RESEARCH ARTICLEOpen Access
Activating mutation in MET oncogene in familial
Deborah W Neklason1,2*, Michelle W Done1, Nykole R Sargent1,2, Ann G Schwartz4, Hoda Anton-Culver5,
Constance A Griffin6, Dennis J Ahnen7, Joellen M Schildkraut8, Gail E Tomlinson9, Louise C Strong10,
Alexander R Miller11, Jill E Stopfer12and Randall W Burt1,3
Background: In developed countries, the lifetime risk of developing colorectal cancer (CRC) is 5%, and it is the
second leading cause of death from cancer. The presence of family history is a well established risk factor with
25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer
syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial
colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-
oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility.
Methods: MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal
cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a
LightScanner (Idaho Technologies). Samples demonstrating alternative melt curves were sequenced. A TaqMan
assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer
cases and to look for allelic amplification in tumors.
Results: Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position
T992I (also reported as MET p.T1010I) in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant
was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with
CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of
colon cancers, and in <1% in the general population. The threonine at amino acid position 992 lies in the tyrosine
kinase domain of MET and a change to isoleucine at this position has been shown to promote metastatic behavior
in cell-based models. The average age of CRC diagnosis in patients in this study is 63 years in mutation carriers,
which is 8 years earlier than the general population average for CRC.
Conclusions: Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues,
this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial
colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different
at-risk populations will be an important extension of this work to define the clinical significance.
Colorectal cancer (CRC) is one of the more familial of
cancers, and the presence of a family history of this malig-
nancy is a well established risk factor. Twin studies suggest
inherited and/or familial factors contribute to 25-35% of
CRC cases . The highly penetrant inherited colon can-
cer conditions including familial adenomatous polyposis,
Lynch syndrome (hereditary nonpolyposis colorectal
cancer), Peutz-Jeghers, Cowden syndrome and juvenile
polyposis account for approximately 5% of CRCs, leaving
greater than 20% without clear genetic definition . An
individual’s risk of CRC doubles with one affected first
degree relative and progressively increases with each addi-
tional affected first, second, or third degree relative [3 ,4].
We have previously reported linkage of the 7q31 locus
in a cohort of sibling pairs affected with CRC . Other
CRC and polyp-affected relative pair studies have also
* Correspondence: firstname.lastname@example.org
1Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
Full list of author information is available at the end of the article
Neklason et al. BMC Cancer 2011, 11:424
© 2011 Neklason et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
reported linkage to this region of chromosome 7 [6,7].
One candidate gene in this region is the proto-oncogene
and tyrosine kinase receptor, MET. MET is expressed
mainly on the surface of epithelial cells. In response to
binding of the MET ligand, hepatocyte growth factor
(HGF), C-terminal tyrosine residues are phosphorylated
followed by a cascade of intracellular signals resulting in
activation of MAPK and/or PI3K/Akt pathways [8,9]
(Figure 1). In this way, aberrant activation of MET leads
to increased cell proliferation, invasion, and metastasis
[10,11]. The MET gene is found to be amplified in
approximately 10% of CRCs, and amplification is asso-
ciated with advanced stages and worse prognoses
[12-14]. Additionally, MET gene missense mutations are
found in ~3% of CRCs, in particular p.R970C and
p.T992I (also reported as p.R988C and p.T1010I) .
Specific missense mutations in the tyrosine kinase
domain of MET (amino acids 1112 to 1268) lead to her-
editary papillary renal carcinoma (MIM ID 164860). Indi-
viduals with this condition are usually symptomatic by
their fourth decade of life due to multifocal kidney
To evaluate the possibility that germline changes in the
MET gene may lead to colon cancer susceptibility in a
familial setting, we scanned and sequenced all coding
exons of MET in our sibling pair cohort . Here we
report that MET p.T992I, a non-synonymous change sug-
gested to have oncogenic potential, is present in the germ-
line DNA of 5.2% of this cohort and this same change is
confirmed in a second familial colon cancer cohort with
two affected first degree relatives at a frequency of 4.1%.
This substitution is reported in <1% of the general popula-
tion and has been reported in cancer cells of multiple ori-
gins, including 2.5% of colon cancers [15-18].
All aspects of this study were approved by University of
Utah’s Institutional Review Board for human subject
research. Research participants were consented to partici-
pate in a study of genetic factors leading to colon cancer
risk. Ascertainment and collection of the sibling pair
study cohort have been previously described . Briefly,
169 siblings (148 affected with CRC and 21 unaffected)
from families with two siblings diagnosed with colorectal
adenocarcinoma or a polyp with high grade dysplasia and
all of age > 20 years were included. A young onset popu-
lation, defined as a CRC diagnosis ≤ 50 years (n = 130)
and a familial colon cancer cohort, defined as two first-
degree relatives diagnosed with CRC (n = 169), was used
for confirmation of the MET p.T992I mutation. These
populations have been previously described as well .
For both of these populations, diagnosis was confirmed
with pathology report or state cancer registry data.
Known syndromes were excluded through medical
record review and/or molecular analysis including analy-
sis for microsatellite instability (MSI) using the “reference
marker panel” (BAT25, BAT26, D2S123, D5S346 and
D17S250) and sequencing of normal tissue from cancers
demonstrating MSI as previously described [5,19].
Figure 1 Location of mutations identified in MET oncogene. The MET protein is 1390 amino acids long (NM_000245.2, NP_000236.2). The
pre-protein is cleaved into alpha and beta chains that are joined by a disulfide bond to create the extracellular receptor. The extracellular region
(blue and yellow) contains a Sema domain, followed by a PSI and four IPT domains and are encoded in exons 2-12 of the mRNA. The
transmembrane domain (green) is encoded in exon 13. The intracellular domain (red) is encoded in exons 14-21. Serine 985 (red star) down
regulates kinase activity when phosphorylated, tyrosine 1234 and 1235 (green stars) positively modulate enzyme activity when phosphorylated,
and tyrosine 1349 and 1356 (blue stars) recruit signal transducers when phosphorylated. Catalog of Somatic Mutations in Cancer (COSMIC)
reports mutations in amino acids 130-370 of the extracellular domain, and 960-1340 of the intracellular tyrosine kinase domain. Amino acid
changes responsible for Hereditary Papillary Renal Carcinoma (HPRC) are found between amino acids 1110 and 1268. Sequencing traces of the
germline DNA mutations in the colon cancer sibling pair population are shown with their approximate location on the gene.
Neklason et al. BMC Cancer 2011, 11:424
Page 2 of 7
The presence of polyposis, defined as greater than 10
colonic polyps resulted in exclusion from the study.
Scanning and Sequencing of MET
Primers were designed using Primer 3  to PCR-amplify
each of the coding exons of MET. Amplicons of 250-500
base-pairs in length were generated using LC Green dye
mastermix (Idaho Technologies, Salt Lake City, UT, USA),
for optimal high-resolution melt-curve analysis (HRM)
using a LightScanner (Idaho Technologies). Samples
demonstrating alternative melt curves were sequenced
using Applied Biosystems 3730XL capillary sequencer.
T specific TaqMan assay",1,0,1,0,0pc,0pc,0pc,0pc>MET
c.2975C > T specific TaqMan assay
Tumor DNA, micro-dissected and extracted from forma-
lin-fixed paraffin-embedded (FFPE) blocks, was assayed
for the presence of the MET c.2975C >T mutation
(NM_000245.2, NP_000236.2), which results in p.T992I in
the protein, using the Applied Biosystems probe assay for
rs56391007 and TaqMan Genotyping Master Mix accord-
ing to manufacturers’ specifications (Applied Biosystems,
Carlsbad, CA, USA). The major “C” allele was labeled with
VIC (517 nm emission) and the minor “T” allele was
labeled with FAM (554 nm emission). Products that
peaked before 35 cycles using the BioRad CFX96 Real-
time PCR machine with a signal of >500 RFU on the
respective VIC or FAM channel were designated for that
allele. When the MET c.2975C > T mutation was identi-
fied in tumors, normal DNA from the same patient (blood
when available, otherwise FFPE micro-dissected normal)
was tested for the mutation. Allelic imbalance was evalu-
ated using cycle-time (CT) data generated by real-time
quantitative PCR with the TaqMan assay. Where ΔCT =
cycle time of VIC (c.2975C, wild type allele) - cycle time of
FAM (c.2975T, mutant allele), with the fold excess mutant
alleles = 2(Δ CT tumor-Δ CT normal).
Because the MET gene resides within the linkage peak
previously reported on chromosome 7q31  and
because it is an oncogene amplified in CRCs, the MET
exons were scanned for variation using high-resolution
melting (HRM) followed by sequencing of samples with
different melt curves in our study population. The sib-
ling pair population was composed of 169 subjects from
77 families including 148 affected with CRC and 21
unaffected . The population is 86% Caucasian, 5%
Black, 1% Native American, and 8% other. All known
MET coding SNPs reported in dbSNP with population
frequencies as well as coding variants identified in germ-
line DNA of the sibling pair population but not present
with population frequencies in dbSNP are listed in
Table 1. The frequency of 9 of the SNPs in the sibling
pair population are representative of the allelic frequen-
cies reported in dbSNP and one unreported SNP results
in a synonymous change (Table 1). Three non-synon-
ymous MET gene changes were identified in the germ-
line DNA of affected individuals whereby a population
frequency was either not available or the minor allele
frequency was less than 1% in dbSNP build 132 (http://
www.ncbi.nlm.nih.gov/projects/SNP) . Two indivi-
duals each had a single change in the extracellular
domain of the MET receptor; p.V136I and p.E168D.
However their affected siblings did not harbor the
respective changes and the changes are not predicted to
disrupt protein function with both Polyphen and SIFT
analysis tools [22,23]. Seven of the 148 affected indivi-
duals, and none of the unaffected siblings, have the
p.T992I germline change, which resides in the tyrosine
kinase domain of MET. These 7 individuals represent 3
affected sibling pairs and 1 affected individual with an
unaffected sibling or 4 of 77 families (5.2%). The con-
sensus threonine amino acid at position 992 is comple-
tely invariant across vertebrates to zebrafish and both
Polyphen and SIFT analyses predict that this change is
damaging. This mutation has been previously reported
in 2.5% of colon tumors . It is reported in dbSNP at
0.7% based on low coverage sequence of ~600 indivi-
duals from the 1000 Genomes project (4 individuals).
There are no clear pathologic characteristics of the indi-
viduals with p.T992I germline mutation (Table 2). The
average age of CRC diagnosis in the sibling pairs with
p.T992I germline mutation was 61.9 years with a range
of 44 to 75 years, whereas the average age of the study
population was 58.7 years (range 28-91).
Because each of the families in the sibling pair cohort
is of Caucasian descent, we were interested to determine
whether there was evidence of a founder mutation.
Using polymorphic markers surrounding the MET locus
(D7S2418, D7S486 and D7S648), the haplotype segregat-
ing with the mutation in each of the 4 families was
identified and found to be distinct. This suggests that
this mutation arose independently.
Using tumor DNA from individuals diagnosed with
CRC ≤50 years (n = 130) or individuals diagnosed with
CRC and having a first degree relative with CRC (n =
169), a TaqMan assay was used to screen for the p.
T992I mutation. We found that 9 of 299 tumors (3.0%)
harbored the change, 1 from diagnosis ≤ 50 years (0.8%)
and 8 from the two affected first-degree relative pro-
bands with CRC (4.7%). Interestingly, two of the 8 are a
second-degree relative pair from a large family with
excess colon cancer; one ascertained as a member of a
first-degree relative pair (hr10-D on Table 2) and the
other ascertained as a member of a parent-child pair
also diagnosed ≤ 50 years (hr16-D on Table 2) .
Since these two are known to be closely related, the
Neklason et al. BMC Cancer 2011, 11:424
Page 3 of 7
frequency is adjusted to 4.1% (7 of 168 families). DNA
from normal tissue was available from all cases except
hr16-D, and this individual was found to be an obligate
carrier based on children’s genotypes, thus the mutation
was present in all 9 suggesting it was germline in origin.
None of the 16 colorectal cancers arising in individuals
with the germline p.T992I had microsatellite instability,
a feature of defective mismatch repair pathway.
Because amplification of the MET gene occurs in
colon cancers, we hypothesized that the allele harboring
p.T992I would be preferentially amplified in colon
tumors. Using cycle time from the TaqMan assay, we
compared the difference of copy number of the mutant
(c.2975T) from wild type (c.2975C) in tumor versus nor-
mal. Six of the 15 cases examined showed an excess of
the mutant c.2975T allele over the wild type allele
Table 1 Allelic frequencies of germline variants in MET coding sequence for CRC sibling pair cohort and those
reported in dbSNP
ExonSNP* Change* # samplesCRC sibling frequencies dbSNP allele frequencies
2 rs11762213 synonymous 16089% GG, 11% GA89% GG 11% GA
2 c.577C > T synonymous16999% CC, 1% CTNot reported
2 c.593G > AV136I16999.4%GG 0.6%GT Not reported
2rs35775721 synonymous16588% CC 12%CT 97% CC 3% CT
99.5%GG 0.5% GT#
2 rs55985569E168D 16599.4%GG 0.6%GT
2 rs35776110 A320V169 100% CC97% CC 3% CT
2 rs77523018M362T169 98% TT 2% CT 98% TT 2% CT
2 rs33917957 N375S169100% AA 97% AA 3% AG
7rs13223756synonymous 16175% AA 25% AG 67% AA 33%AG
99.3% CC 0.7%CT#
14 rs56391007T992I 163 95.7%CC 4.3%CT
20rs41736 synonymous15228% CC 54% GA 18%TT 37% CC 45% GA 18% TT
21 rs2023748synonymous 15726% GG 54% GA 20%AA37% GG 45% GA 18% AA
21rs41737 synonymous157 26% GG 54% GA 20%AA37% GG 45% GA 18% AA
*for variants without a SNP identification number in dbSNP, the nucleotide change is noted with reference to NM_000245.2 with nucleotide 1 referring to A of
the AUG initiation codon and amino acid change is noted with reference to NP_000236.2.#Minor allele frequency from 1000 Genomes in dbSNP, no frequency
data available under population diversity.
Table 2 Cancer cases with MET mutations
Sample*Mutation AgeStage Grade - differentiation Colonic locationRelative copy number c.2975T (Tumor/Normal)
sib1 V136I873moderately welltransverse ND
sib2E168D 713moderately wellsplenic flexureND
sib6-BT992I661not reporteddescending 1.79
sib7-BT992I 661 not reporteddescending0.07
sib8-C T992I 682moderately wellcecum0.31
hr15T992I 352moderate transverse 1.56
hr16-DT992I 474moderate wellcecum ND
hr17 T992I683moderate to focally poor sigmoid 0.05
*sib indicates patient from sibling pair cohort, hr indicates patient from high risk cohort, -letter indicates same family. Not done (ND).
Neklason et al. BMC Cancer 2011, 11:424
Page 4 of 7
(Table 2), but this was not universal. This finding sug-
gests that, in the presence of this mutation, additional
amplification of the gene is not required for establish-
ment of cancer.
Ten percent of all colon cancers arise in a familial setting
when defined as two or more affected first-degree rela-
tives . There is a also two-fold increase of developing
colon cancer with an affected first-degree relative .
Specifics of the genetic etiology of this group are not
defined, leaving a gap in our knowledge of moderate risk
genetic variants. A germline mutation in the MET gene,
p.T992I, was identified in ~4.5% of colon cancers arising
in first-degree relative pairs from two separate cohorts.
The mutation was observed in less than 1% of colon can-
cer cases that occurred ≤ 50 years, suggesting that it does
not promote very young CRC. MET p.T992I is also
reported in the germline DNA of 4% of thyroid cancers
, one endometrial and two melanoma cancer cases,
and one normal individual . In cancers, the p.R970C
and p.T992I mutations are thought to affect phosphory-
lation of the serine residue (p.S985) that negatively regu-
lates MET kinase activity [8,25]. By comparison, the
specific missense mutations reported in hereditary papil-
lary renal carcinoma (HPRC) surround two tyrosine resi-
dues within the catalytic site (p.Y1234 and p.Y1235) that
positively regulate kinase activity (Figure 1). The pheno-
typic differences between p.T992I and HPRC MET muta-
tions could be explained by the difference between
factors driving negative versus positive activation of MET
We propose a model whereby the p.T992I mutation
functions as a progression factor rather than an initiation
factor in the canonical colon cancer model . Specifi-
cally, we hypothesize that an adenoma is initiated through
somatic mutations in the canonical APC pathway, then
the adenoma acquires other proliferative mutations, and in
the presence of an underlying MET p.T992I mutation, is
then able to move beyond the mucosal layer to become
invasive colon cancer. This hypothesis is supported by the
following observations. The individuals we identified with
the MET p.T992I germline mutation do not have the hall-
marks of inherited mutations in initiating factors such as
multiple adenoma formation (APC gene) or microsatellite
instability (mismatch repair genes). Additionally, CRC
diagnosis under age 50 is infrequent. In fact, the chromo-
some 7q genetic locus is associated in affected relative pair
studies when CRCs are included and adenomas are
excluded [5-7]. The average age of CRC diagnosis in the
general population is ~71 years, and it is estimated that 10
years are needed for a small polyp to progress to invasive
CRC . A model of rapid progression of polyp to cancer
in the presence of MET p.T992I is supported in that
individuals with the p.T992I mutation are diagnosed with
CRC at an average age of 63 years. This would be when
the general population, on average, is developing adeno-
mas that will progress to cancer. This mutation also
occurs in a variety of cancers including colon, melanoma,
endometrial, thyroid, and mesothelioma [15-18] with
germline confirmation in colon, thyroid, uterine, and mel-
anoma [16,17] suggesting that it is not a tissue-specific
mechanism. MET p.T992I mutation is proposed to func-
tion through inhibition of phosphorylation of Ser985,
which, when phosphorylated, corresponds with reduced
MET signaling (Figure 1) [28,29]. In cell models, the speci-
fic mutation reported here generally affects invasive beha-
viors including changes in cell morphology, adhesion,
motility, migration and anchorage-independent growth
but not proliferation, such as IL-3 independent growth in
Ba/F3 cells [18,29]. Based on these reports, it is reasonable
to predict that MET p.T992I requires a growth signal
(activation) but then is disabled in its ability to turn off the
activation through phosphorylation of p.S985. It has also
been shown that over expression of MET is an early event
in the colorectal adenoma-carcinoma sequence . In
the context of a proliferating precancerous colonic ade-
noma, over expression MET p.T992I and the inability to
turn off activation could allow the invasive behaviors to
Although, the MET p.T992I genetic mutation has been
commonly found in somatic colorectal cancer tissues, this
is the first report also implicating this MET genetic muta-
tion as a germline inherited risk factor for familial colorec-
tal cancer. A strength of this study is the use of colorectal
cancers enriched for a hereditary component. One of the
limitations, however, is the small sample size and lack of a
large unaffected cohort. Future independent studies on
large case and carefully selected control sets are needed to
replicate these results, confirm the conclusions, and pro-
vide an accurate estimate of the prevalence of this muta-
tion in the cancer and normal populations.
We estimate that the specific germline mutation of this
investigation is responsible for ~4.5% of CRCs that occur
in a familial setting, defined here as two first-degree rela-
tives with CRC. Since 10% of all CRCs occur within this
definition, this would translate to 0.45% of all CRCs.
Future work should be focused on measuring the precise
prevalence of this mutation in a large set of cases and
controls and estimation of CRC risk associated with the
germline mutation. Because MET p.T992I has also been
found in germline DNA of individuals diagnosed with
other cancers, a large-scale study to examine the pene-
trance and risks of all cancers in mutation carriers will be
an important advance in our understanding. Specific
inhibitors of the MET protein are currently in use in
Neklason et al. BMC Cancer 2011, 11:424
Page 5 of 7
human clinical trials and may have a specific utility in
preventing invasion and the metastasis of early-stage can-
cers in individuals with the MET p.T992I mutation .
Acknowledgements and funding
This project has been funded with federal funds from the National Institutes of
Health, National Cancer Institute under contract RO3-CA150067, RO1-CA040641,
PO1-CA073992 and sample collection was supported by Detroit Cancer Registry
SEER program grant number N01-PC35145, and the Cancer Genetics Network,
RFA CA-97-004, RFA-CA-97-019, and RFP N01-PC-55049-40; grants numbers
U24-CA78134, U24- CA78156, U24-CA78148, U24-CA78174, U24- CA78157, U24-
CA78142. Additional support was provided by a Cancer Center Support Grant
P30-CA42014, Utah Cancer Registry grant HHSN 261201000026C from the
National Cancer Institute’s SEER program with additional support from the Utah
State Department of Health, and Utah Population Database supported by the
Huntsman Cancer Foundation.
This project could not have been done without the continued support from
the Cancer Genetics Network who shared DNA samples and data. We
acknowledge University of Utah Sequencing and Genotyping Cores. We thank
Mark Yandell, Barry Moore and Hao Hu for assisting with 1000 genomes pilot
data, Therese Tuohy for critical review of the manuscript, and James P. Evans,
Jan T. Lowery, and Al Ziogas for their participation in CGN sample collection.
1Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
2Department of Oncological Sciences, University of Utah, Salt Lake City, Utah,
USA.3Department of Medicine, University of Utah, Salt Lake City, Utah, USA.
4Karmanos Cancer Institute, Department of Medicine, Wayne State University,
Detroit, Michigan, USA.5Department of Epidemiology, University of California
Irvine, Irvine, California, USA.6Departments of Pathology and Oncology,
Johns Hopkins University, Baltimore, Maryland, USA.7Department of
Medicine, University of Colorado Denver, Aurora, Colorado, USA.
8Department of Community and Family Medicine, Duke University, Durham,
North Carolina, USA.9Department of Pediatrics, University of Texas Health
Science Center at San Antonio, San Antonio, Texas, USA.10Department of
Molecular Genetics, University of Texas M.D. Anderson Medical Center,
Houston, Texas, USA.11Department of Surgical Oncology, START Center for
Cancer Care, San Antonio, Texas, USA.12Abramson Cancer Center, University
of Pennsylvania, Philadelphia, Pennsylvania, USA.
DN conceived of the study, its design, implementation, obtained funding
and drafted the manuscript; MD designed and carried gene scanning and
sequencing and assisted with manuscript; NS assisted with gene analysis,
designed the TaqMan assays and analysis of tumors, and assisted with the
manuscript; AS, HA, CG, DA, JS, GT, LS, AM, JS contributed samples and
assisted with revision of the manuscript; RB participated in study design,
obtained funding, and helped to draft the manuscript. All authors read and
have approved the final manuscript.
The authors declare that they have no competing interests.
Received: 9 July 2011 Accepted: 4 October 2011
Published: 4 October 2011
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Cite this article as: Neklason et al.: Activating mutation in MET
oncogene in familial colorectal cancer. BMC Cancer 2011 11:424.
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