Selective analysis of cancer-cell intrinsic transcriptional traits defines novel clinically relevant subtypes of colorectal cancer.
Selective analysis of cancer-cell intrinsic transcriptional traits defines novel clinically relevant subtypes of colorectal cancer.
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DOI：
10.1038/ncomms15107
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发表时间：
2017-05-31
影响因子：
16.6
通讯作者：
Bertotti A
中科院分区：
文献类型：
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作者：
Isella C;Brundu F;Bellomo SE;Galimi F;Zanella E;Porporato R;Petti C;Fiori A;Orzan F;Senetta R;Boccaccio C;Ficarra E;Marchionni L;Trusolino L;Medico E;Bertotti A
基质含量严重影响结直肠癌 (CRC) 的转录分类，具有临床和生物学意义。因此，谱系依赖性基质转录成分可能主导癌细胞固有的更微妙的表达特征。由于在患者来源的异种移植物 (PDX) 中，人类肿瘤的基质细胞被小鼠对应物取代，因此我们在这里部署 CRC PDX 的人类特异性表达谱来评估癌细胞内在转录特征。通过这种方法，我们确定了五种CRC内在亚型（CRIS），这些亚型具有独特的分子、功能和表型特征：（i）CRIS-A：粘液型、糖酵解型、富含微卫星不稳定性或KRAS突变； (ii) CRIS-B：TGF-β途径活性，上皮-间质转化，预后不良； (iii) CRIS-C：EGFR 信号转导、对 EGFR 抑制剂的敏感性升高； (iv) CRIS-D：WNT激活、IGF2基因过表达和扩增； (v) CRIS-E：潘氏细胞样表型，TP53 突变。 CRIS 亚型成功地对原发性和转移性 CRC 的独立组进行了分类，与现有转录类别的重叠有限，并且具有前所未有的预测和预后性能。基质细胞对结直肠癌 (CRC) 分子亚型进行分类的基因表达谱做出贡献。在这里，来自患者的异种移植物使作者能够通过排除小鼠基质细胞的转录本来获得癌细胞特异性转录组，并据此定义 CRC 内在亚型 (CRIS) 并评估其预后和预测潜力。
Stromal content heavily impacts the transcriptional classification of colorectal cancer (CRC), with clinical and biological implications. Lineage-dependent stromal transcriptional components could therefore dominate over more subtle expression traits inherent to cancer cells. Since in patient-derived xenografts (PDXs) stromal cells of the human tumour are substituted by murine counterparts, here we deploy human-specific expression profiling of CRC PDXs to assess cancer-cell intrinsic transcriptional features. Through this approach, we identify five CRC intrinsic subtypes (CRIS) endowed with distinctive molecular, functional and phenotypic peculiarities: (i) CRIS-A: mucinous, glycolytic, enriched for microsatellite instability or KRAS mutations; (ii) CRIS-B: TGF-β pathway activity, epithelial–mesenchymal transition, poor prognosis; (iii) CRIS-C: elevated EGFR signalling, sensitivity to EGFR inhibitors; (iv) CRIS-D: WNT activation, IGF2 gene overexpression and amplification; and (v) CRIS-E: Paneth cell-like phenotype, TP53 mutations. CRIS subtypes successfully categorize independent sets of primary and metastatic CRCs, with limited overlap on existing transcriptional classes and unprecedented predictive and prognostic performances. Stromal cells contribute to the gene expression profiles based on which colorectal cancer (CRC) molecular subtypes are classified. Here, patient-derived xenografts enable the authors to obtain cancer cell-specific transcriptomes by excluding transcripts from murine stromal cells, based on which they define CRC intrinsic subtypes (CRIS) and evaluate their prognostic and predictive potential.