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c-MET Pathway Mutation PCR Array

Human
 
qBiomarker Somatic Mutation PCR Array: Human c-MET Pathway
c-MET (also known as MET, HGFR) is a membrane receptor essential for embryonic development and wound healing. Hepatocyte growth factor (HGF) is the only known ligand of the c-MET receptor. c-MET is deregulated in many types of human malignancies, including cancers of the kidneys, liver, stomach, breast, and brain. Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active c-MET triggers tumor growth, angiogenesis and metastasis. c-MET activation triggers several key downstream oncogenic pathways including the Ras-MAPK, PI3K, STAT, beta-catenin, and Notch pathways.

The Human c-MET Pathway qBiomarker Somatic Mutation PCR Array is a translational research tool that allows rapid and accurate profiling of the somatic mutation status of the c-MET gene and additional key genes in two major c-MET downstream signaling pathways: the Ras-MAPK pathway and the PI3K pathway. The utility of individual and multiple somatic mutation status information in identifying key signaling transduction disruptions has been demonstrated in numerous research studies. For example, the mutation status of the EGFR and KRAS genes can predict the physiological response to certain drugs targeting these molecules. The c-MET Pathway qBiomarker Somatic Mutation PCR Array, with its comprehensive content coverage, is designed for studying mutations in the context of the c-MET pathway and has the potential for discovering drug target biomarkers for a variety of human cancers involving the c-MET signaling pathway and downstream effectors. This array covers 83 DNA sequence mutation assays designed to detect the most frequent, functionally verified, and biologically most significant mutations in the c-MET pathway. These mutations were chosen from curated, comprehensive somatic mutation databases and peer-reviewed scientific literature. The simplicity of the product format and operating procedure allows routine somatic mutation profiling in any research laboratory with access to real-time PCR instruments.

The qBiomarker Somatic Mutation PCR Arrays are intended for molecular biology applications. This product is not intended for the diagnosis, prevention, or treatment of a disease.

 

Assay Functional Annotations How It Works References Resources
 
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c-MET gene:
The assays included in this panel detect the most frequently identified c-MET gain-of-function mutations, such as the
tyrosine kinase domain and juxtamembrane domain point mutations.

AKT gene:
The mutation assay detects the best known AKT1 mutation, c.49G>A, p.E17K. This is a PH domain mutation that
results in constitutive targeting of AKT1 to plasma membrane.

BRAF gene:
Two classes of mutation assays are included. One class covers mutations that lead to increased BRAF kinase
activity, such as the p.V600 mutations. The other class detects mutations that lead to impaired kinase activity, such
as the p.G469A mutation.

KRAS gene:
12 KRAS mutation assays provide comprehensive analysis capacity for the most frequently occurring mutations in
KRAS codon positions 12, 13, and 61. Mutations at these positions result in reduced intrinsic GTPase activity and/or
cause KRAS to become unresponsive to RasGAP.

HRAS gene:
Similar to KRAS mutation assays, the 8 HRAS mutation assays on this panel aim to cover the most important HRAS
mutations identified in cancers at codon 12, 13, and 61 positions.

NRAS gene:
10 NRAS mutation assays are included on the panel to cover codon positions 12, 13, and 61.

MEK1 gene:
4 assays for mutations with significance in cancer were included on this panel. These mutations cluster in MEK1 Nterminal negative regulatory domain and an adjacent domain, and are all activating mutations (i.e. lead to upregulated intrinsic MEK1 kinase activity).

PIK3CA (phosphatidylinositol 3-kinase catalytic subunit) gene:
The mutation assays covered on this panel can detect 6 of the most frequently occurring PIK3CA mutations that
belong to two classes: p.H1047 mutations, which are activating, kinase domain mutations; and mutations in P539-
E545 region, which are helical domain mutations that mimic activation by growth factors.

PTEN gene:
Included on the panel are 6 most commonly detected PTEN loss-of-function mutations that are due to either
truncation (p.R233* and p.R130*) or point mutation-caused phosphatase inactivation (p.R130 and p.R173
mutations).

PTPN11 gene:
The 15 assays included in this panel detect the most frequently identified PTPN11 mutations, such as lesions
affecting residues located in or close to the N-terminal SH2 domain/PTP-interacting surface, and mutations that
affect residues that control substrate specificity.

VHL gene:
Included on the panel are 6 most commonly detected VHL point mutations or truncation mutations that lead to loss of
tumor suppressor function of the VHL protein.

 

Assay Functional Annotations How It Works References Resources
 

Overview of the qBiomarker Somatic Mutation PCR Array / Assay Protocol

Overview of the qBiomarker Somatic Mutation PCR Array / Assay Protocol.
The procedure involves DNA extraction (QIAGEN QIAamp DNA Mini Kit or FFPE Tissue Kit is recommended), an optional amplification (QIAGEN REPLI-g kit or REPLI-g UltraFast kit is recommended) step for DNA isolated from fresh samples, qPCR detection on qBiomarker Somatic Mutation PCR Arrays or Assays, and data analysis (using the qBiomarker Somatic Mutation Data Analysis Template). An optional DNA sample QC step immediately before the detection array or assay setup allows the user to qualify the DNA samples.

Principle of Mutant Discrimination with ARMS®

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Assay Functional Annotations How It Works References Resources
 
  1. Targeting the c-Met Signaling Pathway in Cancer. Peruzzi B, Bottaro DP. Molecular Pathways 2006 12:3657-3660
  2. The PKB/AKT pathway in cancer.Carnero A. Curr Pharm Des. 2010 Jan; 16(1):34-44.
  3. BRAF, a target in melanoma: implications for solid tumor drug development. Flaherty KT, McArthur G. Cancer. 2010 Jul 13. [Epub ahead of print].
  4. Clinical relevance of KRAS in human cancers. Jancík S, Drábek J, Radzioch D, Hajdúch M. J Biomed Biotechnol. 2010; 2010:150960.
  5. Oncogenic Ras in tumour progression and metastasis. Giehl K. Biol Chem. 2005 Mar; 386(3):193-205.
  6. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, Karpova MB, MacConaill LE, Zhang J, Gray NS, Sellers WR, Dummer R, Garraway LA. Proc Natl Acad Sci U S A. 2009 Dec 1; 106(48):20411-6.
  7. PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches. Ligresti G, Militello L, Steelman LS, Cavallaro A, Basile F, Nicoletti F, Stivala F, McCubrey JA, Libra M. Cell Cycle. 2009 May 1; 8(9):1352-8.
  8. Oncogenic mutations as predictive factors in colorectal cancer. Ličvre A, Blons H, Laurent-Puig P. Oncogene. 2010 May 27; 29(21):3033-43.
  9. PI(3)King Apart PTEN's Role in Cancer. Zhang S, Yu D. Clin Cancer Res. 2010 Jul 8. [Epub ahead of print].
  10. Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease. Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, Zampino G, Burgt I, Palleschi A, Petrucci TC, Sorcini M, Schoch C, Foŕ R, Emanuel PD, and Gelb BD. Am J Hum Genet. 2006 February; 78(2): 279–290.
  11. Role of VHL Gene Mutation in Human Cancer. Kim WY, Kaelin WG. J. Clinical Oncology. 2010 22:4991-5004
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Assay Functional Annotations How It Works References Resources
 

User Manual qBiomarker Somatic Mutation PCR Array System (PDF)
Data Analysis qBiomarker Somatic Mutation PCR Array Data Analysis Software
Application Data Detection Limits, Cancer Pathways
FAQ Frequently Asked Questions about Somatic Mutation Assays and Arrays
Webinar qBiomarker Somatic Mutation Analysis: Real-World Application Data
Slide Presentation> Presentation about qBiomarker Somatic Mutation Assays and Arrays (PDF)
Scientific Poster A Novel Tool for Pathway-Focused Cancer Mutation Profiling (PDF)
Presented at American Association for Cancer Research 2011
White Paper Rapid and accurate cancer somatic mutation profiling with the qBiomarker Somatic Mutation PCR Array (PDF)
Product Profile For screening biology-focused panels of gene mutations (PDF)

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