title: MET receptor sequence variants R970C and T992I lack transforming capacity.
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.
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon 97239, USA. tynerj@ohsu.edu
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Luke B
authors.initials: LB
authors.lastname: Fletcher
authors.forename: Ellen Q
authors.initials: EQ
authors.lastname: Wang
authors.forename: Wayne F
authors.initials: WF
authors.lastname: Yang
authors.forename: Michael L
authors.initials: ML
authors.lastname: Rutenberg-Schoenberg
authors.forename: Carol
authors.initials: C
authors.lastname: Beadling
authors.forename: Motomi
authors.initials: M
authors.lastname: Mori
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D017978:Receptors, Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met