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<p>Abstract</p> <p>Background</p> <p>Colon cancer has been classically described by clinicopathologic features that permit the prediction of outcome only after surgical resection and staging.</p> <p>Methods</p> <p>We performed an <it>unsupervised </it>analysis of microarray data from 326 colon cancers to identify the first principal component (PC1) of the most variable set of genes. PC1 deciphered two primary, <it>intrinsic </it>molecular subtypes of colon cancer that predicted disease progression and recurrence.</p> <p>Results</p> <p>Here we report that the most dominant pattern of intrinsic gene expression in colon cancer (PC1) was tightly correlated (Pearson R = 0.92, P < 10^-135) with the EMT signature-- both in gene identity and directionality. In a global micro-RNA screen, we further identified the most anti-correlated microRNA with PC1 as MiR200, known to regulate EMT.</p> <p>Conclusions</p> <p>These data demonstrate that the biology underpinning the native, molecular classification of human colon cancer--previously thought to be highly heterogeneous-- was clarified through the lens of comprehensive transcriptome analysis.</p>