Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
J Pathol. 2022 Nov;258(3):227-235. doi: 10.1002/path.5994. Epub 2022 Sep 6.
Carcinogenesis of primary sclerosing cholangitis (PSC)-associated cholangiocarcinoma (CCA) is largely unexplored. Improved understanding of the molecular events involved may guide development of novel avenues for rational clinical management. We aimed to assess the genetic alterations during progression of the neoplastic cascade from biliary dysplasia towards CCA in PSC. Forty-four resection specimens or biopsies of PSC patients with biliary dysplasia (n = 2) and/or CCA (n = 42) were included. DNA was extracted from sections of formalin-fixed paraffin-embedded tissue blocks with dysplasia (n = 23), CCA (n = 69), and nonneoplastic tissue (n = 28). A custom-made next-generation sequencing (NGS) panel of 28 genes was used for mutation and copy number variation (CNV) detection. In addition, CNVs of CDKN2A, EGFR, MCL1, and MYC were examined by fluorescence in situ hybridization. Alterations in 16 low-grade dysplasia samples included loss of FGFR1 (19%), CDKN2A (13%), and SMAD4 (6%), amplification of FGFR3 (6%), EGFR (6%), and ERBB2 (6%), and mutations in SMAD4 (13%). High-grade dysplasia (n = 7) is characterized by MYC amplification (43%), and mutations in ERBB2 (71%) and TP53 (86%). TP53 mutations are the most common aberrations in PSC-CCA (30%), whereas mutations in KRAS (16%), GNAS (14%), and PIK3CA (9%) are also common. In conclusion, PSC-CCA exhibits a variety of genetic alterations during progression of the neoplastic cascade, with mainly CNVs being present early, whereas mutations in ERBB2, TP53, and KRAS appear later in the development of CCA. These findings are promising for the development of NGS-guided diagnostic strategies in PSC-CCA. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
原发性硬化性胆管炎（PSC）相关胆管癌（CCA）的致癌作用在很大程度上尚未被探索。深入了解涉及的分子事件可能有助于为合理的临床管理开辟新途径。我们旨在评估PSC 从胆管发育不良到 CCA 的肿瘤级联进展过程中涉及的遗传改变。44 例 PSC 患者的切除标本或活检，其中胆管发育不良（n=2）和/或 CCA（n=42），包括在内。从有发育不良（n=23）、CCA（n=69）和非肿瘤组织（n=28）的福尔马林固定石蜡包埋组织块的切片中提取 DNA。使用定制的下一代测序（NGS）面板对 28 个基因进行突变和拷贝数变异（CNV）检测。此外，通过荧光原位杂交检测 CDKN2A、EGFR、MCL1 和 MYC 的 CNV。在 16 例低级别发育不良样本中发现的改变包括 FGFR1（19%）、CDKN2A（13%）和 SMAD4（6%）的缺失，FGFR3（6%）、EGFR（6%）和 ERBB2（6%）的扩增，以及 SMAD4（13%）的突变。高级别发育不良（n=7）的特征是 MYC 扩增（43%），以及 ERBB2（71%）和 TP53（86%）的突变。TP53 突变是 PSC-CCA 中最常见的异常（30%），而 KRAS（16%）、GNAS（14%）和 PIK3CA（9%）的突变也很常见。总之，PSC-CCA 在肿瘤级联进展过程中表现出多种遗传改变，主要是 CNV 较早出现，而 ERBB2、TP53 和 KRAS 的突变则在 CCA 的发展后期出现。这些发现为 PSC-CCA 的 NGS 引导的诊断策略的发展提供了希望。
