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.
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。