Robust RNA-based in situ mutation detection delineates colorectal cancer subclonal evolution.
Robust RNA-based in situ mutation detection delineates colorectal cancer subclonal evolution.
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DOI：
10.1038/s41467-017-02295-5
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发表时间：
2017-12-08
影响因子：
16.6
通讯作者：
Graham TA
中科院分区：
文献类型：
--
作者：
Baker AM;Huang W;Wang XM;Jansen M;Ma XJ;Kim J;Anderson CM;Wu X;Pan L;Su N;Luo Y;Domingo E;Heide T;Sottoriva A;Lewis A;Beggs AD;Wright NA;Rodriguez-Justo M;Park E;Tomlinson I;Graham TA
肿瘤内异质性(ITH)是治疗抵抗和疾病复发的主要潜在原因，也是肿瘤生长的读出。目前的遗传ITH分析方法不能保存空间背景，也可能无法检测到稀有的亚克隆。在这里，我们通过开发和验证BaseScope-一种新的突变特异性RNA原位杂交试验来解决这些不足。我们针对存档的结直肠癌样本中BRAF、KRAS和PIK3CA癌基因的公共点突变，以精确绘制突变亚克隆的空间和形态背景。计算模型表明，亚克隆必须出现得足够早，或者具有相当大的适应性优势，才能形成大的或空间上不同的亚克隆。观察到在小地形地区分离的假定的治疗耐药细胞的例子。BaseScope试验代表了原位突变检测的重大技术进步，为肿瘤的演变提供了新的见解，并可能对选择患者进行治疗产生影响。分析肿瘤内遗传异质性的方法通常不能保存肿瘤亚克隆的空间背景。在这里，作者提出了一种突变特异性RNA原位杂交方法BaseScope，并对结直肠癌和腺瘤KRAS、BRAF和PIK3CA驱动基因突变亚克隆进行了空间定位。
Intra-tumor heterogeneity (ITH) is a major underlying cause of therapy resistance and disease recurrence, and is a read-out of tumor growth. Current genetic ITH analysis methods do not preserve spatial context and may not detect rare subclones. Here, we address these shortfalls by developing and validating BaseScope—a novel mutation-specific RNA in situ hybridization assay. We target common point mutations in the BRAF, KRAS and PIK3CA oncogenes in archival colorectal cancer samples to precisely map the spatial and morphological context of mutant subclones. Computational modeling suggests that subclones must arise sufficiently early, or carry a considerable fitness advantage, to form large or spatially disparate subclones. Examples of putative treatment-resistant cells isolated in small topographical areas are observed. The BaseScope assay represents a significant technical advance for in situ mutation detection that provides new insight into tumor evolution, and could have ramifications for selecting patients for treatment. Methods that analyze intra-tumor genetic heterogeneity often do not preserve the spatial context of tumor subclones. Here, the authors present BaseScope, a mutation-specific RNA in situ hybridization assay and spatially map colorectal cancer and adenoma KRAS, BRAF and PIK3CA driver gene mutant subclones.
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影响因子：
--
作者：
Gay, Laura;Baker, Ann-Marie;Graham, Trevor A
通讯作者：
Graham, Trevor A
DOI：
10.1073/pnas.1220353110
发表时间：
2013-07-02
影响因子：
11.1
作者：
Humphries, Adam;Cereser, Biancastella;Graham, Trevor A.
通讯作者：
Graham, Trevor A.
影响因子：
21.3
作者：
Vermeulen, Louis;Melo, Felipe De Sousa E.;Medema, Jan Paul
通讯作者：
Medema, Jan Paul
影响因子：
64.8
作者：
Wang, Yong;Waters, Jill;Leung, Marco L.;Unruh, Anna;Roh, Whijae;Shi, Xiuqing;Chen, Ken;Scheet, Paul;Vattathil, Selina;Liang, Han;Multani, Asha;Zhang, Hong;Zhao, Rui;Michor, Franziska;Meric-Bernstam, Funda;Navin, Nicholas E.
通讯作者：
Navin, Nicholas E.
影响因子：
29.4
作者：
Galandiuk, Susan;Rodriguez-Justo, Manuel;Graham, Trevor A.
通讯作者：
Graham, Trevor A.