Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.
Gut. 2022 Feb;71(2):391-401. doi: 10.1136/gutjnl-2020-322983. Epub 2021 Jan 19.
A detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options.
We analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling.
Patients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but mutations occurred exclusively in invasive CCA and mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin.
Integrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.
深入了解不同形式的胆管癌发生过程中的分子改变对于更好地理解胆管癌（CCA）至关重要，并且可能为早期诊断和更好的治疗选择铺平道路。
我们分析了一组临床病理特征明确的患者队列（n=54），这些患者具有高级别胆管内乳头状（IPNB）或管状乳头状（ITPN）肿瘤前病变，并将结果与独立的非 IPNB/ITPN 相关的 CCA 队列（n=294）进行了相关性分析。通过下一代测序、DNA 拷贝数和全基因组甲基化分析，对非肿瘤性胆管上皮、前体和侵袭性 CCA 的三联样本进行了分析。
起源于 IPNB/ITPN 的侵袭性 CCA 患者的预后优于与 IPNB/ITPN 不相关的 CCA 患者。ITPN 主要局限于肝内，而 IPNB 主要起源于肝外。IPNB/ITPN 同样与小胆管和大胆管型肝内 CCA 相关。IPNB 表现出肝外 CCA 的突变特征，而 ITPN 的突变明显较少。大多数突变在前体病变和相应的侵袭性 CCA 中均有发现，但突变仅发生在侵袭性 CCA 中，而突变主要存在于前体病变中。此外，IPNB 和 ITPN 在其 DNA 甲基化谱中存在差异，并且潜伏甲基化成分的分析表明 IPNB 和 ITPN 可能具有不同的细胞起源。
综合分析表明，IPNB 和 ITPN 具有不同的早期遗传改变，IPNB 富含与肝外 CCA 典型相关的突变，而 ITPN 则显示出较少的遗传改变并表现出明显的表观遗传特征。总之，IPNB/ITPN 可能代表肝内和肝外胆管癌发生的一种独特的中间形式。
