MET Receptor Sequence Variants R970C and T992I Lack Transforming Capacity
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 r...
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Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2010-08, Vol.70 (15), p.6233-6237 |
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creator | TYNER, Jeffrey W FLETCHER, Luke B LORIAUX, Marc M WANG, Ellen Q YANG, Wayne F RUTENBERG-SCHOENBERG, Michael L BEADLING, Carol MORI, Motomi HEINRICH, Michael C DEININGER, Michael W DRUKER, Brian J |
description | 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. |
doi_str_mv | 10.1158/0008-5472.can-10-0429 |
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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. 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Drug treatments ; Phosphorylation ; Polymorphism, Single Nucleotide ; Protein Isoforms ; Proto-Oncogene Proteins c-met - genetics ; Proto-Oncogene Proteins c-met - metabolism ; Receptors, Growth Factor - genetics ; Receptors, Growth Factor - metabolism ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2010-08, Vol.70 (15), p.6233-6237</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c506t-22efd5a65ea0c664020a924723df472e9bd8c2b8a34f989babd30eb977e70f153</citedby><cites>FETCH-LOGICAL-c506t-22efd5a65ea0c664020a924723df472e9bd8c2b8a34f989babd30eb977e70f153</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23074444$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20670955$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>TYNER, Jeffrey W</creatorcontrib><creatorcontrib>FLETCHER, Luke B</creatorcontrib><creatorcontrib>LORIAUX, Marc M</creatorcontrib><creatorcontrib>WANG, Ellen Q</creatorcontrib><creatorcontrib>YANG, Wayne F</creatorcontrib><creatorcontrib>RUTENBERG-SCHOENBERG, Michael L</creatorcontrib><creatorcontrib>BEADLING, Carol</creatorcontrib><creatorcontrib>MORI, Motomi</creatorcontrib><creatorcontrib>HEINRICH, Michael C</creatorcontrib><creatorcontrib>DEININGER, Michael W</creatorcontrib><creatorcontrib>DRUKER, Brian J</creatorcontrib><title>MET Receptor Sequence Variants R970C and T992I Lack Transforming Capacity</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>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.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphorylation</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein Isoforms</subject><subject>Proto-Oncogene Proteins c-met - genetics</subject><subject>Proto-Oncogene Proteins c-met - metabolism</subject><subject>Receptors, Growth Factor - genetics</subject><subject>Receptors, Growth Factor - metabolism</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkVFPwjAUhRujEUR_gqYvPg7vunZbX0zMgkqCmiD62tx1HU5hw3aY8O_tAqK-tGnvOef2fiXkPIRhGIr0CgDSQPCEDTXWQQgBcCYPSD8UURoknItD0t9reuTEuXd_FCGIY9JjECcgheiT8cNoRqdGm1XbWPpsPtem1oa-oq2wbh2dygQyinVBZ1KyMZ2g_qAzi7UrG7us6jnNcIW6ajen5KjEhTNnu31AXm5Hs-w-mDzdjbObSaAFxG3AmCkLgbEwCDqOOTBAyfwbo6L0q5F5kWqWpxjxUqYyx7yIwOQySUwCpZ9uQK63uat1vjSFNnVrcaFWtlqi3agGK_W_Uldvat58KSbDiCexDxDbAG0b56wp994QVMdWddxUx01lN4_dbcfW-y7-Nt67fmB6weVOgE7jovSUdOV-dRH4f-E8-gbdZYHV</recordid><startdate>20100801</startdate><enddate>20100801</enddate><creator>TYNER, Jeffrey W</creator><creator>FLETCHER, Luke B</creator><creator>LORIAUX, Marc M</creator><creator>WANG, Ellen Q</creator><creator>YANG, Wayne F</creator><creator>RUTENBERG-SCHOENBERG, Michael L</creator><creator>BEADLING, Carol</creator><creator>MORI, Motomi</creator><creator>HEINRICH, Michael C</creator><creator>DEININGER, Michael W</creator><creator>DRUKER, Brian J</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20100801</creationdate><title>MET Receptor Sequence Variants R970C and T992I Lack Transforming Capacity</title><author>TYNER, Jeffrey W ; FLETCHER, Luke B ; LORIAUX, Marc M ; WANG, Ellen Q ; YANG, Wayne F ; RUTENBERG-SCHOENBERG, Michael L ; BEADLING, Carol ; MORI, Motomi ; HEINRICH, Michael C ; DEININGER, Michael W ; DRUKER, Brian J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c506t-22efd5a65ea0c664020a924723df472e9bd8c2b8a34f989babd30eb977e70f153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Neoplasms - genetics</topic><topic>Neoplasms - metabolism</topic><topic>Pharmacology. 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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. 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subjects | Amino Acid Sequence Animals Antineoplastic agents Biological and medical sciences Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Humans Medical sciences Mice Neoplasms - genetics Neoplasms - metabolism Pharmacology. Drug treatments Phosphorylation Polymorphism, Single Nucleotide Protein Isoforms Proto-Oncogene Proteins c-met - genetics Proto-Oncogene Proteins c-met - metabolism Receptors, Growth Factor - genetics Receptors, Growth Factor - metabolism Tumors |
title | MET Receptor Sequence Variants R970C and T992I Lack Transforming Capacity |
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