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. 2010 Aug 1;70(15):6233-7.
doi: 10.1158/0008-5472.CAN-10-0429.

MET receptor sequence variants R970C and T992I lack transforming capacity

Jeffrey W Tyner  1 , Luke B Fletcher, Ellen Q Wang, Wayne F Yang, Michael L Rutenberg-Schoenberg, Carol Beadling, Motomi Mori, Michael C Heinrich, Michael W Deininger, Brian J Druker, Marc M Loriaux
Affiliations

MET receptor sequence variants R970C and T992I lack transforming capacity

Jeffrey W Tyner et al. Cancer Res. .

Abstract

High-throughput sequencing promises to accelerate the discovery of sequence variants, but distinguishing oncogenic mutations from irrelevant "passenger" mutations remains a major challenge. Here we present an analysis of two sequence variants of the MET receptor (hepatocyte growth factor receptor) R970C and T992I (also designated R988C and T1010I). Previous reports indicated that these sequence variants are transforming and contribute to oncogenesis. We screened patients with chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, thyroid cancer, or melanoma, as well as individuals without cancer, and found these variants at low frequencies in most cohorts, including normal individuals. No evidence of increased phosphorylation or transformative capacity by either sequence variant was found. Because small-molecule inhibitors for MET are currently in development, it will be important to distinguish between oncogenic sequence variants and rare single-nucleotide polymorphisms to avoid the use of unnecessary, and potentially toxic, cancer therapy agents.

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Figures

Figure 1
Figure 1. Characterization of MET Sequence Variants in Ba/F3 Cells
(A) Ba/F3 cells overexpressing human or murine METWT, human METR970C, human METT992I, murine MetR968C, murine MetT990I, or TPR-MET were plated in media without IL-3. Cells were counted daily for one week. Values represent mean ± s.e.m. (n=3). * indicates p < 0.002 with t-test in comparison to human METWT. (B) Whole cell lysates from 293 T17 cells overexpressing human METWT, METR970C, METT992I, or TPR-MET were subjected to immunoblot analysis with antibodies specific for phospho-tyrosine (4G10), phoshpo-MET, total MET, or β-actin. (C) Densitometric analysis of immunoblots shown in panel (B). Phospho-MET is normalized to total MET and values are expressed as fold of WT. Values represent mean ± s.e.m. (n=3). * indicates p < 0.05 with t-test in comparison to human METWT.
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