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.

Tyrosine kinases play a critical role in numerous cellular processes (1). Therapies targeted to dysregulated kinases have proven more successful than conventional approaches (25). One emerging kinase target is the hepatocyte growth factor receptor MET, identified as part of the fusion oncogene, TPR-MET (6, 7). Subsequently, point mutations in MET were identified in renal papillary carcinoma (810). More recently, MET variants R970C and T992I (also designated R988C and T1010I) have been found in lung cancer cell lines, as well as individuals with lung, thyroid, renal, breast cancer, chronic lymphocytic leukemia (CLL), and lymphoma (1118). These variants have been characterized by Ba/F3 transformation and phospho-tyrosine immunoblots, among other assay systems, and were concluded to be transforming (13, 14).

To better understand the cancer genetics of these MET variants we determined R970 and T992 genotypes for patients with CLL, acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, thyroid cancer, or melanoma, as well as normal individuals. This process revealed low frequency METR970C and METT992I in most of the cohorts, including the normal individuals. Because these sequence variants were identified in a wide variety of different malignancies, including individuals without clinically detectable cancer, we hypothesized that these were rare single nucleotide polymorphisms not relevant to oncogenesis. In support of this hypothesis, we examined the human and murine versions of each of these sequence variants in Ba/F3 transformation assays, as well as for tyrosine phosphorylation status, and found no evidence of a transforming phenotype.

Plasmid construction

Human MET was purchased from Origene. Murine Met and TPR-MET were generously provided by Dr. George F. Vande Woude (Van Andel Research Institute, Grand Rapids, MI). All three genes were cloned into MSCV-IRES-green fluorescent protein using the Gateway Cloning system (Invitrogen Corporation). All point mutations were created using the Quikchange kit (Agilent Technologies) according to the manufacturer's instructions.

Cell culture

Ba/F3 cells were obtained from American Type Culture Collection and cultured in RPMI 1640 medium (Invitrogen) with 10% fetal bovine serum (FBS; Atlanta Biologicals), L-glutamine (Invitrogen), penicillin-streptomycin (Invitrogen), fungizone (Invitrogen), and WEHI-conditioned media. Ba/F3 cells were infected with retrovirus-expressing human or murine MET wild type (WT), R970C (R968C in murine version), T992I (T990I in murine version), or TPR-MET. Stable cell lines were sorted for green fluorescent protein expression on a FACSAria flow cytometer (BD Biosciences). Cells were counted daily using Guava ViaCount reagent and Guava Personal Cell Analysis flow cytometer (Guava Technologies).

WEHI-independence assays

Parental Ba/F3 cells or those expressing human or murine MET WT, R970C (R968C in murine version), T992I (T990I in murine version), or TPR-MET were washed three times and resuspended in RPMI media with 10% FBS, penicillin-streptomycin, and fungizone, and counted daily.

Immunoblotting

Human MET WT, R970C, T992I, or TPR-MET were transfected into 293 T17 cells using Fugene6 transfection reagent (Roche). After 48 hours, 293 T17 cells were lysed in lysis buffer (Cell Signaling), and diluted in sample buffer (75 mmol/L Tris pH 6.8, 3% SDS, 15% glycerol, 8% β-mercaptoethanol, 0.1% bromophenol blue). Whole cell lysates were separated by SDS-PAGE. Proteins were transferred to polyvinylidene fluoride (PVDF) membranes (Millipore) and subjected to immunoblot analysis with antibodies specific for phospho-tyrosine (4G10, Millipore), total or phospho-MET (Cell Signaling), or β-actin (Millipore).

Genotypic analysis

All patient material was deidentified and obtained with informed consent with approval from the institutional review board of Oregon Health & Science University. MET juxtamembrane and activation loop domains were sequenced in CLL, AML, CMML, and normal individuals as described (19). For colorectal, endometrial, thyroid, and melanoma patient samples, mass spectrometric genotyping of MET R970 and T992 was done with the Sequenom MassARRAY system and the OncoCarta assay panel (Sequenom) as described (20).

Statistical analysis

The incidence of METR970C and METT992I in each cohort was estimated by the proportion of individuals with mutations (i.e., the number of individuals with mutations divided by the total number of individuals in a cohort) and is expressed as a percentage. The 95% confidence intervals were calculated by using the exact binomial distribution. For Ba/F3 transformation experiments and densitometry of immunoblots, a Student's t test was done for each MET variant compared with METWT, and samples with a P value less than 0.05 were deemed significant.

To determine the frequency of the sequence variants METR970C and METT992I in patients with a variety of malignancies, we screened DNA from 96 CLL, 191 AML, 32 CMML, 109 colorectal cancer, 73 endometrial cancer, 168 thyroid cancer, and 115 melanoma patients, as well as 96 normal individuals. Screening of these cohorts revealed that all groups contained low frequency METR970C or METT992I sequence variants, and most cohorts contained both variants. Matched buccal cell samples were available for three cases exhibiting each variant (T992I, two melanoma and one endometrial cancer; R970C, two thyroid and one endometrial cancer), and all six cases showed presence of the variant allele in the germline material. Interestingly, we also identified one normal individual with METR970C and one normal individual with METT992I (Table 1). These alleles have not been detected previously in normal samples. Thus, our findings, as well as those by others, suggest these sequence variants occur at similar frequencies among many different types of malignancy as well as in individuals without cancer (Table 1; refs. 1118, 21). In addition, 95% confidence intervals of the incidence of each sequence variant are overlapping for each diagnosis compared with all other diagnoses and compared with the individuals without cancer (Table 1). This finding indicates a lack of evidence for statistically significant differences in the incidence of either sequence variant in individuals with or without cancer. Because we (and others) have also found that these variants are generally germline, we functionally characterized these variants for transforming capacity.

Table 1.

Incidence of MET Sequence Variants R970C and T992I in Normal and Cancer Specimens

Cohort (N)Incidence95% Exact CIReference
Incidence of R970C 
Normal (96) 1 (1%) 0-6% Reported here 
CLL (96) 0-4% Reported here 
AML (191) 0-2% Reported here 
CMML (32) 2 (6%) 0-21% Reported here 
Colorectal cancer (109) 1 (1%) 0-5% Reported here 
Endometrial cancer (73) 1 (1%) 0-7% Reported here 
Thyroid cancer (168) 2 (1%) 0-4% Reported here 
Melanoma (115) 1 (1%) 0-5% Reported here 
 
Total (880) 8 (0.9%) 0-2%  
Papillary renal carcinoma (129) 0-3% Schmidt et al. 1999 (15) 
Other solid tumors (201) 0-2% Schmidt et al. 1999 (15) 
Breast cancer (30) 0-12% Lee et al. 2000 (12) 
CLL (95) 0-4% Brown et al. 2008 (11) 
CLL (8) 1 (13%) 0-53% Tjin et al. 2006 (17) 
Follicular lymphoma (15) 1 (7%) 0-32% Tjin et al. 2006 (17) 
Burkitt's lymphoma (12) 1 (8%) 0-38% Tjin et al. 2006 (17) 
Diffuse large B-cell lymphoma (39) 1 (3%) 0-13% Tjin et al. 2006 (17) 
Small cell lung cancer (32) 0-11% Ma et al. 2003 (13) 
Non-small cell lung carcinoma (20) 0-17% Tengs et al. 2006 (16) 
Lung carcinoma (361) 0-1% Tengs et al. 2006 (16) 
Follicular carcinoma (21) 0-16% Wasenius et al. 2005 (18) 
Papillary carcinoma (53) 0-7% Wasenius et al. 2005 (18) 
Medullary carcinoma (13) 0-25% Wasenius et al. 2005 (18) 
Mesothelioma (43) 0-8% Jagadeeswaran et al. 2006 (21) 
Gastric carcinoma (85) 0-4% Lee et al. 2000 (12) 
Total (1,157) 4 (0.35%) 0-1%  
Incidence of T992I 
Normal (96) 1 (1%) 0-6% Reported here 
CLL (96) 2 (2%) 0-7% Reported here 
AML (191) 2 (1%) 0-4% Reported here 
CMML (32) 0-11% Reported here 
Colorectal Cancer (109) 0-3% Reported here 
Endometrial Cancer (73) 2 (3%) 0-10% Reported here 
Thyroid Cancer (168) 0-2% Reported here 
Melanoma (115) 2 (2%) 0-6% Reported here 
Total (880) 9 (1.0%) 0-2%  
Papillary renal carcinoma (129) 1 (1%) 0-4% Schmidt et al. 1999 (15) 
Other solid tumors (201) 0-2% Schmidt et al. 1999 (15) 
Breast cancer (30) 1 (3%) 0-17% Lee et al. 2000 (12) 
CLL (95) 1 (1%) 0-6% Brown et al. 2008 (11) 
Small cell lung cancer (32) 1 (3%) 0-16% Ma et al. 2003 (13) 
Non-small cell lung carcinoma (20) 1 (5%) 0-25% Tengs et al. 2006 (16) 
Lung carcinoma (361) 5 (1%) 0-3% Tengs et al. 2006 (16) 
Follicular carcinoma (21) 2 (10%) 1-30% Wasenius et al. 2005 (18) 
Papillary carcinoma (53) 3 (6%) 1-16% Wasenius et al. 2005 (18) 
Medullary carcinoma (13) 1 (8%) 0-36% Wasenius et al. 2005 (18) 
Mesothelioma (43) 0-8% Jagadeeswaran et al. 2006 (21) 
Gastric carcinoma (85) 0-5% Lee et al. 2000 (12) 
Total (1,083) 16 (1.5%) 0-2%  
Cohort (N)Incidence95% Exact CIReference
Incidence of R970C 
Normal (96) 1 (1%) 0-6% Reported here 
CLL (96) 0-4% Reported here 
AML (191) 0-2% Reported here 
CMML (32) 2 (6%) 0-21% Reported here 
Colorectal cancer (109) 1 (1%) 0-5% Reported here 
Endometrial cancer (73) 1 (1%) 0-7% Reported here 
Thyroid cancer (168) 2 (1%) 0-4% Reported here 
Melanoma (115) 1 (1%) 0-5% Reported here 
 
Total (880) 8 (0.9%) 0-2%  
Papillary renal carcinoma (129) 0-3% Schmidt et al. 1999 (15) 
Other solid tumors (201) 0-2% Schmidt et al. 1999 (15) 
Breast cancer (30) 0-12% Lee et al. 2000 (12) 
CLL (95) 0-4% Brown et al. 2008 (11) 
CLL (8) 1 (13%) 0-53% Tjin et al. 2006 (17) 
Follicular lymphoma (15) 1 (7%) 0-32% Tjin et al. 2006 (17) 
Burkitt's lymphoma (12) 1 (8%) 0-38% Tjin et al. 2006 (17) 
Diffuse large B-cell lymphoma (39) 1 (3%) 0-13% Tjin et al. 2006 (17) 
Small cell lung cancer (32) 0-11% Ma et al. 2003 (13) 
Non-small cell lung carcinoma (20) 0-17% Tengs et al. 2006 (16) 
Lung carcinoma (361) 0-1% Tengs et al. 2006 (16) 
Follicular carcinoma (21) 0-16% Wasenius et al. 2005 (18) 
Papillary carcinoma (53) 0-7% Wasenius et al. 2005 (18) 
Medullary carcinoma (13) 0-25% Wasenius et al. 2005 (18) 
Mesothelioma (43) 0-8% Jagadeeswaran et al. 2006 (21) 
Gastric carcinoma (85) 0-4% Lee et al. 2000 (12) 
Total (1,157) 4 (0.35%) 0-1%  
Incidence of T992I 
Normal (96) 1 (1%) 0-6% Reported here 
CLL (96) 2 (2%) 0-7% Reported here 
AML (191) 2 (1%) 0-4% Reported here 
CMML (32) 0-11% Reported here 
Colorectal Cancer (109) 0-3% Reported here 
Endometrial Cancer (73) 2 (3%) 0-10% Reported here 
Thyroid Cancer (168) 0-2% Reported here 
Melanoma (115) 2 (2%) 0-6% Reported here 
Total (880) 9 (1.0%) 0-2%  
Papillary renal carcinoma (129) 1 (1%) 0-4% Schmidt et al. 1999 (15) 
Other solid tumors (201) 0-2% Schmidt et al. 1999 (15) 
Breast cancer (30) 1 (3%) 0-17% Lee et al. 2000 (12) 
CLL (95) 1 (1%) 0-6% Brown et al. 2008 (11) 
Small cell lung cancer (32) 1 (3%) 0-16% Ma et al. 2003 (13) 
Non-small cell lung carcinoma (20) 1 (5%) 0-25% Tengs et al. 2006 (16) 
Lung carcinoma (361) 5 (1%) 0-3% Tengs et al. 2006 (16) 
Follicular carcinoma (21) 2 (10%) 1-30% Wasenius et al. 2005 (18) 
Papillary carcinoma (53) 3 (6%) 1-16% Wasenius et al. 2005 (18) 
Medullary carcinoma (13) 1 (8%) 0-36% Wasenius et al. 2005 (18) 
Mesothelioma (43) 0-8% Jagadeeswaran et al. 2006 (21) 
Gastric carcinoma (85) 0-5% Lee et al. 2000 (12) 
Total (1,083) 16 (1.5%) 0-2%  

Abbreviation: CI, confidence interval.

We created Ba/F3 cells stably expressing human or murine METWT, human METR970C, human METT992I, murine MetR968C, murine MetT990I, or TPR-MET and withdrew interleukin-3 (IL-3) from culture media. Ba/F3 cells that have been transformed by an oncogene such as TPR-MET are capable of proliferating without IL-3 as shown in Fig. 1A; however, we did not observe transformation by any of the full-length MET transgenes, including the sequence variants (Fig. 1A). Importantly, Ba/F3 cells are not a universally effective system for evaluation of tyrosine kinase oncogenicity, depending on the particular kinase and the physical location of the mutation in the protein. However, previous reports of the METR970C and METT992I variants suggested that these variants were capable of transforming Ba/F3 cells, hence this system was employed to directly test this prior claim (14). In addition to the Ba/F3 system, we next assessed the phosphorylation status of wild-type MET compared with each variant; a technique that was also previously used to show increased phosphorylation of these sequence variants (14). We expressed human METWT, METR970C, METT992I, or TPR-MET in 293 T17 cells and immunoblotted with antibodies specific for global phospho-tyrosine (4G10), phospho-MET, total MET, or β-actin. Although cells expressing TPR-MET exhibited markedly increased levels of global phosphotyrosine as well as phospho-MET, we did not observe any differences in phosphorylation levels with the MET R970C or T992I variants, again arguing against a direct transforming or dysregulated role for METR970C or METT992I (Fig. 1B and C).

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 1 week. Values represent mean ± standard error of the mean (SEM; 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 B. Phospho-MET is normalized to total MET, and values are expressed as fold of WT. Values represent mean ± SEM (n = 3). * indicates P < 0.05 with t test in comparison to human METWT.

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 1 week. Values represent mean ± standard error of the mean (SEM; 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 B. Phospho-MET is normalized to total MET, and values are expressed as fold of WT. Values represent mean ± SEM (n = 3). * indicates P < 0.05 with t test in comparison to human METWT.

Close modal

Several forms of MET have been implicated in oncogenesis, including fusion with TPR and point mutation at residues D1228, Y1230, and M1250 (6, 7, 9, 10). The capacity for METR970C and METT992I to contribute to oncogenesis has been a topic of debate. First identified by Schmidt and colleagues (15), METT992I was thought to represent a rare polymorphism, owing to lack of disease segregation and failure to induce focus formation or phosphorylation in NIH3T3 cells. Lee and colleagues also observed no functional consequence of these variants using similar assays, but did observe slightly faster tumor growth in nude mice (12). Consequences of these variants were identified in assays for cytoskeletal function (13, 14, 21). Of note, neither variant was previously observed in samples from healthy individuals (13, 14). We find no difference in transformative capacity or phosphorylation status of either variant compared with wild-type MET and suggest that these alleles are not transforming. This conclusion is also based on the presence of these variants in a wide variety of malignancies as well as individuals without cancer. We cannot rule out the possibility that these alleles may play a role in disease pathogenesis in some other manner, such as promoting changes in migration or differentiation. In this way, these alleles may predispose an individual toward cancer when combined with an oncogene that drives cellular proliferation. However, we find no evidence that these alleles directly promote transformation. Given the recent emergence of MET inhibitors as clinical cancer therapeutics (22), it will be important to carefully evaluate these alleles for their role in oncogenesis.

No potential conflicts of interest were disclosed.

Grant Support: The Leukemia and Lymphoma Society, the TJ Martell Foundation, and the Doris Duke Charitable Foundation. J. W. Tyner is supported by grants from the William Lawrence and Blanche Hughes Fund, and the Oregon Clinical and Translational Research Institute (OCTRI) grant number UL1 RR024140 from the National Center for Research Resources (NRCC), a component of the NIH, and NIH Roadmap for Medical Research. M. C. Heinrich is supported in part by a VA Merit Review Grant. B. J. Druker is an investigator of the Howard Hughes Medical Institute and principal investigator of the OHSU cancer center support grant 5 p30 CA069533. M. M. Loriaux is supported by the Leukemia and Lymphoma Society and the TJ Martell Foundation. Biostatistics support (M. Mori) is in part provided by the Biostatistics Shared Resource of the Knight Cancer Institute (5P50CA069533) and the Biostatistics & Design Program of the Oregon Clinical & Translational Research Institute (UL1 RR024140).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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