Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY.
Appl Immunohistochem Mol Morphol. 2022 Jul 1;30(6):435-440. doi: 10.1097/PAI.0000000000001032. Epub 2022 May 10.
Gene fusions involving NTRK are not common in solid tumors. The aim of this study was to investigate the TRK protein expression and molecular characteristics of gene fusions in primary liver carcinomas. A total of 110 hepatocellular carcinomas (HCC) and 69 intrahepatic cholangiocarcinomas were retrieved for tissue microarray (TMA) construction and clinicopathologic characterization. Immunohistochemistry (IHC) for pan-TRK was initially performed on TMA slides and evaluated for staining intensity. Twelve (10.9%) of 110 HCC showed weak cytoplasmic TRK expression by IHC on TMA, while all others, including 69 intrahepatic cholangiocarcinomas, were negative for TRK. The TRK expression did not correlate with patient's age, sex, tumor differentiation, or tumor stage. The 12 cases were then validated by IHC on whole sections but all turned out to be negative. Further, RNA sequencing analysis did not detect any NTRK fusions in all 12 HCC cases; however, it did identify many fusions frequently involving genes that encode mitochondrial and ribosomal proteins, microRNAs, and some transcription factors. A few fusions were recurrent, including MT-ATP6/MT-ATP8 fusion (n=9, 75%), Ig κ light chain gene IGKV/IGKJ fusion (n=5, 41.7%), and histocompatibility complex gene HLA-C/HLA-B fusion (n=4, 33.3%). In summary, NTRK fusion is very rare in primary liver carcinomas. IHC on TMA for TRK expression yields high false positive results, which should be validated on whole sections and confirmed by molecular genetic studies such as RNA sequencing. Many fusions involving genes other than NTRK are detected in HCC, the significance of which warrants further studies.
涉及 NTRK 的基因融合在实体肿瘤中并不常见。本研究旨在探讨原发性肝癌中 TRK 蛋白表达和基因融合的分子特征。共检索了 110 例肝细胞癌（HCC）和 69 例肝内胆管细胞癌，用于构建组织微阵列（TMA）和临床病理特征分析。首先对 TMA 切片进行 pan-TRK 的免疫组化（IHC）染色，并评估染色强度。110 例 HCC 中有 12 例（10.9%）在 TMA 上的 IHC 显示出弱的细胞质 TRK 表达，而其余所有病例，包括 69 例肝内胆管细胞癌，均为 TRK 阴性。TRK 表达与患者的年龄、性别、肿瘤分化或肿瘤分期均无相关性。这 12 例病例随后在全切片上进行了 IHC 验证，但结果均为阴性。此外，RNA 测序分析未在所有 12 例 HCC 病例中检测到任何 NTRK 融合，但确实鉴定出许多经常涉及编码线粒体和核糖体蛋白、microRNAs 和一些转录因子的基因融合。一些融合是反复出现的，包括 MT-ATP6/MT-ATP8 融合（n=9，75%）、Ig κ 轻链基因 IGKV/IGKJ 融合（n=5，41.7%）和主要组织相容性复合体基因 HLA-C/HLA-B 融合（n=4，33.3%）。总之，NTRK 融合在原发性肝癌中非常罕见。TMA 上的 TRK 表达免疫组化（IHC）会产生很高的假阳性结果，应在全切片上进行验证，并通过 RNA 测序等分子遗传学研究进行确认。在 HCC 中还检测到许多涉及非 NTRK 基因的融合，其意义需要进一步研究。
