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Retrospective Review of MET Gene Mutations

2015-05-14 00:01:15

Oncoscience; 2015; 2(5): 533–541



Maryam Zenali, James deKay, Zesheng Liu, Stanley Hamilton, Zhuang Zuo, Xinyan Lu, Rania Bakkar, Gordon Mills, Russell Broaddus



Abstract



C-MET proto-oncogene is a tyrosine kinase situated on chromosome 7. C-MET and its ligand hepatocyte growth factor/scatter factor (HGF/SF) play a role in proliferation, differentiation and organ development. C-MET genetic aberrations are found associated with driving tumorigenesis. In this retrospective study, we reviewed molecular analysis data gathered from a cancer institute during a two-year period (2010-2012). Upon detection of tumors harboring c-MET mutations, we determined the status of the other mutations tested and evaluated c-MET expression by fluorescent in-situ hybridization (FISH). Our search resulted in identification of 134 c-MET mutations, 44% of which had mutations of at least one of the other genes tested. No c-MET expression aberrancy was detected in this subset by FISH. Survival amongst the patients with surgically resected metastatic colorectal cancers (CRC) was slightly better in those with only a c-MET mutation compared to those with no mutation detected, although the difference was not statistically significant. When c-MET inhibition becomes an integrated part of chemotherapy practice, our observed frequency of co-mutations will be an argument for utilizing c-MET targeted treatment in combination with other targeted drugs and therapeutic strategies. Larger studies can aid to further parse out c-MET prognostic and therapeutic significance.



INTRODUCTION



C-MET tyrosine kinase was first discovered in the1980s. C-MET and its ligand HGF/SF are essential cellular components during embryogenesis, morphogenesis, and development of organs such as liver, skeletal muscle, and placenta. C-MET aberrations at the genetic level or post-translational overexpression of the receptor have been studied in many tumors; association of these alterations with oncogenesis and tumor progression has been proposed.



C-MET, as detailed in a study by Ma et. al, contains 3 main structural domains: an extracellular Sema domain (Exon 2), a juxtamembrane domain (Exons 14/15) and a tyrosine kinase domain where many of the c-MET mutations have been reported. Activation of c-MET is achieved via HGF/SF binding which results in a variety of actions depending on the cellular context, varying from proliferation, motility and differentiation in wild type cells to invasion and metastasis in neoplastic cells. In tyrosine kinase pathways where c-MET is a component, ligand binding precedes receptor dimerization. Mutations in these or associated genes circumvent the appropriate ligand dependent regulation. C-MET activation can occur by amplification/overexpression, activating point mutations, paracrine signaling or over expression of its ligand hepatocyte growth factor/scatter factor.



C-Met signaling has been implicated in a variety of malignancies, including gastrointestinal, genitourinary, breast, gynecologic, pulmonary, head and neck cancers and melanoma. Its genetic aberrations have been reported in a small percentage of this wide variety of tumors. Certain c-MET mutations are found to be germline with unknown transforming activity while others are implicated in driving neoplasia.



Availability HGF/SF-MET inhibitors with a range of potencies and specificities has provided a base for assessing their therapeutic value, and initial clinical trials have shown benefit from these treatments in several tumor types. Since c-MET signaling converges with a multitude of pathways, it can lead to activation of several downstream effectors. This diversity substantiates the efforts of c-MET targeting, but biochemical crosstalk between pathways with potential neoplastic rescue process argues for combination chemotherapy.



In this retrospective study we reviewed molecular diagnostic data resulting from a series of mutational analysis during the 2010-2012 period in a cancer center institution. The primary objective was to gain insight into patterns of c-MET mutations and patterns and frequency of co-mutations. We also compared survival outcome in metastatic colorectal adenocarcinoma between those harboring only c-MET mutations as opposed to those with no mutations detected on a 14-gene test.



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Key Words



C-MET | co-mutations | FISH | targeted therapy