Walter Dirk, Döring Claudia, Feldhahn Magdalena, Battke Florian, Hartmann Sylvia, Winkelmann Ria, Schneider Markus, Bankov Katrin, Schnitzbauer Andreas, Zeuzem Stefan, Hansmann Martin Leo, Peveling-Oberhag Jan
Department of Internal Medicine I, Johann Wolfgang Goethe-University Hospital, 60590 Frankfurt, Germany.
Dr. Senckenberg Institute of Pathology, Johann Wolfgang Goethe-University Hospital, 60590 Frankfurt, Germany.
Oncotarget. 2017 Feb 28;8(9):14957-14968. doi: 10.18632/oncotarget.14844.
No personalized therapy regimens could demonstrate a benefit in survival of intrahepatic cholangiocarcinoma (iCCA). Since genetic heterogeneity might influence single biopsy based targeted therapy or the outcome of clinical trials, aim of the present study was to investigate intratumoral heterogeneity of iCCA by whole exome sequencing. Therefore, samples from tumor center and tumor periphery of large iCCA lesions as well as a control from healthy liver tissue were obtained from four patients and whole exome sequencing was performed. Mutations that occurred only in the tumor center or periphery were defined as private, whereas mutations present in both samples were regarded as common. A mean of 3 non-synonymous private mutations (range 0-14) per sample compared to 33,3 common mutations per sample (range 24-41) was identified. Mean percentage of non-synonymous private mutations per sample was 12% (range 0-58). In all samples of patient 1-3 as well as the central sample of patient 4 ≤ 10% private mutations were found, whereas 58% of private mutations were identified in the peripheral sample of patient 4. In this sample a private mutation in the DNA mismatch repair protein MSH6 could be identified most likely causing the high amount of private mutations. No substantial intratumoral heterogeneity was found in copy number variation analysis. In conclusion, iCCA show a small but distinct intratumoral heterogeneity. Somatic mutations in mismatch repair proteins might contribute significantly to increased spatial tumor burden and thereby may influence clinical management.
没有个性化治疗方案能证明对肝内胆管癌（iCCA）的生存有益。由于基因异质性可能会影响基于单次活检的靶向治疗或临床试验结果，本研究的目的是通过全外显子组测序来研究iCCA的肿瘤内异质性。因此，从4例患者的大iCCA病变的肿瘤中心和肿瘤周边获取样本以及健康肝组织对照，并进行全外显子组测序。仅在肿瘤中心或周边出现的突变被定义为私有突变，而两个样本中都存在的突变被视为共有突变。每个样本平均鉴定出3个非同义私有突变（范围为0 - 14个），而每个样本平均有33.3个共有突变（范围为24 - 41个）。每个样本中非同义私有突变的平均百分比为12%（范围为0 - 58%）。在患者1 - 3的所有样本以及患者4的中心样本中，发现的私有突变≤10%，而在患者4的周边样本中鉴定出58%的私有突变。在该样本中，可能鉴定出DNA错配修复蛋白MSH6中的一个私有突变，这很可能导致了大量的私有突变。在拷贝数变异分析中未发现明显的肿瘤内异质性。总之，iCCA显示出较小但明显的肿瘤内异质性。错配修复蛋白中的体细胞突变可能对增加的空间肿瘤负荷有显著贡献，从而可能影响临床管理。
