Surface microstructures are associated with mutational intratumoral heterogeneity in colorectal tumors
Surface microstructures are associated with mutational intratumoral heterogeneity in colorectal tumors
复制标题
DOI：
10.1007/s00535-018-1481-z
复制
发表时间：
2018-12-01
影响因子：
6.3
通讯作者：
Suzuki, Hiromu
中科院分区：
文献类型：
--
作者：
Harada, Taku;Yamamoto, Eiichiro;Suzuki, Hiromu
背景最近的研究表明，结直肠肿瘤由遗传多样性的亚克隆组成。我们的目的是阐明结直肠肿瘤的表面微结构是否与遗传瘤内异质性（ITH）相关。方法采用放大内镜观察结直肠肿瘤的表面微结构（凹坑图案），并在肿瘤表现出多个凹坑图案时从相应区域获取活检标本。使用焦磷酸测序和直接测序分析了来自 477 个结直肠肿瘤的总共 711 个样本的 BRAF、KRAS 和 TP53 突变。通过靶向测序对 7 个肿瘤的一组癌症相关基因进行了分析。结果具有多个凹陷模式的结直肠肿瘤比具有单一凹陷模式的肿瘤表现出更先进的凹陷模式以及更高的 KRAS 和/或 TP53 突变频率。在具有多个凹坑模式的肿瘤中，观察到的突变为公共（所有区域共有）或私人（特定于某些区域），并且私人 KRAS 和/或 TP53 突变通常是可变的并且与凹坑图案等级无关。值得注意的是，侵袭性结直肠癌经常表现出公共 TP53 突变，即使在腺瘤区域也是如此，这表明它们具有早期恶性潜力。靶向测序揭示了具有多个凹坑模式的肿瘤中额外的公共和私人突变，表明它们是单一克隆起源。结论我们的结果表明，瘤内凹坑模式变异并不仅仅反映了结直肠肿瘤进化的过程，而是代表了遗传多样性的亚克隆，这种多样性可能与恶性潜能相关。
BackgroundRecent studies revealed that colorectal tumors are composed of genetically diverse subclones. We aimed to clarify whether the surface microstructures of colorectal tumors are associated with genetic intratumoral heterogeneity (ITH).MethodsThe surface microstructures (pit patterns) of colorectal tumors were observed using magnifying endoscopy, and biopsy specimens were obtained from respective areas when tumors exhibited multiple pit patterns. A total of 711 specimens from 477 colorectal tumors were analyzed for BRAF, KRAS and TP53 mutations using pyrosequencing and direct sequencing. A panel of cancer-related genes was analyzed through targeted sequencing in 7 tumors.ResultsColorectal tumors with multiple pit patterns exhibited more advanced pit patterns and higher frequencies of KRAS and/or TP53 mutations than tumors with a single pit pattern. In tumors with multiple pit patterns, mutations were observed as public (common to all areas) or private (specific to certain areas), and private KRAS and/or TP53 mutations were often variable and unrelated to the pit pattern grade. Notably, invasive CRCs frequently exhibited public TP53 mutations, even in adenomatous areas, which is indicative of their early malignant potential. Targeted sequencing revealed additional public and private mutations in tumors with multiple pit patterns, indicating their single clonal origin.ConclusionsOur results suggest intratumoral pit pattern variation does not simply reflect the process of colorectal tumor evolution, but instead represents genetically diverse subclones, and this diversity may be associated with malignant potential.