A colorectal cancer classification system that associates cellular phenotype and responses to therapy.
A colorectal cancer classification system that associates cellular phenotype and responses to therapy.
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结直肠癌（CRC）是癌症死亡的主要原因。有些病人对治疗反应良好，有些则不然，因此需要更精确、个性化的治疗策略。为此，我们使用基于共识的无监督聚类分析了1290例结直肠癌肿瘤的基因表达谱。由此产生的簇然后与80例患者对表皮生长因子受体靶向药物西妥昔单抗的治疗反应数据相关联。这些研究的结果定义了六种临床相关的CRC亚型。每种亚型与正常结肠隐窝内的不同细胞类型有相似之处，并表现出不同程度的“干性”和Wnt信号。亚型特异性基因特征被提出来识别这些亚型。三种亚型在手术切除后有明显更好的无病生存（DFS），这表明当这些患者有局限性疾病时，可能免于化疗的不良影响。这三种亚型中的一种，通过丝蛋白A的表达确定，对西妥昔单抗没有反应，但在转移情况下可能对cMET受体酪氨酸激酶抑制剂有反应。另外两种亚型，低和中等DFS，在辅助或转移情况下与对化疗方案FOLFIRI的改善反应相关。开发针对这些亚型的临床可部署的检测方法和针对亚型的治疗方法可能有助于更有效地管理这种具有挑战性的疾病。
Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor–targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of ‘stemness’ and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease.
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影响因子：
46.9
作者：
通讯作者：
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影响因子：
37.3
作者：
Banerjea A;Ahmed S;Hands RE;Huang F;Han X;Shaw PM;Feakins R;Bustin SA;Dorudi S
通讯作者：
Dorudi S
影响因子：
8.4
作者：
André, T;Louvet, C;de Gramont, A
通讯作者：
de Gramont, A
影响因子：
5.8
作者：
Benito, M;Parker, J;Marron, JS
通讯作者：
Marron, JS
影响因子：
64.5
作者：
Schwitalla, Sarah;Fingerle, Alexander A.;Greten, Florian R.
通讯作者：
Greten, Florian R.