Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
J Pathol. 2019 Jun;248(2):164-178. doi: 10.1002/path.5243. Epub 2019 Mar 8.
Combined hepatocellular-cholangiocarcinomas (CHC) are mixed tumours with both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) components. CHC prognosis is similar to intrahepatic CC (ICC) and worse than HCC; staging and treatment generally follow ICC algorithms. However, the molecular biology of CHC remains poorly characterised. We performed capture-based next-generation sequencing of 20 CHC and, for comparison, 10 ICC arising in cirrhosis. Intratumour heterogeneity was assessed by separately sequencing the HCC and CC components of nine CHC. CHC demonstrated molecular profiles similar to HCC, even in the CC component. CHC harboured recurrent alterations in TERT (80%), TP53 (80%), cell cycle genes (40%; CCND1, CCNE1, CDKN2A), receptor tyrosine kinase/Ras/PI3-kinase pathway genes (55%; MET, ERBB2, KRAS, PTEN), chromatin regulators (20%; ARID1A, ARID2) and Wnt pathway genes (20%; CTNNB1, AXIN, APC). No CHC had alterations in IDH1, IDH2, FGFR2 or BAP1, genes typically mutated in ICC. TERT promoter mutations were consistently identified in both HCC and CC components, supporting TERT alteration as an early event in CHC evolution. TP53 mutations were present in both components in slightly over half the TP53-altered cases. By contrast, focal amplifications of CCND1, MET and ERRB2, as well as Wnt pathway alterations, were most often exclusive to one component, suggesting that these are late events in CHC evolution. ICC in cirrhosis demonstrated alterations similar to ICC in non-cirrhotic liver, including in IDH1 or IDH2 (30%), CDKN2A (40%), FGFR2 (20%), PBRM1 (20%), ARID1A (10%) and BAP1 (10%). TERT promoter and TP53 mutation were present in only one ICC each. Our data demonstrate that CHC genetics are distinct from ICC (even in cirrhosis) and similar to HCC, which has diagnostic utility and implications for treatment. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
肝细胞癌-胆管细胞癌（CHC）是一种具有肝细胞癌（HCC）和胆管细胞癌（CC）成分的混合肿瘤。CHC 的预后与肝内 CC（ICC）相似，比 HCC 差；分期和治疗通常遵循 ICC 算法。然而，CHC 的分子生物学仍未得到很好的描述。我们对 20 例 CHC 进行了基于捕获的下一代测序，并为比较，对 10 例在肝硬化中发生的 ICC 进行了测序。通过分别对 9 例 CHC 的 HCC 和 CC 成分进行测序，评估了肿瘤内异质性。CHC 显示出与 HCC 相似的分子特征，即使在 CC 成分中也是如此。CHC 中经常发生 TERT（80%）、TP53（80%）、细胞周期基因（40%；CCND1、CCNE1、CDKN2A）、受体酪氨酸激酶/Ras/PI3-激酶途径基因（55%；MET、ERBB2、KRAS、PTEN）、染色质调节剂（20%；ARID1A、ARID2）和 Wnt 途径基因（20%；CTNNB1、AXIN、APC）的改变。没有 CHC 有 IDH1、IDH2、FGFR2 或 BAP1 的改变，这些基因通常在 ICC 中发生突变。在 HCC 和 CC 成分中都一致地发现了 TERT 启动子突变，支持 TERT 改变是 CHC 进化的早期事件。TP53 突变在 TP53 改变的病例中超过一半存在于两个成分中。相比之下，CCND1、MET 和 ERBB2 的局灶性扩增以及 Wnt 途径改变，最常仅存在于一个成分中，表明这些是 CHC 进化的晚期事件。肝硬化中的 ICC 显示出与非肝硬化肝脏中的 ICC 相似的改变，包括 IDH1 或 IDH2（30%）、CDKN2A（40%）、FGFR2（20%）、PBRM1（20%）、ARID1A（10%）和 BAP1（10%）。每个 ICC 中只有一个存在 TERT 启动子和 TP53 突变。我们的数据表明，CHC 的遗传学与 ICC（即使在肝硬化中）不同，与 HCC 相似，这具有诊断效用，并对治疗有影响。版权所有 © 2019 英国和爱尔兰病理学学会。由 John Wiley & Sons，Ltd. 出版。
