综合肝细胞胆管癌（cHCC-CCA）是一种罕见的原发性肝癌，在单个肿瘤结节中具有两种不同的肿瘤表型。cHCC-CCA的遗传突变与临床病理特征之间的关系尚待阐明。本研究对十三例原发性和两例复发性cHCC-CCA进行了全外显子测序分析，并整合了全外显子分析和临床病理信息。本队列中，TP53基因突变最为频繁，其次为BAP1、IDH1/2和NFE2L2基因突变。所有直径小于3 cm的肿瘤均具有TP53突变。相反，直径大于等于3 cm的七个肿瘤中有六个没有TP53突变，但所有七个肿瘤均具有与多个途径相关的基因突变，包括Wnt、RAS/PI3K和表观遗传调节剂。在签名分析中，TP53突变组的突变模式更倾向于肝细胞癌（HCC）而非TP53非突变组。复发性cHCC-CCA肿瘤的突变频繁与原发性肿瘤相同，说明这些肿瘤来源于原发性cHCC-CCA肿瘤的相同克隆。患有cHCC-CCA的同一患者中复发和同时发生的HCC肿瘤在突变模式上可能与每个病例中的原发性cHCC-CCA肿瘤相同或不同。本研究指出cHCC-CCA有两个亚型，一个在癌变过程的早期涉及到TP53突变，另一个则不涉及此类突变。原发性和复发性肿瘤之间变异的比较表明cHCC-CCA来源于相同的克隆。本文受版权保护。版权所有。

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that has two different tumor phenotypes in a single tumor nodule. The relationship between genetic mutations and clinicopathological features of cHCC-CCA remains to be elucidated.Whole-exome sequencing analyses were performed in thirteen primary and two recurrent cHCC-CCAs. The whole-exome analyses and clinicopathological information were integrated.TP53 was the most frequently mutated gene in this cohort, followed by BAP1, IDH1/2, and NFE2L2 mutations in multiple cases. All tumors with diameters <3 cm had TP53 mutations. In contrast, six of seven tumors with diameters ≥3 cm did not have TP53 mutations, but all seven tumors had mutations in genes associated with various pathways, including Wnt, RAS/PI3K, and epigenetic modulators. In the signature analysis, the pattern of mutations shown in the TP53 mutation group tended to be more similar to HCC than the TP53 non-mutation group. Mutations in recurrent cHCC-CCA tumors were frequently identical to those in the primary tumor, suggesting that those tumors originated from identical clones of the primary cHCC-CCA tumors. Recurrent and co-occurrent HCC tumors in the same patients with cHCC-CCA had either common or different mutation patterns from the primary cHCC-CCA tumors in each case.The study suggested that there were two subtypes of cHCC-CCA, one involving TP53 mutations in the early stage of the carcinogenic process and the other not involving such mutations. The comparison of the variants between primary and recurrent tumors suggested that cHCC-CCA was derived from an identical clone. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.