAP1, fewer TP53, and no ARID1A/KRAS mutations.
- Better DSS on univariate (HR 0.29) but not multivariate analysis; the authors attribute it to accompanying clinicopathologic and co-molecular features rather than FGFR2/3 status alone.
Scope: PubMed abstract only. The article is subscription-only (Unpaywall: closed); the publisher page showed only the abstract to this site, so full text, figures and tables were not collected.
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is an aggressive neoplasm with a poor prognosis. Fibroblast Growth Factor Receptor (FGFR) has emerged as a therapeutic target; however, the clinicopathologic, molecular, and prognostic features of FGFR-altered iCCAs remain incompletely defined. Thus, a 5-year retrospective study of genomically profiled iCCAs using dual whole-exome and whole-transcriptome sequencing, stratified by FGFR2/3 alteration status, to examine their clinicopathologic characteristics, biomarker expression, molecular profile, and prognostic significance on overall (OS), metastasis-free (MFS), progression-free (PFS), and disease-specific survival (DSS) was performed. Ninety iCCAs (25 [27.8%] FGFR2/3-altered and 65 [72.2%] FGFR2/3-wild-type) were identified. FGFR2/3-altered iCCAs encompassed FGFR2 fusions (BICC1, AHCYL1, CREB5, NOL4, NRAP, PAH, POC1B, SH3GLB1, BAIAP2L1, FKBP15, LRRFIP2, and TNS3), FGFR3::TACC3 fusion, and FGFR2 mutations (C382R and Y375C). FGFR2/3-altered iCCA patients were significantly younger (median = 61.0 vs. 68.0 years; p = 0.014), with larger (median = 9.6 vs. 6.4 cm; p = 0.002), well-differentiated (24.0% vs. 1.5%; p < 0.001), non-mucin-producing (84.0% vs. 3.1%; p < 0.001), and small duct tumors (100% vs. 32.3%; p < 0.001), harboring higher BAP1 (36.0% vs. 12.3%; p = 0.016), lower TP53 mutations (4.0% vs. 26.2%; p = 0.019), and ARID1A/KRAS wild-type (0.0% and 0.0% vs. 20% and 13.8%; p = 0.016 and 0.058). FGFR2/3-wild-type iCCAs were TP53/KRAS-enriched and harbored rare fusions (ST7::MET, NRG1::RBPMS, and RAB3GAP2::BRAF). FGFR2/3-altered iCCA patients had significantly higher 1-, 2-, and 3-year DSS (95.8%, 79.1%, and 79.1% vs. 68.4%, 48.2%, and 43.8%; univariate analysis: HR 0.29; 95% CI 0.09-0.95; p = 0.041) but not on multivariate analysis (HR 2.52; 95% CI 0.14-45.07; p = 0.530). In small duct iCCAs, FGFR2/3-altered iCCAs maintained significantly higher DSS versus their wild-type counterparts (95.8%, 79.1%, and 79.1% vs. 60.5%, 32.3%, and 32.3%; HR 0.24; 95% CI 0.06-0.90; p = 0.022), indicating improved survival is attributed to factors beyond small duct subtype. Independent prognostic factors included tumor multifocality (lower MFS), CEA > 2.5 ng/mL (lower PFS), TP53 mutation (lower OS), KRAS mutation (lower OS and DSS), radiotherapy (higher OS), and surgical resection (higher OS, MFS, and DSS). FGFR2/3-altered iCCAs represent a distinct subtype associated with improved DSS, driven by inherent clinicopathologic and co-molecular characteristics rather than FGFR2/3 alteration status alone. Genomic profiling expands the molecular landscape of iCCAs, refines prognostication, and informs patient selection for targeted therapy.