Publication details
MUTANT KRAS AND BRAF GENE EXPRESSION PROFILES IN COLORECTAL CANCER: RESULTS OF THE TRANSLATIONAL STUDY ON THE PETACC 3-EORTC 40993-SAKK 60-00 TRIAL
| Authors | |
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| Year of publication | 2010 |
| Type | Conference abstract |
| MU Faculty or unit | |
| Citation | |
| Description | Background: KRAS and BRAF activating mutations (mut) are frequent in colorectal cancer (CRC). Both genes act in the ERK pathway, but they occur in different CRC subtypes and have different prognostic implications, suggesting they might entail disruptions in different signaling pathways. Results: KRAS mut were found in 37%, BRAF mut in 8%. Outcome correlations were reported (Roth A,JCO 2010). To date, 244 hybridized samples were analyzed (25 BRAF mut, 91 KRAS mut), additional samples are ongoing. (a) Gene expression downstream of KRAS and BRAF mut is highly different (common 6 genes, different 166). Supervised classification using 42 genes achieved an AUC of 0.98 (95% CI: 0.97-0.99) in separating KRAS from BRAF mut. (b) BRAF mut induce highly consistent gene expression changes (in 725 genes, 1% FDR) in comparison to wt, allowing trained classifiers to discriminate BRAF mut from wt with an AUC of 0.94 (95% CI:0.92-0.96), using 30 selected genes. The differential gene expression downstream of BRAF indicates unique activation of key developmental pathways, including Wnt, TGF-beta and MAPK. (c) KRAS mut tumors are heterogeneous in their gene expression signatures.The AUC of trained classifier (KRAS mut vs. wt) was 0.73 (95% CI:0.69-0.76), using 148 selected genes, indicating that the signatures explain a large part of the variance, but there is additional heterogeneity within the KRAS mut and wt subgroups. Conclusions: KRAS and BRAF mutations induce very different downstream gene activation in CRC. The strikingly uniform and novel BRAF mut downstream gene signature, might lead to novel therapeutic avenues for these aggressive tumors. |