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.Despite advances in the last decade, lung cancer remains the most lethal tumor in women and men still exceeding the combined mortality of breast, prostate, colorectal and pancreatic cancers.1 Non-small cell lung cancer (NSCLC) accounts for nearly 85% of all lung cancer cases and is further classified into different subtypes including adenocarcinoma (AC), squamous cell carcinoma and large cell carcinoma.

muTarget: A platform linking gene expression changes and mutation status in solid tumors

“…We previously demonstrated that by linking different types of data—somatic mutations and gene expression—it is possible to identify genes with prognostic relevance. We performed such studies on KRAS in lung adenocarcinoma patients 32 and on NPM1 in acute myeloid leukemia, 33 and potential druggable target genes were identified in breast 34 and colon cancer 35 . Finally, somatic mutations associated with elevated PD‐L1 expression were identified in gastric cancer 36 .…”

Stability Indicating and Cost-Effective Analytical Method Development and Validation of Sotorasib by Using Rp-HPLC

“…Sotorasib, sold under the brand name Lumakras is an anti-cancer medication [1,2] used to treat non-small-cell lung cancer (NSCLC) [3,4]. It targets a specific mutation, G12C, in the protein KRAS [5,6] , which is responsible for various forms of cancer [7]. The most common side effects include diarrhea [8], musculoskeletal pain [9], nausea [10], fatigue [11,12], and liver damage [13] and cough [14].…”

Non-small cell lung cancer

“…Various clinical trials are underway to investigate whether NOTCH blockade using γ-secretase inhibitors improves cancer treatment [48]. However, one of the major challenges on the way is the untoward side effects associated with NOTCH inhibitors, especially the cytotoxicity in the gastrointestinal tract [49]. Most of the available γ-secretase inhibitors are originally engineered for treatment of Alzheimer's diseases and therefore are designed for long-term and systemic treatments and are able to pass the blood brain barrier.…”

“…It seems plausible, that combination therapy targeting dually and specifically stem cells and non-stem cells, would be required to be successful in, or at least be closer to, eradicating cancer [48]. There is now mounting evidence that the normal stem cell pathways such as Wnt, Notch and Hh (Hedgehog) are deregulated and mutated in cancer and cancer stem cells [49]. NOTCH signaling plays a role in the maintenance of cancer stem cells in different cancer types including T-ALL [50], brain [51], breast [52], colon [53] and lung cancer [54].…”

“…Recently, resistance against Osimertinib has been observed as well (C797S mutation) [47] emphasizing that tumor evolution is a continuous process and that treatments imposes a selection pressure for the development of resistant subclones. Recent studies have postulated (as discussed in chapter 2) that "cancer mutation signatures" are more predictive for treatment response than single mutation status [48] and other groups have reported that they are predictive of prognosis [49]. This brings us back the essence of cancer development: the multistep acquisition of mutations in gene pathways, encompassing the hallmarks of cancers, driving the adenoma-carcinoma sequence leading to invasive metastatic cancer [50].…”