Zhang Xin, Bai Qianming, Wang Yulin, Jiang Zhengzeng, Han Jing, Xue Cheng, Huang Kai, Luan Lijuan, Huang Xiaoyong, Huang Xiaowu, Shi Guoming, Hou Yingyong, Ji Yuan
Department of Pathology, Fudan University Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032, China.
Department of Pathology, Fudan University Shanghai Cancer Centre, 270 Dong'an Road, Shanghai, 200032, China.
Virchows Arch. 2025 Apr 8. doi: 10.1007/s00428-025-04067-9.
Patients with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusion/rearrangement benefit from targeted therapies, highlighting the need for reliable testing strategies to identify FGFR2 alterations. We assessed 226 iCCA cases using RNA-based NGS, DNA-based NGS, and break-apart FISH to evaluate the effectiveness of these methods in detecting FGFR2 fusion/rearrangement. The detection rates for FGFR2 fusion/rearrangement were 9.7% (22/226) for RNA-based NGS, 7.1% (16/226) for DNA-based NGS, and 10.2% (23/226) for FISH. Among the 26 FGFR2 fusion/rearrangement-positive cases identified by any method, only 15 (57.7%) were positive by all three techniques, yielding a concordance rate of 95.1% (215/226). RNA-based NGS confirmed oncogenic FGFR2 fusion in 81% (21/26) of positive cases and identified five novel oncogenic fusions. Thirty-five percent (6/17) of the partner genes were located on chromosome 10, with BICC1 being the most common fusion partner, while the rest were distributed across the other 9 chromosomes. FISH demonstrated a sensitivity of 95.2% and specificity of 98.5%, compared to oncogenic FGFR2 fusions confirmed by RNA-based NGS, while DNA-based NGS exhibited a sensitivity of 71.4% and specificity of 99.5%, identifying FGFR2 mutations in 4 cases. FGFR2-FISH positive cases displayed no significant heterogeneity in positive cell distribution. Oncogenic FGFR2 fusion/rearrangement was associated with small duct type iCCA, especially in cases with positive serum HBsAg and absent cholangiolocarcinoma components and peripheral liver steatosis. This study provides a comprehensive comparison of three assays for detecting FGFR2 fusion/rearrangement, along with clinicopathologic characterization of oncogenic FGFR2 fusion in iCCA.
携带FGFR2融合/重排的肝内胆管癌（iCCA）患者可从靶向治疗中获益，这凸显了采用可靠检测策略来识别FGFR2改变的必要性。我们使用基于RNA的二代测序（NGS）、基于DNA的NGS和断裂分离荧光原位杂交（FISH）对226例iCCA病例进行评估，以评价这些方法在检测FGFR2融合/重排方面的有效性。基于RNA的NGS检测FGFR2融合/重排的阳性率为9.7%（22/226），基于DNA的NGS为7.1%（16/226），FISH为10.2%（23/226）。在通过任何一种方法鉴定出的26例FGFR2融合/重排阳性病例中，只有15例（57.7%）在所有三种技术检测中均为阳性，一致率为95.1%（215/226）。基于RNA的NGS在81%（21/26）的阳性病例中证实了致癌性FGFR2融合，并鉴定出5种新的致癌性融合。35%（6/17）的伙伴基因位于10号染色体上，其中BICC1是最常见的融合伙伴，其余分布在其他9条染色体上。与基于RNA的NGS证实的致癌性FGFR2融合相比，FISH显示敏感性为95.2%，特异性为98.5%，而基于DNA的NGS敏感性为71.4%，特异性为99.5%，在4例病例中鉴定出FGFR2突变。FGFR2-FISH阳性病例在阳性细胞分布上无显著异质性。致癌性FGFR2融合/重排与小胆管型iCCA相关，尤其是血清HBsAg阳性、无胆管癌成分和肝周脂肪变性的病例。本研究对检测FGFR2融合/重排的三种检测方法进行了全面比较，并对iCCA中致癌性FGFR2融合进行了临床病理特征分析。
