Isoform specific gene expression analysis of KRAS in the prognosis of lung adenocarcinoma patients

In Seok Yang,Sangwoo Kim

doi:10.1186/s12859-018-2011-y

Abstract

BackgroundAberrant mutations in KRAS play a critical role in tumor initiation and progression, and are a negative prognosis factor in lung adenocarcinoma (LUAD).ResultsUsing genomic analysis for K-Ras isoforms (K-Ras4A and K-Ras4B) and large-scale multi-omics data, we inspected the overall survival (OS) and disease-free survival (DFS) of LUAD patients based on the abundance of transcript variants by analyzing RNA expression and somatic mutation data from The Cancer Genome Atlas (n = 516). The expression of the minor transcript K-Ras4A and its proportion were positively correlated with the presence of KRAS mutations in LUAD. We found that both K-Ras4A abundance measures (expression and proportion) have a strong association with poor OS (p = 0.0149 and p = 3.18E-3, respectively) and DFS (p = 3.03E-4 and p = 0.0237, respectively), but only in patients harboring KRAS mutations. A Cox regression analysis showed significant results in groups with low expression (hazard ratio (HR) = 2.533, 95% confidence interval (CI) = 1.380−4.651, p = 2.72E-3) and low proportion (HR = 2.549, 95% CI = 1.387−4.684, p = 2.58E-3) of K-Ras4A.ConclusionsBased on the above results, we report the possible use of abundance measures for K-Ras4A for predicting the survival of LUAD patients with KRAS mutations.

Highlights

Aberrant mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in tumor initiation and progression, and are a negative prognosis factor in lung adenocarcinoma (LUAD)
We found that the abundance measurements for the K-Ras4A isoform are strongly associated with the presence of KRAS mutations as well as a positive prognosis for lung cancer patients harboring KRAS mutations
Expression levels and proportions of K-Ras isoforms The distributions for expression levels (A) and proportions (B) of the two K-Ras isoforms for the LUAD cancer types are shown in Fig. 1, where the K-Ras4B isoform was observed as a major type as reported in a previous study [13]

Summary

Introduction

Aberrant mutations in KRAS play a critical role in tumor initiation and progression, and are a negative prognosis factor in lung adenocarcinoma (LUAD). KRAS mutations are present in approximately 30% of cases of lung cancer [1,2,3,4], in which amino acid alterations from Gly to Ala, Cys, Asp, and Val are most frequently detected. Mutated KRAS has been shown to play a critical role in cancer initiation and maintenance by modulating oncogenic downstream effectors including Raf and PI3K, followed by the Raf/ MEK/ERK and the PI3K/Akt pathways, respectively [5]. KRAS amplification has been known to be frequently occurred in non-small cell lung cancer (NSCLC) [9, 10], of which the prevalence was reported to approximately 15%, revealing one of the common molecular alterations in NSCLC.

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