Cancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification.
Cancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification.
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DOI：
10.1038/ncomms15657
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发表时间：
2017-05-31
影响因子：
16.6
通讯作者：
Lawler M
中科院分区：
文献类型：
--
作者：
Dunne PD;Alderdice M;O'Reilly PG;Roddy AC;McCorry AMB;Richman S;Maughan T;McDade SS;Johnston PG;Longley DB;Kay E;McArt DG;Lawler M
基质源性肿瘤内异质性（ITH）已被证明会破坏将患者分子分层为适当的预后/预测亚组。在这里，使用几个临床相关的结直肠癌（CRC）基因表达的签名，我们评估了这些签名的易感性，使用基因表达微阵列数据从多个肿瘤区域的24例患者的队列，包括中央肿瘤，肿瘤浸润前沿和淋巴结转移的ITH的混杂效应。样本聚类以及相关评估显示，每个签名根据多区域数据集中的患者来源而不是来源区域对样本进行聚类的能力存在差异。发现集中于癌细胞内在基因表达的特征产生更临床有用的、以患者为中心的分类器，如CRC内在特征（CRIS）所例示的，其通过患者来源而不是来源区域来稳健地聚类样本。这些发现强调了癌细胞内在特征的潜力，通过最大限度地减少基质源性ITH的混淆效应，可靠地分层CRC患者。肿瘤表达谱目前用于预后和预测目的，而不考虑患者内的异质性。在这里，作者表明癌细胞特异性特征克服了肿瘤异质性效应，并导致结直肠癌患者的更好分类。
Stromal-derived intratumoural heterogeneity (ITH) has been shown to undermine molecular stratification of patients into appropriate prognostic/predictive subgroups. Here, using several clinically relevant colorectal cancer (CRC) gene expression signatures, we assessed the susceptibility of these signatures to the confounding effects of ITH using gene expression microarray data obtained from multiple tumour regions of a cohort of 24 patients, including central tumour, the tumour invasive front and lymph node metastasis. Sample clustering alongside correlative assessment revealed variation in the ability of each signature to cluster samples according to patient-of-origin rather than region-of-origin within the multi-region dataset. Signatures focused on cancer-cell intrinsic gene expression were found to produce more clinically useful, patient-centred classifiers, as exemplified by the CRC intrinsic signature (CRIS), which robustly clustered samples by patient-of-origin rather than region-of-origin. These findings highlight the potential of cancer-cell intrinsic signatures to reliably stratify CRC patients by minimising the confounding effects of stromal-derived ITH. Tumour expression profiling is currently used for prognostic and predictive purposes without taking into account the intra patient heterogeneity. Here the authors show that cancer cell specific signatures overcome the tumour heterogeneity effect and result in better classification of colorectal cancer patients.