Data from Coevolution of Atypical <i>BRAF</i> and <i>KRAS</i> Mutations in Colorectal Tumorigenesis
Woolley CE., Domingo E., Fernandez-Tajes J., Pennel KAF., Roxburgh P., Edwards J., Richman SD., Maughan TS., Kerr DJ., Soriano I., Tomlinson IPM.
<div>Abstract<p><i>BRAF</i> mutations in colorectal cancer comprise three functional classes: class 1 (V600E) with strong constitutive activation, class 2 with pathogenic kinase activity lower than that of class 1, and class 3 which paradoxically lacks kinase activity. Non–class 1 mutations associate with better prognosis, microsatellite stability, distal tumor location, and better anti-EGFR response. An analysis of 13 colorectal cancer cohorts (<i>n</i> = 6,605 tumors) compared class 1 (<i>n</i> = 709, 10.7% of colorectal cancers), class 2 (<i>n</i> = 31, 0.47%), and class 3 (<i>n</i> = 81, 1.22%) mutations. Class 2–mutant and class 3–mutant colorectal cancers frequently co-occurred with additional Ras pathway mutations (29.0% and 45.7%, respectively, vs. 2.40% in class 1; <i>P</i> < 0.001), often at atypical sites (<i>KRAS</i> noncodon 12/13/61, <i>NRAS</i>, or <i>NF1</i>). Ras pathway activation was highest in class 1 and lowest in class 3, with a greater distal expression of EGFR ligands (amphiregulin/epiregulin) supporting weaker <i>BRAF</i> driver mutations. Unlike class 1 mutants, class 3 tumors resembled chromosomally unstable colorectal cancers in mutation burdens, signatures, driver mutations, and transcriptional subtypes, whereas class 2 mutants displayed intermediate characteristics. Atypical <i>BRAF</i> mutations were associated with longer overall survival than class 1 mutations (HR = 0.25; <i>P</i> = 0.011) but lost this advantage in cancers with additional Ras mutations (HR = 0.94; <i>P</i> = 0.86). This study supports the suggestion that class 3 <i>BRAF</i> mutations amplify existing Ras signaling in a two-mutation model and that the enhancement of weak/atypical Ras mutations may suffice for tumorigenesis, with potentially clinically important heterogeneity in the class 2/3 subgroup.</p><p><b>Implications:</b> The heterogeneous nature of <i>BRAF</i>-mutant colorectal cancers, particularly among class 2/3 mutations which frequently harbor additional Ras mutations, highlights the necessity of comprehensive molecular profiling.</p></div>