MET Receptor Sequence Variants R970C and T992I Lack Transforming Capacity

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BlankMET Receptor Sequence Variants R970C and T992I Lack Transforming Capacity

1.. W. Tyner1,4,

2.. Luke B. Fletcher1,4,

3.. Ellen Q. Wang1,4,

4.. Wayne F. Yang1,4,

5.. L. Rutenberg-Schoenberg1,4,

6.. Carol Beadling2,4,

7.. Motomi Mori3,4,

8.. C. Heinrich2,4,

9.. W. Deininger1,4,

10.. J. Druker1,4,5, and

11.. Marc M. Loriaux1,4,6

+ Author Affiliations

1.. Authors' Affiliations:1Division of Hematology and Medical Oncology, Oregon

Health and Science University; 2Portland Veterans Affairs Medical Center;

3Division of Biostatistics, Department of Public Health & Preventive Medicine,

Oregon Health and Science University; 4Oregon Health and Science University

Knight Cancer Institute; 5 Medical Institute; and 6Department of

Pathology, Oregon Health and Science University, Portland, Oregon

1.. Corresponding Author:

W. Tyner, Oregon Health and Science University Knight Cancer

Institute, 3181 SW Sam Park Road, Mailcode L592, Portland, OR 97239.

Phone: 503-494-9188; Fax: 503-494-3688; E-mail: tynerj@....

1.. Note: J.W. Tyner and L.B. Fletcher contributed equally to this work.

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. Cancer Res; 70(15);

6233–7. ©2010 AACR.