Genome wide SNP comparative analysis between EGFR and KRAS mutated NSCLC and characterization of two models of oncogenic cooperation in non-small cell lung carcinoma

Blons, Hélène; Pallier, Karine; Corre, Delphine Le; Danel, Claire; Tremblay-Gravel, Maxime; Houdayer, Claude; Fabre-Guillevin, Élizabeth; Riquet, Marc; Dessen, Philippe; Laurent‐Puig, Pierre

doi:10.1186/1755-8794-1-25

Cited by 33 publications

(38 citation statements)

References 31 publications

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“…Homozygous deletion was seen only at 9p21.3 including CDKN2A and limited to EGFR -mutated tumours among ALK fusion-negative neoplasms as reported in the literature [44] and also seen in ALK -fusion positive ones . That deletion of 9p23-24.1 and 13q14.2 including tumour suppressor genes was rare in ALK fusion-positive tumours suggests that they can grow even if the functions of these suppressor genes are retained.…”

Section: Discussionmentioning

confidence: 71%

Allelotypes of lung adenocarcinomas featuring ALK fusion demonstrate fewer onco- and suppressor gene changes

et al. 2013

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BackgroundA subset of lung adenocarcinomas harboring an EML4-ALK fusion gene resulting in dominant oncogenic activity has emerged as a target for specific therapy. EML4-ALK fusion confers a characteristic histology and is detected more frequently in never or light smokers and younger patients.MethodsTo gain insights into etiology and carcinogenic mechanisms we conducted analyses to compare allelotypes of 35 ALK fusion-positive and 95 -negative tumours using single nucleotide polymorphism (SNP) arrays and especially designed software which enabled precise global genomic profiling.ResultsOverall aberration numbers (gains + losses) of chromosomal alterations were 8.42 and 9.56 in tumours with and without ALK fusion, respectively, the difference not being statistically significant, although patterns of gain and loss were distinct. Interestingly, among selected genomic regions, oncogene-related examples such as 1p34.3(MYCL1), 7q11.2(EGFR), 7p21.1, 8q24.21(MYC), 16p13.3, 17q12(ERBB2) and 17q25.1 showed significantly less gain. Also, changes in tumour suppressor gene-related regions, such as 9p21.3 (CDKN2A) 9p23-24.1 (PTPRD), 13q14.2 (RB1), were significantly fewer in tumours with ALK fusion.ConclusionGlobal genomic comparison with SNP arrays showed tumours with ALK fusion to have fewer alterations in oncogenes and suppressor genes despite a similar overall aberration frequency, suggesting very strong oncogenic potency of ALK activation by gene fusion.

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Section: Discussionmentioning

confidence: 71%

Allelotypes of lung adenocarcinomas featuring ALK fusion demonstrate fewer onco- and suppressor gene changes

et al. 2013

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“…The ATM missense p.F858L is known to impact the interaction of ATM with beta-adaptin, which is necessary for clatherin mediated receptor endocytosis and is proposed to contribute to the hereditary radio sensitivity and breast cancer3738. In addition to breast cancer-associated variants, a missense substitution in STK11 , p.H175Y, previously reported in a lung carcinoma39 was been found in one patient. One non-TNBC patient carried simultaneously pathogenic variants in BRCA1 and ATM .…”

Section: Resultsmentioning

confidence: 85%

Novel Insights into Breast Cancer Genetic Variance through RNA Sequencing

Horvath

Pakala

Mudvari

et al. 2013

Sci Rep

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Using RNA sequencing of triple-negative breast cancer (TNBC), non-TBNC and HER2-positive breast cancer sub-types, here we report novel expressed variants, allelic prevalence and abundance, and coexpression with other variation, and splicing signatures. To reveal the most prevalent variant alleles, we overlaid our findings with cancer- and population-based datasets and validated a subset of novel variants of cancer-related genes: ESRP2, GBP1, TPP1, MAD2L1BP, GLUD2 and SLC30A8. As a proof-of-principle, we demonstrated that a rare substitution in the splicing coordinator ESRP2 (R353Q) impairs its ability to bind to its substrate FGFR2 pre-mRNA. In addition, we describe novel SNPs and INDELs in cancer relevant genes with no prior reported association of point mutations with cancer, such as MTAP and MAGED1. For the first time, this study illustrates the power of RNA-sequencing in revealing the variation landscape of breast transcriptome and exemplifies analytical strategies to search regulatory interactions among cancer relevant molecules.

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“…Prognostic markers have not been specifically studied in EGFR mutated cancers and could help classify this new entity [3]. In a previous work, using SNP array, we showed that tumors with EGFR mutations had a copy number increase of a region on chromosome 7 (7p21.1-7p15.3) encompassing the TWIST1 gene, a highly conserved basic helix-loop-helix transcription factor regulator of embryogenesis [4]. This was confirmed on CGH arrays with 40% of EGFR mutated tumors showing copy number increase of this region.…”

Section: Introductionmentioning

confidence: 96%

TWIST1 a New Determinant of Epithelial to Mesenchymal Transition in EGFR Mutated Lung Adenocarcinoma

et al. 2012

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Metastasis is a multistep process and the main cause of mortality in lung cancer patients. We previously showed that EGFR mutations were associated with a copy number gain at a locus encompassing the TWIST1 gene on chromosome 7. TWIST1 is a highly conserved developmental gene involved in embryogenesis that may be reactivated in cancers promoting both malignant conversion and cancer progression through an epithelial to mesenchymal transition (EMT). The aim of this study was to investigate the possible implication of TWIST1 reactivation on the acquisition of a mesenchymal phenotype in EGFR mutated lung cancer. We studied a series of consecutive lung adenocarcinoma from Caucasian non-smokers for which surgical frozen samples were available (n = 33) and showed that TWIST1 expression was linked to EGFR mutations (P<0.001), to low CDH1 expression (P<0.05) and low disease free survival (P = 0.044). To validate that TWIST1 is a driver of EMT in EGFR mutated lung cancer, we used five human lung cancer cell lines and demonstrated that EMT and the associated cell mobility were dependent upon TWIST1 expression in cells with EGFR mutation. Moreover a decrease of EGFR pathway stimulation through EGF retrieval or an inhibition of TWIST1 expression by small RNA technology reversed the phenomenon. Collectively, our in vivo and in vitro findings support that TWIST1 collaborates with the EGF pathway in promoting EMT in EGFR mutated lung adenocarcinoma and that large series of EGFR mutated lung cancer patients are needed to further define the prognostic role of TWIST1 reactivation in this subgroup.

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Genome wide SNP comparative analysis between EGFR and KRAS mutated NSCLC and characterization of two models of oncogenic cooperation in non-small cell lung carcinoma

Cited by 33 publications

References 31 publications

Allelotypes of lung adenocarcinomas featuring ALK fusion demonstrate fewer onco- and suppressor gene changes

Allelotypes of lung adenocarcinomas featuring ALK fusion demonstrate fewer onco- and suppressor gene changes

Novel Insights into Breast Cancer Genetic Variance through RNA Sequencing

TWIST1 a New Determinant of Epithelial to Mesenchymal Transition in EGFR Mutated Lung Adenocarcinoma

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