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Abstract：
Genetic alterations including fusions in fibroblast growth factor receptor 2 (FGFR2) are detected in 10-20% of intrahepatic cholangiocarcinoma (iCCA), and FGFR2 inhibitors are effective for the treatment of iCCA. We examined a prevalence of FGFR2 genetic alterations and their clinicopathological significance in combined hepatocellular-cholangiocarcinoma (cHCC-CCA). FGFR2 expression, which is a surrogate marker for FGFR2 genetic alterations, was immunohistochemically assessed in the liver sections from 75 patients with cHCC-CCA, 35 with small duct-type iCCA, 30 with large duct-type iCCA, and 35 with hepatocellular carcinoma (HCC). FGFR2 genetic alterations were detected by reverse transcription-PCR and direct sequence. An association of FGFR2 expression with clinicopathological features was investigated in cHCC-CCAs. FGFR2 expression was detected in significantly more patients with cHCC-CCA (21.3%) and small duct-type iCCA (25.7%), compared to those with large duct-type iCCA (3.3%) and HCC (0%) (p < 0.05). FGFR2-positive cHCC-CCAs were significantly smaller size (p < 0.05), with more predominant cholangiolocarcinoma component (p < 0.01) and less nestin expression (p < 0.05). Genetic alterations of ARID1A and BAP1 and multiple genes were significantly more frequent in FGFR2-positive cHCC-CCAs (p < 0.05). 5\'/3\' imbalance in FGFR2 genes indicating exon18-truncated FGFR2 was significantly more frequently detected in FGFR2-positive cHCC-CCAs and small duct iCCAs, compared to FGFR2-negative ones (p < 0.05). FGFR2::BICC fusion was detected in a case of cHCC-CCAs. FGFR2 genetic alterations may be prevalent in cHCC-CCAs as well as small duct-type iCCAs, which suggest cHCC-CCAs may also be a possible therapeutic target of FGFR2 inhibitors.
摘要：
在10-20％的肝内胆管癌（iCCA）中检测到包括成纤维细胞生长因子受体2（FGFR2）融合在内的遗传改变，和FGFR2抑制剂对于iCCA的治疗是有效的。我们检查了FGFR2遗传改变的患病率及其在联合肝细胞胆管癌（cHCC-CCA）中的临床病理意义。FGFR2表达，这是FGFR2遗传改变的替代标记，在75例cHCC-CCA患者的肝脏切片中进行免疫组织化学评估，35采用小导管型iCCA，30采用大风管型iCCA，35例肝细胞癌（HCC）。通过逆转录PCR和直接测序检测FGFR2遗传改变。在cHCC-CCA中研究了FGFR2表达与临床病理特征的关联。在cHCC-CCA（21.3％）和小导管型iCCA（25.7％）的患者中检测到FGFR2表达，与大导管型iCCA（3.3％）和HCC（0％）相比（p<0.05）。FGFR2阳性cHCC-CCA的大小明显较小（p<0.05），胆管癌成分较多（p<0.01），巢蛋白表达较少（p<0.05）。在FGFR2阳性的cHCC-CCA中，ARID1A和BAP1以及多个基因的遗传改变明显更频繁（p<0.05）。FGFR2基因的5'/3'失衡表明外显子18截短的FGFR2在FGFR2阳性cHCC-CCAs和小导管iCCAs中明显更频繁地检测到，与FGFR2阴性的相比（p<0.05）。在cHCC-CCA病例中检测到FGFR2::BICC融合。FGFR2基因改变可能在cHCC-CCA以及小导管型iCCA中普遍存在，这表明cHCC-CCA也可能是FGFR2抑制剂的可能治疗靶标。
