Identification of genomic and transcriptomic alterations in intraductal papillary and tubulopapillary neoplasms of the bile duct

胆管细胞癌(CCA)是一种预后不佳的胆道癌，由于诊断较晚，无法进行根治性手术切除，且缺乏有效的全身治疗方案。最近，我们发表了一篇关于不同CCA前体病变的综合分析，即胆管内乳头状瘤(IPNB)和管乳头状瘤(ITPN)(Goeppert等)。Gut，2021年；IF：23.059)。通过面板测序，我们证明了IPNB/ITPN和相应的侵袭性CCA具有共同的突变。此外，全基因组DNA甲基化图谱显示，IPNB/ITPN可能来自不同的起源细胞。目前，我们的目标是确定在某些IPNB/ITPN亚型中可能发现的早期基因改变，并揭示参与CCA发展的早期转录改变。我们综合的和特征明确的队列的先前小组测序数据显示，IPNB/ITPN的一个亚组没有表现出任何热点突变。因此，通过全外显子组测序、基因表达谱分析和RNA测序鉴定基因融合，对这些病例进行更深入的分析可能会揭示新的致癌机制。在该项目中，将对非肿瘤性胆管、相应的前驱病变(30例IPNB和20例ITPN)和50例患者的侵袭性CCA样本(总N=150)进行完整的外显子组测序和RNA测序，以揭示早期胆管癌变的分子变化，这可能对未来高危患者(如原发性硬化性胆管炎)的筛查计划和推定的治疗方案具有重要意义。

Cholangiocarcinoma (CCA) is a biliary tract cancer with dismal prognosis due to late diagnosis precluding curative surgical resection and the lack of effective systemic therapeutic options. Recently, we published an integrative analysis on distinct CCA precursor lesions, i.e. intraductal papillary (IPNB) and tubulopapillary (ITPN) neoplasms of the bile duct (Goeppert et al. Gut, 2021; IF: 23.059). Using panel sequencing, we demonstrated that IPNB/ITPN and the corresponding invasive CCA share common mutations. In addition, genome-wide DNA methylation profiling revealed that IPNB/ITPN may arise from different cells-of-origin. Currently, we aim at identifying early genetic alterations which may be found in certain subtypes of IPNB/ITPN and at revealing early transcriptomic alterations involved in CCA development. Previous panel sequencing data of our comprehensive and well-characterized cohort showed that a subgroup of IPNB/ITPN does not exhibit any hot spot mutations. Therefore, deeper analysis of these cases by whole exome sequencing, gene expression profiling and identification of gene fusions by RNA sequencing may reveal novel oncogenic mechanisms. For this project, whole exome sequencing and RNA sequencing of non-neoplastic bile duct, the corresponding precursor lesions (30 IPNB and 20 ITPN) and the invasive CCA samples of 50 patients (total N=150) will be performed in order to reveal molecular alterations in early cholangiocarcinogenesis which may be of great importance for future screening programs in high-risk patients (e.g. Primary Sclerosing Cholangitis) and putative treatment options.