Clinical validation study of RAKSET-B, a multiple detection kit for BRAF and RAS gene mutations in colorectal cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2637999 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Primary outcome(s): Concordance rate of both KRAS and NRAS gene exon 2, 3 and 4 mutations between standard genetic testings including sanger sequencing and an established in vitro diagnostic (IVD) kit for KRAS exon2, and a newly developed Luminex-based all RAS assay kit
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Project description:BACKGROUND. Poorly-differentiated (PDTC) and anaplastic (ATC) thyroid cancers are rare and frequently lethal tumors, which so far have not been subjected to comprehensive genetic characterization. METHODS. We performed next generation sequencing of 341 cancer genes in 117 PDTCs and ATCs, and a transcriptomic analysis of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas (TCGA) study of papillary thyroid cancers (PTC). RESULTS. ATCs have a greater mutation burden than PDTCs, and higher mutation frequency of TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits and histone methyltransferases. BRAF and RAS are the predominant drivers, and dictate remarkably distinct tropism for nodal vs. distant metastases in PDTC. RAS and BRAF sharply distinguish between PDTCs defined by the Turin (PDTC-Turin) vs. MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, are markedly enriched in PDTCs and ATCs, and have a striking pattern of co-occurrence with RAS. TERT promoter mutations are rare and subclonal in PTCs, whereas they are clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) shows a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs are BRAF-like irrespective of driver mutation. CONCLUSIONS. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared to PDTC underscore their greater virulence and higher mortality. 37 tumor specimens, including 17 poorly-differentiated and 20 anaplastic thyroid cancers were expression-profiled with Affymetrix U133 plus 2.0 array
2016-02-15 | E-GEOD-76039 | biostudies-arrayexpress
Project description:BRAFV600E mutation is the most frequent molecular event in papillary thyroid carcinoma. The relation of this genetic alteration with the factors od poor prognosis has been reported as well as its influence on PTC gene signature. However human material disables distinction of cancer causes from its effect. We used our transgenic mouse model of papillary thyroid carcinoma induced by the BRAFV600E mutation to select BRAFV600E-specifi gene signature which was than compared to human material The human microarray data were obtained for: 27 papillary thyroid carcinomas including 18 BRAF(+), 8 RET(+), 1 RAS(+); 18 apparently healthy thyroids. In order to find BRAFV600E-specific gene signature data obtained from our transgenic mouse model of PTC were compared to human material. The analyses were performed taking into account not only the BRAF mutation but also other PTC initiating events including RET rearrangements and RAS poin mutations. Morover the microarray data were validated with the QPCR reaction.
2015-12-31 | E-GEOD-58545 | biostudies-arrayexpress
Project description:BACKGROUND. Poorly-differentiated (PDTC) and anaplastic (ATC) thyroid cancers are rare and frequently lethal tumors, which so far have not been subjected to comprehensive genetic characterization. METHODS. We performed next generation sequencing of 341 cancer genes in 117 PDTCs and ATCs, and a transcriptomic analysis of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas (TCGA) study of papillary thyroid cancers (PTC). RESULTS. ATCs have a greater mutation burden than PDTCs, and higher mutation frequency of TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits and histone methyltransferases. BRAF and RAS are the predominant drivers, and dictate remarkably distinct tropism for nodal vs. distant metastases in PDTC. RAS and BRAF sharply distinguish between PDTCs defined by the Turin (PDTC-Turin) vs. MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, are markedly enriched in PDTCs and ATCs, and have a striking pattern of co-occurrence with RAS. TERT promoter mutations are rare and subclonal in PTCs, whereas they are clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) shows a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs are BRAF-like irrespective of driver mutation. CONCLUSIONS. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared to PDTC underscore their greater virulence and higher mortality.
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Project description:The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a novel function of eIF4F in the negative regulation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for maintaining optimal ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.
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Project description:Oncogenic activating mutations in Ras genes are among the most common drivers of human disease. Treating mouse skin with the chemical carcinogen DMBA induces a characteristic mutation in Hras at codon 61. To understand how skin responds to a constitutive lack of Hras, we generated a cohort of Hras knockout mice.
2015-03-01 | GSE60769 | GEO
Project description:Human samples of various thyroid carcinomas, adenomas, and normals, each from a different patient, had mRNA assays performed using Affymetrix HG_U133A arrays, with 22283 probe-sets. The 99 samples consisted of 4 normals, 10 follicular adenomas, 13 follicular carcinomas, 7 oncocytic adenomas, 8 oncocytic carcinomas, 51 papillary carcinomas (each typed as having classical, follicular or tall cell morphology), 4 anaplastic carcinomas, and 2 medullary carcinomas. Interesting additional information on common mutations are provided including RAS mutation, BRAF mutation, RET/PTC rearrangements, and PAX8/PPARG translocations. Details of those assays are provided in our linked publications, as well as additional details on the specific mutations in a few special cases. No survival data is provided. Information for 93 of the 99 samples was previously made available on the web. The anaplastic and medullary carcinoma data were not previously shared. A supplementary Excel spreadsheet holding the same processed data as the series matrix file is provided and is more compact. The raw (.CEL) files are also provided. Human samples of various thyroid carcinomas, adenomas, and normals. The 99 samples consisted of 4 normals, 10 follicular adenomas, 13 follicular carcinomas, 7 oncocytic adenomas, 8 oncocytic carcinomas, 51 papillary carcinomas (each typed as having classical, follicular or tall cell morphology), 4 anaplastic carcinomas, and 2 medullary carcinomas. Additional information on common mutations are provided including RAS mutation, BRAF mutation, RET/PTC rearrangements, and PAX8/PPARG translocations.
2011-02-09 | E-GEOD-27155 | biostudies-arrayexpress
Project description:Results: In subjects who completed treatment and surgery, the pCR and near-complete response rates were 15.8% in HER2-negative and 50% in HER2-positive subjects. When stratified by genomic subtype, subjects of the HER2-enriched subtype had the best response (66.7%), the luminal A (11%) and B (4.8%) subtypes the poorest. Of 147 patients tested for p53 mutations using the AmpliChip test, 78 variants were detected; 55 were missense. The response rate among TP53 mutated patients was 30%, significantly higher than the rate in TP53 wild-type patients (10%, P = .0032). Concordance between AmpliChip mutation status versus IHC staining was 65%, with AmpliChip status being predictive of response and IHC status being not being predictive. Conclusion: Capecitabine plus docetaxel in HER2-negative subjects, and with trastuzumab in HER2-positive subjects, provided a good response rate with fewer cycles. p53 mutational analysis using the AmpliChip p53 assay, and genomic subtyping using the PAM50 assay, were promising predictive tests of response. reference x sample
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