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The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma.

ABSTRACT: KRAS mutant non-small cell lung cancers (NSCLCs) vary in clinical outcome depending on which specific KRAS mutation is present. Shorter progression free survival has been associated with KRAS variants G12C and G12V. Cell lines with these variants depend to a greater extent on the RAS/RAF/MEK/ERK signaling pathway and become more susceptible to MEK inhibition. Because different KRAS mutations may lead to altered drug sensitivity, we aimed to determine specific KRAS mutation status in a NSCLC patient cohort at our institution. A total of 502 NSCLC samples were screened for somatic mutations using the 50 gene AmpliSeq™ Cancer Hotspot Panel v2 (CHPv2). However only samples positive for variants in the KRAS gene were included in this study. Variants identified in the KRAS genes were curated using publicly available databases. The overall mutation rate in the KRAS gene was 32.7% (164/502). The most common KRAS mutations were G12C (41%), G12V (19%), and G12D (14%) along with less frequent variants. After re-mining our sequencing data, we found that more than a half of our KRAS mutant NSCLC patients could potentially benefit from the addition of a MEK inhibitor such as selumetinib to standard chemotherapeutic agents. Due to mutated KRAS, these patients will likely fail traditional anti-EGFR therapies but be eligible for newer combination therapies.

SUBMITTER: Biernacka A

PROVIDER: S-EPMC5506544 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma.

Biernacka Anna A Tsongalis Peter D PD Peterson Jason D JD de Abreu Francine B FB Black Candice C CC Gutmann Edward J EJ Liu Xiaoying X Tafe Laura J LJ Amos Christopher I CI Tsongalis Gregory J GJ

Cancer genetics 20160318 5

KRAS mutant non-small cell lung cancers (NSCLCs) vary in clinical outcome depending on which specific KRAS mutation is present. Shorter progression free survival has been associated with KRAS variants G12C and G12V. Cell lines with these variants depend to a greater extent on the RAS/RAF/MEK/ERK signaling pathway and become more susceptible to MEK inhibition. Because different KRAS mutations may lead to altered drug sensitivity, we aimed to determine specific KRAS mutation status in a NSCLC pati ...[more]

PMID: 27068338

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Project description:IntroductionIn lung adenocarcinoma, the mutational spectrum is dominated by EGFR and KRAS mutations. Improved knowledge about genomic and transcriptional alterations in and between mutation-defined subgroups may identify genes involved in disease development or progression.MethodsGenomic profiles from 457 adenocarcinomas, including 113 EGFR-mutated, 134 KRAS-mutated and 210 EGFR and KRAS-wild type tumors (EGFRwt/KRASwt), and gene expression profiles from 914 adenocarcinomas, including 309 EGFR-mutated, 192 KRAS-mutated, and 413 EGFRwt/KRASwt tumors, were assembled from different repositories. Genomic and transcriptional differences between the three mutational groups were analyzed by both supervised and unsupervised methods.ResultsEGFR-mutated adenocarcinomas displayed a larger number of copy number alterations and recurrent amplifications, a higher fraction of total loss-of-heterozygosity, higher genomic complexity, and a more distinct expression pattern than EGFR-wild type adenocarcinomas. Several of these differences were also consistent when the three mutational groups were stratified by stage, gender and smoking status. Specific copy number alterations were associated with mutation status, predominantly including regions of gain with the highest frequency in EGFR-mutated tumors. Differential regions included both large and small regions of gain on 1p, 5q34-q35.3, 7p, 7q11.21, 12p12.1, 16p, and 21q, and losses on 6q16.3-q21, 8p, and 9p, with 20-40% frequency differences between the mutational groups. Supervised gene expression analyses identified 96 consistently differentially expressed genes between the mutational groups, and together with unsupervised analyses these analyses highlighted the difficulty in broadly resolving the three mutational groups into distinct transcriptional entities.ConclusionsWe provide a comprehensive overview of the genomic and transcriptional landscape in lung adenocarcinoma stratified by EGFR and KRAS mutations. Our analyses suggest that the overall genomic and transcriptional landscape of lung adenocarcinoma is affected, but only to a minor extent, by EGFR and KRAS mutation status.

Project description:Anti-EGFR targeted therapy is of increasing importance in advanced colorectal cancer and prior KRAS mutation testing is mandatory for therapy. However, at which occasions this should be performed is still under debate. We aimed to assess in patients with locally advanced rectal cancer whether there is intra-specimen KRAS heterogeneity prior to and upon preoperative chemoradiotherapy (CRT), and if there are any changes in KRAS mutation status due to this intervention.KRAS mutation status analyses were performed in 199 tumor samples from 47 patients with rectal cancer. To evaluate the heterogeneity between different tumor areas within the same tumor prior to preoperative CRT, 114 biopsies from 34 patients (mean 3 biopsies per patient) were analyzed (pre-therapeutic intratumoral heterogeneity). For the assessment of heterogeneity after CRT residual tumor tissue (85 samples) from 12 patients (mean 4.2 tissue samples per patient) were analyzed (post-therapeutic intratumoral heterogeneity) and assessment of heterogeneity before and after CRT was evaluated in corresponding patient samples (interventional heterogeneity). Primer extension method (SNaPshot™) was used for initial KRAS mutation status testing for Codon 12, 13, 61, and 146. Discordant results by this method were reevaluated by using the FDA-approved KRAS Pyro Kit 24, V1 and the RAS Extension Pyro Kit 24, V1 Kit (therascreen® KRAS test).For 20 (43%) out of the 47 patients, a KRAS mutation was detected. With 12 out of 20, the majority of these mutations affected codon 35. We did not obtained evidence that CRT results in changes of the KRAS mutation pattern. In addition, no intratumoral heterogeneity in the KRAS mutational status could be proven. This was true for both the biopsies prior to CRT and the resection specimens thereafter. The discrepancy observed in some samples when using the SNaPshot™ assay was due to insufficient sensitivity of this technique upon massive tumor regression by CRT as application of the therascreen® KRAS test revealed concordant results.Our results indicate that the KRAS mutation status at the primary tumor site of rectal cancer is homogenous. Its assessment for therapeutic decisions is feasible in pre-therapeutic biopsies as well as in post-therapeutic resected specimens. The amount of viable tumor cells seems to be an important determinant for assay sensitivity and should thus be considered for selection of the analytical method.

Project description:KRAS mutation testing helps oncologists decide whether patients diagnosed with metastatic colorectal cancer (CRC) should be treated with epidermal growth factor receptor (EGFR) inhibitors. These drugs block the EGFR signaling pathway in tumor cells, and thus can slow tumor progression. Mutated KRAS is found in 30?45% of all CRC tumors, with mutations occurring at codons 12 and 13 being the most common. Patients with a mutated KRAS found in tumor tissue show limited clinical response to EGFR inhibitor therapy. Several factors can influence the results of KRAS mutation testing in tumor specimens. Variation can result from tumor heterogeneity, sample handling, DNA preparation, and differences in assay design and methodology. The purpose of this study was to evaluate comparability of KRAS test results among five labs currently used to determine KRAS mutation status of colorectal cancer specimens in a large multi-center study.Three commercial labs (Genzyme, Clarient, Quest Diagnostics), one clinical lab (Henry Ford Health System), and one research lab (Oregon Health Sciences University) were contracted to analyze KRAS mutational status; all are Clinical Laboratory Improvement Amendments (CLIA) certified. Twenty formalin-fixed paraffin-embedded (FFPE) human CRC samples that had been previously tested for KRAS mutations were selected based on mutation status (7 wild type samples, 7 with codon 12 mutations, and 6 with codon 13 mutations) from two clinical settings (Kaiser Permanente Colorado and Northwest). To ensure sufficient sample quantity, only surgical specimens from colon resections were used. Before being sent to each lab, the FFPE samples were reviewed by a pathologist to determine that the sample was of sufficient quality and quantity for testing. We asked each lab to use their standard clinical testing procedures. Clarient uses a polymerase chain reaction (PCR) method for mutation detection, Genzyme uses single nucleotide primer extension assay with fragment analysis by capillary electrophoresis, and the other three labs all use sequencing. Preliminary data (n=11 samples tested to date) suggests good agreement across laboratories despite differences in mutation detection methodologies.

Dataset Information

The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma.

Publications

The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma.

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