PDF(Pubmed)
Abstract：
BACKGROUND: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease.
METHODS: We describe an integrated whole-exome sequencing and transcriptomic study of 37 iCCAs patients in Germany.
RESULTS: We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs.
CONCLUSIONS: By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.
METHODS: We describe an integrated whole-exome sequencing and transcriptomic study of 37 iCCAs patients in Germany.
RESULTS: We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs.
CONCLUSIONS: By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.
摘要：
背景：胆管癌（CCA）是一种致命的胆管癌，由于治疗选择有限，预后不良。肝内CCA（iCCA）的发病率在全球范围内增加，它的分子基础正在出现。环境因素可能导致欧洲iCCA患者突变谱的区域差异，在疾病的系统基因组和转录组学研究中代表性不足。
方法：我们描述了一项针对德国37例iCA患者的完整外显子组测序和转录组学研究。
结果：我们观察到ARID1A是最常见的突变基因（14％），IDH1,BAP1,TP53,KRAS,和ATM在8%的患者中。我们在两个肿瘤中确定了FGFR2::BICC1融合，和FGFR2::KCTD1和TMEM106B::ROS1是在iCCA中具有潜在治疗意义的新型融合体，并在体外证实了TMEM106B::ROS1的致癌特性。使用数据集成框架，我们将PBX1鉴定为iCCA中的新型中枢调控基因。我们通过对另外40个CCA的靶向测序进行了扩展筛选。在联合分析中，IDH1（13%），BAP1（10%），TP53（9%），KRAS（7%），ARID1A（7%），NF1（5%），ATM（5%）是最常见的突变基因，我们发现PBX1在20%的肿瘤中显示出拷贝增加。根据其他研究,与肝吸虫相关的亚洲iCCAs相比，PBX1的扩增倾向于在欧洲iCCAs中发生。
结论：通过分析另一个欧洲iCCA患者队列，我们发现PBX1蛋白表达是预后不良的标志。总的来说,我们的发现提供了对iCCA中关键分子改变的见解，揭示新的可靶向融合基因，并表明PBX1是这种疾病的新型调节剂。
方法：我们描述了一项针对德国37例iCA患者的完整外显子组测序和转录组学研究。
结果：我们观察到ARID1A是最常见的突变基因（14％），IDH1,BAP1,TP53,KRAS,和ATM在8%的患者中。我们在两个肿瘤中确定了FGFR2::BICC1融合，和FGFR2::KCTD1和TMEM106B::ROS1是在iCCA中具有潜在治疗意义的新型融合体，并在体外证实了TMEM106B::ROS1的致癌特性。使用数据集成框架，我们将PBX1鉴定为iCCA中的新型中枢调控基因。我们通过对另外40个CCA的靶向测序进行了扩展筛选。在联合分析中，IDH1（13%），BAP1（10%），TP53（9%），KRAS（7%），ARID1A（7%），NF1（5%），ATM（5%）是最常见的突变基因，我们发现PBX1在20%的肿瘤中显示出拷贝增加。根据其他研究,与肝吸虫相关的亚洲iCCAs相比，PBX1的扩增倾向于在欧洲iCCAs中发生。
结论：通过分析另一个欧洲iCCA患者队列，我们发现PBX1蛋白表达是预后不良的标志。总的来说,我们的发现提供了对iCCA中关键分子改变的见解，揭示新的可靶向融合基因，并表明PBX1是这种疾病的新型调节剂。
