title: 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.
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Magyar, Hungary.|Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary.
authors.forename: Ádám
authors.initials: Á
authors.lastname: Nagy
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Magyar, Hungary.|Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary.
authors.forename: Lőrinc Sándor
authors.initials: LS
authors.lastname: Pongor
authors.affiliation: Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Szabó
authors.affiliation: Medical Oncology Unit, Department of Human Pathology 'G. Barresi', University of Messina, Italy.
authors.forename: Mariacarmela
authors.initials: M
authors.lastname: Santarpia
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Magyar, Hungary.|Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm
keywords: Cox regression; Mann-Whitney analysis; SNP; TCGA; biomarker; lung cancer; microarrays; mutation; survival