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

胆管癌（CCA）是一种胆道癌，由于诊断晚，无法进行根治性手术切除，缺乏有效的全身治疗方案，预后不良。最近，我们发表了一项关于不同CCA前驱病变的综合分析，即胆管内乳头状（IPNB）和小管乳头状（ITPN）肿瘤（Goeppert et al. Gut，2021; IF：23.059）。使用面板测序，我们证明了IPNB/ITPN和相应的侵入性CCA共享共同的突变。此外，全基因组DNA甲基化分析显示，IPNB/ITPN可能来自不同的起源细胞。目前，我们的目标是确定早期的遗传变异，可能会发现在某些亚型的IPNB/ITPN和揭示早期转录组的变化参与CCA的发展。我们的综合和充分表征的队列的先前面板测序数据显示，IPNB/ITPN的亚组不表现出任何热点突变。因此，通过全外显子组测序、基因表达谱分析和通过RNA测序鉴定基因融合对这些病例进行更深入的分析可能揭示新的致癌机制。对于本项目，非肿瘤性胆管的全外显子组测序和RNA测序，相应的前驱病变（30例IPNB和20例ITPN）和50例患者的侵入性CCA样本（总N=150）将进行，以揭示早期胆管癌发生的分子改变，这可能对高危患者的未来筛查计划非常重要。（例如原发性硬化性胆管炎）和假定的治疗方案。

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.