Unknown,Transcriptomics,Genomics,Proteomics

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Genome and transcriptome integrative study to identify a likely driver of cell proliferation in lung adenocarcinoma (CIT - Homo sapiens - APUP)

ABSTRACT: A Cartes d'Identite des Tumeurs (CIT) project from the French National League Against Cancer (http://cit.ligue-cancer.net ) : 165 lung adenocarcinomas without prior chemotherapy, hybridized on Illumina SNP HumanCNV370 and Affymetrix HGU133Plus2 arrays. Project leader : Prof. Pierre FOURET (pierre.fouret@igr.fr). Note: Bronchiolo-alveolarComponent : a non invasive tumor component shown in well differentiated tumor cells. EGFR Gene Mutation Status: Gene mutation status of epidermal growth factor receptor (erythroblastic leukemia viral (v; -erb-b) ; oncogene homolog, avian) ; HGNC:3236 ; Approved Symbol:EGFR; Chromosome:7p12 ; UniProt ; ID:P00533 ; OMIMID:131550 ; EntrezGeneID:1956 ; ; RefSeq:NM_201283 ; M=mutated ; WT=non mutated=wild type. KRAS Gene Mutation Status: Gene mutation status of v-Ki-ras2 Kirsten rat ; sarcoma viral oncogene homolog ; HGNC:6407 ; Approved Symbol:KRAS ; Chromosome:12p12.1 ; UniProtID:P01116; OMIM ID:190070 ; EntrezGeneID:3845 ; ;RefSeq:NM_033360 ; M=yes=mutated ; WT=non mutated.

ORGANISM(S): Homo sapiens

SUBMITTER: Fabien PETEL

PROVIDER: E-MTAB-923 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:INTRODUCTION: CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. METHODS: We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non-small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. RESULTS: p16 inactivation was the major mechanism of RB pathway perturbation in non-small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. CONCLUSION: Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status. 40 NSCLC cell lines were profiled on Illumina WG6-V3 expression arrays. They consist of 4 groups of 10 cell lines each: non-smokers with EGFR mutation, non-smokers with EGFR wild-type, smokers with KRAS mutation, smokers with KRAS wild-type. Note that smoking status is not always clear.

Project description:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. Here, we assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Good response was associated with 12p12.1 copy number loss, even in patients with a KRAS mutation, while copy number gain in wild-type KRAS patients was correlated with a poor response. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good response. In wild-type KRAS patients, miRNA expression did not predict response in a multivariate model. Thus, assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of patients eligible for anti-EGFR therapy. Copy number detection was performed using NimbleScan and Nexus software Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 metastisized colorectal cancer patients in a phase III trial (CKTO 2005-02; ClinTrials.gov NCT00208546) of the Dutch Colorectal Cancer Group (DCCG), who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab.

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Genome and transcriptome integrative study to identify a likely driver of cell proliferation in lung adenocarcinoma (CIT - Homo sapiens - APUP)

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