Departments of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China.
Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, Jiangsu Province, China.
Pathol Res Pract. 2020 Apr;216(4):152857. doi: 10.1016/j.prp.2020.152857. Epub 2020 Feb 11.
As an increasing number of gene alterations have been discovered in intrahepatic cholangiocarcinoma (ICC), molecular targets are promising for the diagnosis and treatment of distinct subpopulations carrying unique molecular signatures. C-MET amplification is associated with a variety of tumors, including ICC; however, the characteristics of this alteration have not been assessed in ICC. By determining the ratios of C-MET/chromosome enumeration probe (CEP) 7 double-colour probes, we evaluated the presence of C-MET amplification in a cohort of 133 ICC tumors by fluorescence in situ hybridization (FISH). We further determined the levels of MET protein expression by immunohistochemistry (IHC) and analyzed clinicopathologic records. Of the samples, 21 (15.8 %) had high-frequency and 41 (30.8 %) had low-frequency C-MET genetic amplification, and 71 (53.4 %) had a normal C-MET gene. There were significant differences in gross classification (p = 0.045), microscopic cholangitis (p = 0.030), mucus level in tumors (p = 0.012) and T stage (p = 0.007) between the three groups. When we combined high-frequency and low-frequency amplifications of C-MET into one group, only microscopic cholangitis (p = 0.010) and stage (p = 0.016) showed significant differences compared to normal C-MET gene expression. However, when we combined the low-frequency C-MET amplification group with the normal C-MET group and compared this combined group with the high-frequency C-MET amplification group, the high-frequency group had more younger patients (p = 0.047), had more non-mass-forming (MF)-type cases according to gross classification (p = 0.015), secreted more mucus (p = 0.002) and appeared to have a higher T stage (p = 0.031) than the combined group. For IHC results, although only cluster C-MET amplification predicted protein overexpression, high-frequency amplification was associated with more protein expression than the other genetic statuses (p = 0.000). As low-frequency C-MET amplification exhibited similar biology to that of the normal gene, we regarded high-frequency amplification of C-MET as a unique molecular subtype. It may play important roles in tumor progression and may be used as a prognostic marker for targeted therapy.
随着越来越多的基因改变在肝内胆管癌（ICC）中被发现，分子靶点对于诊断和治疗具有独特分子特征的不同亚群具有很大的潜力。MET 扩增与多种肿瘤有关，包括 ICC；然而，这种改变的特征尚未在 ICC 中进行评估。通过确定 C-MET/染色体计数探针（CEP）7 双色探针的比值，我们通过荧光原位杂交（FISH）评估了 133 例 ICC 肿瘤样本中 C-MET 扩增的存在。我们进一步通过免疫组织化学（IHC）测定 MET 蛋白的表达水平，并分析临床病理记录。在样本中，21 例（15.8%）存在高频 C-MET 基因扩增，41 例（30.8%）存在低频 C-MET 基因扩增，71 例（53.4%）存在正常的 C-MET 基因。三组间大体分类（p = 0.045）、镜下胆管炎（p = 0.030）、肿瘤内黏液水平（p = 0.012）和 T 分期（p = 0.007）存在显著差异。当我们将 C-MET 的高频和低频扩增合并为一组时，只有镜下胆管炎（p = 0.010）和分期（p = 0.016）与正常 C-MET 基因表达相比有显著差异。然而，当我们将低频 C-MET 扩增组与正常 C-MET 组合并，并将合并组与高频 C-MET 扩增组进行比较时，高频组的年轻患者更多（p = 0.047），根据大体分类，非肿块型（MF）病例更多（p = 0.015），分泌的黏液更多（p = 0.002），T 分期更高（p = 0.031）。对于 IHC 结果，虽然只有簇 C-MET 扩增预测蛋白过表达，但高频扩增与其他遗传状态相比，蛋白表达更高（p = 0.000）。由于低频 C-MET 扩增表现出与正常基因相似的生物学特征，我们将 C-MET 的高频扩增视为一种独特的分子亚型。它可能在肿瘤进展中发挥重要作用，并可能作为靶向治疗的预后标志物。
