KRAS driven expression signature has prognostic power superior to mutation status in non‐small cell lung cancer

Abstract

KRAS is the most frequently mutated oncogene in non‐small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer.We divided NSCLC patients with mutation and RNA‐seq data into KRAS mutated and wild type groups. Mann‐Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a “transcriptomic fingerprint” of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using univariate and multivariate Cox regression analysis.Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3 and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p < 0.01). The KRAS signature also remained significant (p < 0.01) in a multivariate analysis including age, gender, smoking history and tumor stage.We generated a “surrogate signature” of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself.

Molecular epidemiology and diagnostics of KRAS mutations in human cancer

“…An analysis of the TCGA’s KRAS mutant lung adenocarcinoma cohort defined a 4-gene signature of mutant tumors (overexpressing FOXRED2, TOP1, PEX3, and ABL2). This was completely different from KRAS-amplified or KRAS wild-type deleted groups [ 31 ]. In another study of large public datasets of the KRAS mutant lung adenocarcinoma [ 32 ], three subtypes were observed based on gene expression signatures, which were also characterized by different co-mutations, i.e., cluster1/CDKN2A/2B-mutant/LOH, cluster 2/TP53 mutant, and cluster3/LKB1 mutant (Table 3 ).…”

Drug Resistance in Non-Small Cell Lung Cancer: A Potential for NOTCH Targeting?

“…Better and more holistic approaches have been proposed showing that a “cancer mutation signature” is more predictive for treatment response than the individual mutation status ( 27 ). In KRAS -driven NSCLC, the signature— FOXRED2, KRAS, TOP1, PEX3 , and ABL2 —was more predictive for prognosis than the single mutation status of KRAS ( 28 ). An RNA-sequence-based prognostic model built with four genes ( RHOV, CD109, FRRS1 , and LINC00941 ) was statistically associated with worse OS and metastasis-free survival, and is able to stratify patients bearing KRAS or EGFR mutations versus their wild-type counterparts in OS outcome ( 29 ).…”

A case report of tongue metastasis from lung squamous cell carcinoma and literature review

“…[ 18 ] Current research suggests that KRAS mutation is the main driver of poor prognosis in patients with NSCLC, and also may be a common cause of cancer recurrence, but unfortunately, no drugs are available that directly address KRAS mutation. [ 19 , 20 ] Mutations leading to the inactivation of Tp53 had also been shown to be frequent in human lung SCCs, and may lead to expansion of mutant stem cell clones. [ 21 ] This would lead to disease progression.…”