TY - JOUR
T1 - Integrating RAS Status into Prognostic Signatures for Adenocarcinomas of the Lung
AU - Starmans, Maud H. W.
AU - Pintilie, Melania
AU - Chan-Seng-Yue, Michelle
AU - Moon, Nathalie C.
AU - Haider, Syed
AU - Nguyen, Francis
AU - Lau, Suzanne K.
AU - Liu, Ni
AU - Kasprzyk, Arek
AU - Wouters, Bradly G.
AU - Der, Sandy D.
AU - Shepherd, Frances A.
AU - Jurisica, Igor
AU - Penn, Linda Z.
AU - Tsao, Ming-Sound
AU - Lambin, Philippe
AU - Boutros, Paul C.
PY - 2015/3/15
Y1 - 2015/3/15
N2 - Purpose: While the dysregulation of specific pathways in cancer influences both treatment response and outcome, few current prognostic markers explicitly consider differential pathway activation. Here we explore this concept, focusing on K-Ras mutations in lung adenocarcinoma (present in 25%-35% of patients). Experimental Design: The effect of K-Ras mutation status on prognostic accuracy of existing signatures was evaluated in 404 patients. Genes associated with K-Ras mutation status were identified and used to create a RAS pathway activation classifier to provide a more accurate measure of RAS pathway status. Next, 8 million random signatures were evaluated to assess differences in prognosing patients with or without RAS activation. Finally, a prognostic signature was created to target patients with RAS pathway activation. Results: We first show that K-Ras status influences the accuracy of existing prognostic signatures, which are effective in K-Raswild-type patients but fail in patients with K-Ras mutations. Next, we show that it is fundamentally more difficult to predict the outcome of patients with RAS activation (RAS(mt)) than that of those without (RAS(wt)). More importantly, we demonstrate that different signatures are prognostic in RAS(wt) and RAS(mt). Finally, to exploit this discovery, we create separate prognostic signatures for RAS(wt) and RAS(mt) patients and show that combining them significantly improves predictions of patient outcome. Conclusions: We present a nested model for integrated genomic and transcriptomic data. This model is general and is not limited to lung adenocarcinomas but can be expanded to other tumor types and oncogenes.
AB - Purpose: While the dysregulation of specific pathways in cancer influences both treatment response and outcome, few current prognostic markers explicitly consider differential pathway activation. Here we explore this concept, focusing on K-Ras mutations in lung adenocarcinoma (present in 25%-35% of patients). Experimental Design: The effect of K-Ras mutation status on prognostic accuracy of existing signatures was evaluated in 404 patients. Genes associated with K-Ras mutation status were identified and used to create a RAS pathway activation classifier to provide a more accurate measure of RAS pathway status. Next, 8 million random signatures were evaluated to assess differences in prognosing patients with or without RAS activation. Finally, a prognostic signature was created to target patients with RAS pathway activation. Results: We first show that K-Ras status influences the accuracy of existing prognostic signatures, which are effective in K-Raswild-type patients but fail in patients with K-Ras mutations. Next, we show that it is fundamentally more difficult to predict the outcome of patients with RAS activation (RAS(mt)) than that of those without (RAS(wt)). More importantly, we demonstrate that different signatures are prognostic in RAS(wt) and RAS(mt). Finally, to exploit this discovery, we create separate prognostic signatures for RAS(wt) and RAS(mt) patients and show that combining them significantly improves predictions of patient outcome. Conclusions: We present a nested model for integrated genomic and transcriptomic data. This model is general and is not limited to lung adenocarcinomas but can be expanded to other tumor types and oncogenes.
U2 - 10.1158/1078-0432.CCR-14-1749
DO - 10.1158/1078-0432.CCR-14-1749
M3 - Article
C2 - 25609067
SN - 1078-0432
VL - 21
SP - 1477
EP - 1486
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -