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Departments of Oncology [M. E., A. S., M. T., S. B. B., J. G. H.] and Otolaryngology-Head and Neck Surgery, Division of Head and Neck Cancer Research [M. S-C., D. S.], The Johns Hopkins Oncology Center, Baltimore, Maryland 21231; Institut Catala d’Oncologia and Institut de Recerca Oncologica, 08907 Barcelona, Spain [G. C., M. A. P., S. G., G. T.]; and Department of Medicine (Gastroenterology Division), Greenbaum Cancer Center, University of Maryland School of Medicine and Baltimore Veterans Affairs Hospital, Baltimore, Maryland 21201 [S. J. M.]
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ABSTRACT |
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Introduction |
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The majority of APC mutations causing FAP result in truncation of the APC protein (1 , 2) . The defective APC protein produced in these cases is not able to bind and degrade ß-catenin, and the resultant increased ß-catenin levels lead to activation of growth-promoting genes such as c-myc via the action of increased ß-catenin/Tcf-4 transcription complexes (7 , 8) . APC mutations are emblematic of the common paradigm that genes mutated in cancer families are frequently mutated in sporadic tumors of the same type. Indeed, APC somatic mutations are present in 80% (9 , 10) of sporadic colorectal carcinomas and appear very early in colorectal tumor progression (9) . However, some of these nonfamilial tumors with APC mutations lack a second identifiable inactivating event on the remaining allele, and up to 20% of tumors have no APC mutation. In addition to colorectal cancer, APC somatic mutations have been occasionally described in other gastrointestinal tumors, including gastric, pancreatic, esophageal, and hepatic carcinomas (11, 12, 13, 14) . However, the rates of mutation of APC are much lower than colorectal tumors, despite a high rate of loss of heterozygosity at the APC locus in these tumor types (15 , 16) . One explanation for the failure to detect genetic alterations in these tumors is that the APC is a large gene containing 15 exons, and mutational screening is technically laborious.
Alternatively, other mechanisms associated with gene inactivation, such as transcriptional silencing by promoter hypermethylation, could play a role in loss of APC function in those tumors in the absence of APC mutations or with only one "hit" occurring in the APC gene. Methylation is the main epigenetic modification in humans, and changes in methylation patterns play an important role in cancer. In particular, hypermethylation of normally unmethylated CpG islands located in the promoter regions of many tumor suppressor and DNA repair genes, such as p16INK4a and hMLH1, correlates with loss of expression in cancer cell lines and primary tumors (17) . Methylation of APC has been described in a subset of colorectal tumors (18 , 19) , but the precise position and density of this change, its functional consequences, and its tumor distribution are not known. In the present study, we demonstrate that hypermethylation frequently affects the APC promoter, is associated with loss of expression of the gene early in colorectal tumorigenesis, and occurs in carcinomas arising from regions of the GI tract other than the colon.
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Materials and Methods |
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Bisulfite Genomic Sequencing of Individual Alleles.
DNA was modified by sodium bisulfite as described previously
(22)
. Using 3 µl of resuspended, sodium
bisulfite-treated DNA, PCR was performed in a 50-µl reaction
(22)
. Reactions were hot-started at 95°C for 5 min and
held at 80°C before addition of 1.25 units of Taq (Sigma).
Temperature conditions for PCR were as follows: 39 cycles of 95°C for
30 s, 55°C for 30 s, and 72°C for 1 min, followed by 1
cycle of 72°C for 5 min. Primers used were 5'-ATT TAT TGT AAT TTA TTT
AAT ATT ATT GTT-3' (sense) and 5'-AAC TAC ACC AAT ACA ACC ACA TAT C-3'
(antisense), which amplify a 356-bp product. The 5' position of the
sense and antisense primers corresponds to bp 440 and 826 of GenBank
U02509, respectively. Our sequenced products include 25 CpG sites
between positions -366 and -42 relative to the APC major
transcription start site (23)
. PCR products were cloned
into the TA vector pCR2.1-TOPO (Invitrogen, Carlsbad, CA) and
transformed into bacteria. Clones were single-colony purified. Plasmid
DNA from isolated clones was purified using Wizard mini-prep (Promega
Corp., Madison, WI) and analyzed by automated DNA sequencing (ABI).
MSP.
DNA methylation patterns in the CpG islands of the APC gene
were determined by MSP (22)
. The primer sequences designed
for the promoters 1A and 1B of APC spanned 7 and 6 CpGs,
respectively. Primer sequences of APC promoter 1A for the
unmethylated reaction were 5'-GTG TTT TAT TGT GGA GTG TGG GTT-3'
(sense) and 5'-CCA ATC AAC AAA CTC CCA ACA A-3' (antisense), which
amplify a 108-bp product; and for the methylated reaction, 5'-TAT TGC
GGA GTG CGG GTC-3' (sense) and 5'-TCG ACG AAC TCC CGA CGA-3'
(antisense), which amplify a 98-bp product. The 5' position of the
sense unmethylated and methylated primers corresponds to bp 696 and 702
of GenBank sequence no. U02509, respectively. Both antisense primers
originate from bp 782 of this sequence. Primer sequences of
APC promoter 1B for the unmethylated reaction were 5'-GAT
AGA ATA GTG AAT GAG TGT TT-3' (sense) and 5'-CTT CCA ACA ACC ACA CCC
CA-3' (antisense), which amplify a 195-bp product; and for the
methylated reaction 5'-TAG AAT AGC GAA CGA GTG TTC-3' (sense) and
5'-TCC GAC GAC CAC ACC CCG-3' (antisense), which amplify a 190-bp
product. The 5' position of the sense unmethylated and methylated
primers corresponds to bp 77 and 75 of GenBank sequence no. D13981. The
unmethylated and methylated antisense primers originate from bp 257
and 259 of this sequence, respectively. The annealing temperature for
both the unmethylated and methylated reactions of promoters 1A and 1B
was 55°C. Placental DNA treated in vitro with
SssI methyltransferase was used as a positive control for
methylated alleles. DNA from normal lymphocytes was used as negative
control for methylated genes. PCR products were analyzed as described
(22)
.
Restriction Enzyme Analysis after Bisulfite Modification.
To check for a specific cytosine methylation within the APC
promoter region studied, MSP products were digested with the
restriction enzymes SfaNI and AciI as described
(22)
. The SfaNI and AciI recognition
sites will remain only if the CpGs are methylated after bisulfite
treatment and amplification but will be lost if the CpGs are
unmethylated. In vitro methylated DNA was used as positive
control for APC promoter hypermethylation.
RT-PCR.
RT-PCR was performed as described previously (24)
using 3
mg of total cellular RNA to generate cDNA. One hundred ng of this cDNA
were amplified by PCR with primers for exon 1A, 5'-GAG ACA GAA TGG AGG
TGC TGC-3' (sense), and exon 2, 5'-GTA AGA TGA TTG GAA TTA TCT TCT
A-3', (antisense) of APC, which amplify a 170-bp product.
Glyceraldehyde-3-phosphate dehydrogenase served as a positive control
(24)
. Ten ml of each PCR reaction were directly loaded
onto nondenaturing 6% polyacrylamide gels, stained with ethidium
bromide, and visualized under UV illumination.
Mutational Analysis of APC and ß-Catenin.
Samples with full-length expression or without prior evidence of
APC mutation were analyzed for mutations in codons 680-1693.
This region of APC was amplified by PCR from genomic DNA in
two segments (2 and 3) as described previously (1)
.
Segment 2 was analyzed for mutations by the in
vitro-synthesized protein assay (1)
, whereas segment
3 was analyzed for mutations by DNA sequencing (9)
. For
ß-catenin, a genomic PCR fragment including codon 1 in exon 2 to
codon 90 in exon 4 and encompassing the
NH2-terminal regulatory region was amplified as
described previously (21)
. PCR products were gel purified
and sequenced directly with internal primers using ThermoSequenase
(Amersham Corp.) and 33P-labeled ddNTPs
(Amersham) according to the manufacturer. Each mutation was verified in
both the sense and antisense directions.
Loss of Heterozygosity Analysis at the APC Gene.
Allelic loss at the APC gene was determined using the
D5S346 microsatellite (or D5S429 in those
patients homozygous for the D5S346). PCR was performed on 20
ng each lymphocyte and tumor DNA. Before amplification, 200 ng of one
primer from each pair were end labeled with
[-32P[rsqbATP(20 mCi/ml; Amersham Life Science,
Inc., Arlington Heights, IL) and bacteriophage T4 kinase (New England
Biolabs, Inc., Beverly, MA) in a total volume of 50 µl. PCR reactions
were carried out in a total volume of 10 µl containing 2 ng of
labeled primer and 60 ng of each unlabeled primer. The PCR buffer
included 16.6 mM ammonium sulfate, 67
mM Tris (pH 8.8), 6.7 mM
magnesium chloride, 10 mM ß-mercaptoethanol,
and 1% DMSO to which were added 1.5 mM
deoxynucleotide triphosphates and 1.0 unit of Taq DNA polymerase
(Boehringer Mannheim Biochemicals, Indianapolis, IN). PCR
amplifications of each primer set were performed for 35 cycles
consisting of denaturation at 95°C for 30 s, annealing at 55°C
for 60 s, and extension at 72°C for 60 s. One-third of the
PCR product was separated on 8% urea-formamide-polyacrylamide gels and
exposed to X-ray film for 4 to 48 h. For informative cases, LOH
was scored if one allele was decreased by >40% in tumor DNA when
compared with the same allele in normal DNA.
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Results |
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), as expected for a CpG island. To extend the study to
additional normal tissues, MSP primers were designed in this area and
used to screen other normal tissues, including colon, stomach, lung,
breast, brain, esophagus, and kidney (n = 16). No APC promoter hypermethylation was observed in any
case (Fig. 1B
).
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APC Promoter Hypermethylation in Primary Colorectal
Tumors.
DNA from 108 primary colorectal carcinomas was evaluated for
APC promoter 1A methylation using MSP. APC
promoter hypermethylation was present in 20 of 108 (18%) of these
tumors (Fig. 2A
). In 28 patients where DNA from normal adjacent colorectal
mucosa was available, no methylation of the APC promoter was
observed in any matched case, even among 17 cases where the adjacent
tumor had aberrant APC methylation (Fig. 2B
). The
presence of methylation was confirmed by bisulfite-restriction cut
analysis using two different enzymes, as outlined above. For two of the
tumors designated as hypermethylated by MSP, we also performed
bisulfite genomic sequencing of individual alleles. Most allelic clones
demonstrated a dense methylation pattern, with almost every CpG
methylated (Fig. 3 and C
). In both tumors, a few clones were
found completely unmethylated, and these were most likely derived from
contaminating normal cells such as normal colon epithelium,
fibroblasts, or lymphocytes. Indeed, bisulfite genomic sequencing of
APC in the normal colorectal mucosa from one of the two
patients with hypermethylated tumors revealed an almost completely
unmethylated CpG island in all of the alleles studied (Fig. 3A
). Bisulfite genomic sequencing for one colon cancer that
was unmethylated at APC by MSP revealed a completely
unmethylated CpG island (Fig. 3D
). Thus, APC
promoter hypermethylation is a tumor-specific change that densely
affects the APC promoter 1A in some primary colorectal
carcinomas.
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Correlates of APC Methylation.
Abnormal methylation of the APC 1A promoter region in the
colorectal carcinomas was not associated with significant differences
of gender, age of onset, clinical status, Duke’s stage, DNA ploidy, or
the presence of residual disease after initial surgical excision of
primary tumor (Fisher’s exact test two-tailed, P > 0.05). Furthermore, APC promoter hypermethylation
was also not associated with aberrant methylation of other genes
analyzed previously in some of these primary colorectal carcinomas
(24
, 25) , including the cell cycle inhibitor
p16INK4a, the mdm2 regulator
p14ARF, and the DNA repair gene
MGMT. Finally, APC methylation was not more
common in tumors with MSI than in MS stable neoplasms (1 methylated of
6 MSI+ tumors versus 19 methylated of 102 MSI- tumors).
APC Hypermethylation Occurs Early during Colon
Neoplasia Progression.
The above data, notably the lack of association of higher Duke’s stage
with methylation, suggested that aberrant APC methylation
might not arise in the progression of established colon carcinomas but
might represent an early change, as do APC coding mutations. We
examined this possibility by studying aberrant APC
methylation in benign colorectal adenomas, a precursor lesion to
invasive colorectal tumors. Nine of 48 adenomas (18%) demonstrated
hypermethylation of APC (Fig. 4A
), a frequency similar to invasive colon carcinomas.
Furthermore, APC hypermethylation was present in both small
(
15 mm) and large adenomas (>15 mm), 3 of 18 (17%)
versus 6 of 30 (20%), respectively. These data point to
methylation of APC as an early event in colorectal
tumorigenesis.
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Functional and Mutational Context of Aberrant APCMethylation in Colon Tumorigenesis.
To further determine the precise relationship in colon cancers
between APC coding region mutations, allelic status, and
hypermethylation, we studied the APC methylation status in
an additional 66 colorectal carcinomas where the APC
mutational status had been characterized previously (7
, 21)
. It would be expected that if hypermethylation is
functionally important as a loss of function event, then this change
should be less frequent in those tumors with coding region mutations of
the gene. APC promoter hypermethylation was present in 8 of
66 (12%) samples. When the samples were decoded for their
APC mutational status, APC was hypermethylated in
5 of 19 (26%) colorectal tumors with wild-type APC but only
in 3 of 47 (6%) tumors with a mutant APC (Fisher’s exact
test, two-tailed P = 0.04). Thus,
APC promoter hypermethylation is biased toward tumors with
genetically intact APC.
In these three tumors with APC methylation and mutation, only mutant APC protein is produced, as demonstrated by the in vitro-synthesized protein assay (7 , 21) . One possibility for this is methylation-mediated silencing of a second retained wild-type allele. LOH studies of the APC locus using microsatellite analysis demonstrated retention of both APC alleles in two of these three cases. Genomic sequencing also showed a heterozygous APC mutation, thus suggesting methylation and silencing of the wild-type allele. Methylation of a transcriptionally silenced wild-type allele and mutation of an expressed unmethylated allele has been reported previously for p16INK4a in the colorectal cancer cell line HCT-116 (27) . In the third case, the presence of only one mutant allele was demonstrated by deletion and sequencing analysis, and it must be assumed that this allele is also methylated in the APC promoter. However, when an APC allele harbors a mutation, in 98% of the cases (46 of 47) that APC promoter remains unmethylated.
To further address the relevance of hypermethylation changes in tumor
suppressor genes, one may examine the incidence of this change in
tumors arising in a familial setting, where a germ-line mutation is
already present. Hypermethylation should be very infrequent in this
setting, because most often the second allele is deleted or inactivated
by a somatic mutation in the tumor (1, 2, 3
, 28)
. However,
aberrant methylation of the remaining allele as a "second hit" for
gene inactivation can occasionally occur for genes such as
VHL and LKB1/STK11 (17)
. However, in
37 colorectal neoplasms obtained from 6 FAP families, we found that
none demonstrated APC hypermethylation, even in tumors where
both alleles of APC where retained (Fig. 2C
).
The functional consequences of APC methylation may also be correlated with the status of other components of the APC pathway. As reported previously, ß-catenin is a critical downstream component of the APC pathway. The role of APC in modulating ß-catenin activation would predict the diminishing need of ß-catenin mutations in tumors with APC promoter hypermethylation, assuming that only one "hit" in the same pathway would be necessary during transformation. Indeed, ß-catenin mutations are usually only found in colorectal tumors containing a wild-type APC (7 , 21 , 29) . However, APC was hypermethylated in colorectal tumors with wild-type ß-catenin (6 of 53; 11%) and tumors with mutant ß-catenin (1 of 7; 14%). In this regard, although infrequent, ß-catenin and APC mutations have been found in the same tumor sample (29) . Furthermore, ß-catenin mutations have been found in tumor types without frequent APC mutations, suggesting that ß-catenin and APC mutations are not completely exchangeable genetic lesions.
One of the most critical tests of the functional significance of
APC hypermethylation in colon tumors is the relationship of
this promoter change to expression of the gene. To address this
question, we examined the expression of the APC transcript
in colorectal adenomas using RT-PCR. All 20 colorectal adenomas without
APC methylation showed APC mRNA expression,
whereas none of four adenomas with APC methylation had
detectable APC mRNA transcripts (Fig. 4B
). Thus,
as demonstrated for other genes (17)
, promoter
hypermethylation was associated with transcriptional silencing.
Pattern of APC Promoter Hypermethylation in Human
Cancer.
Although the mutational data from sporadic tumors pinpoints the colon
as the main target for APC inactivation, tumors from other
organs develop in the FAP families and LOH in the APC region
is common in other tumor types. APC promoter
hypermethylation was examined in 208 primary human tumors of multiple
origins and was only relatively common in other gastrointestinal
neoplasia, including stomach (13 of 38; 34%), pancreas (6 of 18;
33%), liver (6 of 18; 33%), and esophagus (4 of 27; 15%; Fig. 5
). In contrast, among other solid malignancies, APC
methylation was less frequent, including tumors derived from the
bladder (2 of 19; 10%), kidney (1 of 12; 8%), or breast (1 of 19;
5%) or was not observed at all: brain (0 of 10), lung (0 of 17), head
and neck (0 of 10), or ovary (0 of 20). Examples are shown in Fig. 5
.
Thus, APC promoter hypermethylation was not restricted to
colorectal tumors but included extracolonic carcinomas particularly
within the GI tract.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Although APC gene mutations are confined mostly to the colon, they may occur occasionally in other tumor types, most frequently those originating in other regions of the GI tract (11, 12, 13, 14) . APC promoter hypermethylation has a very similar distribution, although this epigenetic change is more frequent in extracolonic GI tract tumors. One possible explanation for the paucity of extracolonic mutations in APC is that mutations have been missed or not yet studied. The recent introduction of improved techniques for detection of APC mutations, such as the monoallelic mutation analysis (3) or the mass spectrometric approach (30) , and the search for APC mutations in unexplored regions such as the promoter (3) will help to clarify this issue.
An alternative explanation for the observed frequencies of APC methylation is the apparent predilection for epigenetic versus genetic lesions in various tumor types. The tumor suppressor genes p16INK4a and p14ARF provide us with an illustrative example. Both genes are located at the 9p21 region and are common targets of homozygous deletions. However, this loss has marked variation among different tumor types. For example, lung and breast carcinomas commonly undergo homozygous deletion of this INK4a/ARF locus, which is uncommon in colorectal carcinoma (31) . Colorectal neoplasia, however, exhibit frequent promoter hypermethylation of p16INK4a and p14ARF (24) . Similarly, it appears that APC promoter hypermethylation is more common in gastric tumors, whereas mutation of APC is the principle mechanism for APC inactivation in colorectal neoplasia. The presence of frequent LOH at the APC locus in GI tumors with APC methylation, i.e., gastric, pancreas, liver, and esophagus (15 , 16) , supports a role for APC in these tumors. The current finding of APC promoter hypermethylation as a tumor-specific epigenetic inactivation further underscore the importance of the APC pathway as a critical event in neoplasia arising from other locations in the GI tract.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was partially funded by NIH Grants
CA54396 and CA77057. M. E., M. S-C., and G. T. are recipients of
Spanish Ministerio de Educacion y Cultura Awards. 
2 To whom requests for reprints should be
addressed, at Tumor Biology, Cancer Research Building, 1650 Orleans
Street, Baltimore, MD 21231. E-mail: hermanji{at}jhmi.edu
3 The abbreviations used are: APC,
adenomatous polyposis coli; FAP, familial adenomatous polyposis; GI,
gastrointestinal tract; MSP, methylation-specific PCR; RT-PCR, reverse
transcription-PCR; MSI, microsatellite instability.
Received 4/26/00. Accepted 6/28/00.
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M. van den Donk, M. van Engeland, L. Pellis, B. J.M. Witteman, F. J. Kok, J. Keijer, and E. Kampman Dietary Folate Intake in Combination with MTHFR C677T Genotype and Promoter Methylation of Tumor Suppressor and DNA Repair Genes in Sporadic Colorectal Adenomas Cancer Epidemiol. Biomarkers Prev., February 1, 2007; 16(2): 327 - 333. [Abstract] [Full Text] [PDF]
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J R Jass and J Behrens Wnt pathway may not be implicated in all routes to colorectal cancer * Author's reply Gut, February 1, 2007; 56(2): 309 - 310. [Full Text] [PDF]
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J J L Wong, N J Hawkins, and R L Ward Colorectal cancer: a model for epigenetic tumorigenesis Gut, January 1, 2007; 56(1): 140 - 148. [Full Text] [PDF]
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A. H. Ting, K. M. McGarvey, and S. B. Baylin The cancer epigenome--components and functional correlates Genes & Dev., December 1, 2006; 20(23): 3215 - 3231. [Abstract] [Full Text] [PDF]
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M. Guo, J. Ren, M. G. House, Y. Qi, M. V. Brock, and J. G. Herman Accumulation of Promoter Methylation Suggests Epigenetic Progression in Squamous Cell Carcinoma of the Esophagus Clin. Cancer Res., August 1, 2006; 12(15): 4515 - 4522. [Abstract] [Full Text] [PDF]
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M Hitchins, C Suter, J Wong, K Cheong, N Hawkins, B Leggett, R Scott, A Spigelman, I Tomlinson, D Martin, et al. Germline epimutations of APC are not associated with inherited colorectal polyposis. Gut, April 1, 2006; 55(4): 586 - 587. [Full Text] [PDF]
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T. Shevchuk, L. Kretzner, K. Munson, J. Axume, J. Clark, O. V. Dyachenko, M. Caudill, Y. Buryanov, and S. S. Smith Transgene-induced CCWGG methylation does not alter CG methylation patterning in human kidney cells Nucleic Acids Res., October 24, 2005; 33(19): 6124 - 6136. [Abstract] [Full Text] [PDF]
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M. O. Hoque, O. Topaloglu, S. Begum, R. Henrique, E. Rosenbaum, W. Van Criekinge, W. H. Westra, and D. Sidransky Quantitative Methylation-Specific Polymerase Chain Reaction Gene Patterns in Urine Sediment Distinguish Prostate Cancer Patients From Control Subjects J. Clin. Oncol., September 20, 2005; 23(27): 6569 - 6575. [Abstract] [Full Text] [PDF]
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H. Liu, W. Liu, Y. Wu, Y. Zhou, R. Xue, C. Luo, L. Wang, W. Zhao, J.-D. Jiang, and J. Liu Loss of Epigenetic Control of Synuclein-{gamma} Gene as a Molecular Indicator of Metastasis in a Wide Range of Human Cancers Cancer Res., September 1, 2005; 65(17): 7635 - 7643. [Abstract] [Full Text] [PDF]
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Q. Feng, A. Balasubramanian, S. E. Hawes, P. Toure, P. S. Sow, A. Dem, B. Dembele, C. W. Critchlow, L. Xi, H. Lu, et al. Detection of Hypermethylated Genes in Women with and Without Cervical Neoplasia J Natl Cancer Inst, February 16, 2005; 97(4): 273 - 282. [Abstract] [Full Text] [PDF]
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E. Asatiani, W.-X. Huang, A. Wang, E. Rodriguez Ortner, L. R. Cavalli, B. R. Haddad, and E. P. Gelmann Deletion, Methylation, and Expression of the NKX3.1 Suppressor Gene in Primary Human Prostate Cancer Cancer Res., February 15, 2005; 65(4): 1164 - 1173. [Abstract] [Full Text] [PDF]
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 B. Suarez-Merino, M. Hubank, T. Revesz, W. Harkness, R. Hayward, D. Thompson, J. L. Darling, D. G.T. Thomas, and T. J. Warr Microarray analysis of pediatric ependymoma identifies a cluster of 112 candidate genes including four transcripts at 22q12.1-q13.3 Neuro-oncol, January 1, 2005; 7(1): 20 - 31. [Abstract] [PDF]
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J. Chen, C. Rocken, C. Lofton-Day, H.-U. Schulz, O. Muller, N. Kutzner, P. Malfertheiner, and M. P.A. Ebert Molecular analysis of APC promoter methylation and protein expression in colorectal cancer metastasis Carcinogenesis, January 1, 2005; 26(1): 37 - 43. [Abstract] [Full Text] [PDF]
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C. M. Lewis, L. R. Cler, D.-W. Bu, S. Zochbauer-Muller, S. Milchgrub, E. Z. Naftalis, A. M. Leitch, J. D. Minna, and D. M. Euhus Promoter Hypermethylation in Benign Breast Epithelium in Relation to Predicted Breast Cancer Risk Clin. Cancer Res., January 1, 2005; 11(1): 166 - 172. [Abstract] [Full Text] [PDF]
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N. Umetani, H. Takeuchi, A. Fujimoto, M. Shinozaki, A. J. Bilchik, and D. S. B. Hoon Epigenetic Inactivation of ID4 in Colorectal Carcinomas Correlates with Poor Differentiation and Unfavorable Prognosis Clin. Cancer Res., November 15, 2004; 10(22): 7475 - 7483. [Abstract] [Full Text] [PDF]
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 W. K. Leung, K.-F. To, E. P.S. Man, M. W.Y. Chan, A. H.C. Bai, A. J. Hui, F. K.L. Chan, J. F.Y. Lee, and J. J. Y. Sung Detection of Epigenetic Changes in Fecal DNA as a Molecular Screening Test for Colorectal Cancer: A Feasibility Study Clin. Chem., November 1, 2004; 50(11): 2179 - 2182. [Full Text] [PDF]
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G. Clement, F. T. Bosman, C. Fontolliet, and J. Benhattar Monoallelic Methylation of the APC Promoter Is Altered in Normal Gastric Mucosa Associated with Neoplastic Lesions Cancer Res., October 1, 2004; 64(19): 6867 - 6873. [Abstract] [Full Text] [PDF]
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I. I. de Caceres, C. Battagli, M. Esteller, J. G. Herman, E. Dulaimi, M. I. Edelson, C. Bergman, H. Ehya, B. L. Eisenberg, and P. Cairns Tumor Cell-Specific BRCA1 and RASSF1A Hypermethylation in Serum, Plasma, and Peritoneal Fluid from Ovarian Cancer Patients Cancer Res., September 15, 2004; 64(18): 6476 - 6481. [Abstract] [Full Text] [PDF]
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E. Dulaimi, J. Hillinck, I. I. de Caceres, T. Al-Saleem, and P. Cairns Tumor Suppressor Gene Promoter Hypermethylation in Serum of Breast Cancer Patients Clin. Cancer Res., September 15, 2004; 10(18): 6189 - 6193. [Abstract] [Full Text] [PDF]
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N. J. Belshaw, G. O. Elliott, E. A. Williams, D. M. Bradburn, S. J. Mills, J. C. Mathers, and I. T. Johnson Use of DNA from Human Stools to Detect Aberrant CpG Island Methylation of Genes Implicated in Colorectal Cancer Cancer Epidemiol. Biomarkers Prev., September 1, 2004; 13(9): 1495 - 1501. [Abstract] [Full Text] [PDF]
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P. Parrella, M. L. Poeta, A. P. Gallo, M. Prencipe, M. Scintu, A. Apicella, R. Rossiello, G. Liguoro, D. Seripa, C. Gravina, et al. Nonrandom Distribution of Aberrant Promoter Methylation of Cancer-Related Genes in Sporadic Breast Tumors Clin. Cancer Res., August 15, 2004; 10(16): 5349 - 5354. [Abstract] [Full Text] [PDF]
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Y Shoji, M Takahashi, T Kitamura, K Watanabe, T Kawamori, T Maruyama, Y Sugimoto, M Negishi, S Narumiya, T Sugimura, et al. Downregulation of prostaglandin E receptor subtype EP3 during colon cancer development Gut, August 1, 2004; 53(8): 1151 - 1158. [Abstract] [Full Text] [PDF]
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G. Deng, G.-A. Song, E. Pong, M. Sleisenger, and Y. S. Kim Promoter Methylation Inhibits APC Gene Expression by Causing Changes in Chromatin Conformation and Interfering with the Binding of Transcription Factor CCAAT-Binding Factor Cancer Res., April 15, 2004; 64(8): 2692 - 2698. [Abstract] [Full Text] [PDF]
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E. Dulaimi, R. G. Uzzo, R. E. Greenberg, T. Al-Saleem, and P. Cairns Detection of Bladder Cancer in Urine by a Tumor Suppressor Gene Hypermethylation Panel Clin. Cancer Res., March 15, 2004; 10(6): 1887 - 1893. [Abstract] [Full Text] [PDF]
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D. T. McManus, A. Olaru, and S. J. Meltzer Biomarkers of Esophageal Adenocarcinoma and Barrett's Esophagus Cancer Res., March 1, 2004; 64(5): 1561 - 1569. [Abstract] [Full Text] [PDF]
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C. Battagli, R. G. Uzzo, E. Dulaimi, I. Ibanez de Caceres, R. Krassenstein, T. Al-Saleem, R. E. Greenberg, and P. Cairns Promoter Hypermethylation of Tumor Suppressor Genes in Urine from Kidney Cancer Patients Cancer Res., December 15, 2003; 63(24): 8695 - 8699. [Abstract] [Full Text] [PDF]
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L. Kopelovich, J. A. Crowell, and J. R. Fay The Epigenome as a Target for Cancer Chemoprevention J Natl Cancer Inst, December 3, 2003; 95(23): 1747 - 1757. [Abstract] [Full Text] [PDF]
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G. Tarafa, E. Prat, R.-A. Risques, S. Gonzalez, J. Camps, M. Grau, E. Guino, V. Moreno, M. Esteller, J. G. Herman, et al. Common Genetic Evolutionary Pathways in Familial Adenomatous Polyposis Tumors Cancer Res., September 15, 2003; 63(18): 5731 - 5737. [Abstract] [Full Text] [PDF]
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A. Villar-Garea, M. F. Fraga, J. Espada, and M. Esteller Procaine Is a DNA-demethylating Agent with Growth-inhibitory Effects in Human Cancer Cells Cancer Res., August 15, 2003; 63(16): 4984 - 4989. [Abstract] [Full Text] [PDF]
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M. V. Brock, M. Gou, Y. Akiyama, A. Muller, T.-T. Wu, E. Montgomery, M. Deasel, P. Germonpre, L. Rubinson, R. F. Heitmiller, et al. Prognostic Importance of Promoter Hypermethylation of Multiple Genes in Esophageal Adenocarcinoma Clin. Cancer Res., August 1, 2003; 9(8): 2912 - 2919. [Abstract] [Full Text] [PDF]
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M. van Engeland, M. P. Weijenberg, G. M. J. M. Roemen, M. Brink, A. P. de Bruine, R. A. Goldbohm, P. A. van den Brandt, S. B. Baylin, A. F. P. M. de Goeij, and J. G. Herman Effects of Dietary Folate and Alcohol Intake on Promoter Methylation in Sporadic Colorectal Cancer: The Netherlands Cohort Study on Diet and Cancer Cancer Res., June 15, 2003; 63(12): 3133 - 3137. [Abstract] [Full Text] [PDF]
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A. Gupta, A. K. Godwin, L. Vanderveer, A. Lu, and J. Liu Hypomethylation of the Synuclein{gamma} Gene CpG Island Promotes Its Aberrant Expression in Breast Carcinoma and Ovarian Carcinoma Cancer Res., February 1, 2003; 63(3): 664 - 673. [Abstract] [Full Text] [PDF]
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J. Brabender, H. Usadel, R. Metzger, P. M. Schneider, J. Park, D. Salonga, D. D. Tsao-Wei, S. Groshen, R. V. Lord, N. Takebe, et al. Quantitative O6-Methylguanine DNA Methyltransferase Methylation Analysis in Curatively Resected Non-Small Cell Lung Cancer: Associations with Clinical Outcome Clin. Cancer Res., January 1, 2003; 9(1): 223 - 227. [Abstract] [Full Text] [PDF]
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T. Tokugawa, H. Sugihara, T. Tani, and T. Hattori Modes of Silencing of p16 in Development of Esophageal Squamous Cell Carcinoma Cancer Res., September 1, 2002; 62(17): 4938 - 4944. [Abstract] [Full Text] [PDF]
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M. Zysman, A. Saka, A. Millar, J. Knight, W. Chapman, and B. Bapat Methylation of Adenomatous Polyposis Coli in Endometrial Cancer Occurs More Frequently in Tumors with Microsatellite Instability Phenotype Cancer Res., July 1, 2002; 62(13): 3663 - 3666. [Abstract] [Full Text] [PDF]
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S. Toyooka, K. O. Toyooka, K. Harada, K. Miyajima, P. Makarla, U. G. Sathyanarayana, J. Yin, F. Sato, N. Shivapurkar, S. J. Meltzer, et al. Aberrant Methylation of the CDH13 (H-cadherin) Promoter Region in Colorectal Cancers and Adenomas Cancer Res., June 1, 2002; 62(12): 3382 - 3386. [Abstract] [Full Text] [PDF]
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W. M. Clements, J. Wang, A. Sarnaik, O. J. Kim, J. MacDonald, C. Fenoglio-Preiser, J. Groden, and A. M. Lowy {beta}-Catenin Mutation Is a Frequent Cause of Wnt Pathway Activation in Gastric Cancer Cancer Res., June 1, 2002; 62(12): 3503 - 3506. [Abstract] [Full Text] [PDF]
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R. Maruyama, S. Toyooka, K. O. Toyooka, A. K. Virmani, S. Zochbauer-Muller, A. J. Farinas, J. D. Minna, J. McConnell, E. P. Frenkel, and A. F. Gazdar Aberrant Promoter Methylation Profile of Prostate Cancers and Its Relationship to Clinicopathological Features Clin. Cancer Res., February 1, 2002; 8(2): 514 - 519. [Abstract] [Full Text] [PDF]
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H. Usadel, J. Brabender, K. D. Danenberg, C. Jeronimo, S. Harden, J. Engles, P. V. Danenberg, S. Yang, and D. Sidransky Quantitative Adenomatous Polyposis Coli Promoter Methylation Analysis in Tumor Tissue, Serum, and Plasma DNA of Patients with Lung Cancer Cancer Res., January 1, 2002; 62(2): 371 - 375. [Abstract] [Full Text] [PDF]
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 M. Esteller, M. F. Fraga, M. Guo, J. Garcia-Foncillas, I. Hedenfalk, A. K. Godwin, J. Trojan, C. Vaurs-Barriere, Y.-J. Bignon, S. Ramus, et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis Hum. Mol. Genet., December 1, 2001; 10(26): 3001 - 3007. [Abstract] [Full Text] [PDF]
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R. Maruyama, S. Toyooka, K. O. Toyooka, K. Harada, A. K. Virmani, S. Zochbauer-Muller, A. J. Farinas, F. Vakar-Lopez, J. D. Minna, A. Sagalowsky, et al. Aberrant Promoter Methylation Profile of Bladder Cancer and Its Relationship to Clinicopathological Features Cancer Res., December 1, 2001; 61(24): 8659 - 8663. [Abstract] [Full Text] [PDF]
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A. Andreassen, R. Vikse, I.-L. Steffensen, J. E. Paulsen, and J. Alexander Intestinal tumours induced by the food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in multiple intestinal neoplasia mice have truncation mutations as well as loss of the wild-type Apc+ allele Mutagenesis, July 1, 2001; 16(4): 309 - 315. [Abstract] [Full Text] [PDF]
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S. M. Dong, H.-S. Kim, S.-H. Rha, and D. Sidransky Promoter Hypermethylation of Multiple Genes in Carcinoma of the Uterine Cervix Clin. Cancer Res., July 1, 2001; 7(7): 1982 - 1986. [Abstract] [Full Text] [PDF]
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A. K. Virmani, A. Rathi, U. G. Sathyanarayana, A. Padar, C. X. Huang, H. T. Cunnigham, A. J. Farinas, S. Milchgrub, D. M. Euhus, M. Gilcrease, et al. Aberrant Methylation of the Adenomatous Polyposis Coli (APC) Gene Promoter 1A in Breast and Lung Carcinomas Clin. Cancer Res., July 1, 2001; 7(7): 1998 - 2004. [Abstract] [Full Text] [PDF]
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T. Iwama Somatic Mutation Rate of the APC Gene Jpn. J. Clin. Oncol., May 1, 2001; 31(5): 185 - 187. [Abstract] [Full Text] [PDF]
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S. B. Baylin, M. Esteller, M. R. Rountree, K. E. Bachman, K. Schuebel, and J. G. Herman Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer Hum. Mol. Genet., April 1, 2001; 10(7): 687 - 692. [Abstract] [Full Text] [PDF]
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N. S. Fearnhead, M. P. Britton, and W. F. Bodmer The ABC of APC Hum. Mol. Genet., April 1, 2001; 10(7): 721 - 733. [Abstract] [Full Text] [PDF]
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P. Peltomaki Deficient DNA mismatch repair: a common etiologic factor for colon cancer Hum. Mol. Genet., April 1, 2001; 10(7): 735 - 740. [Abstract] [Full Text] [PDF]
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M. Esteller, C. Cordon-Cardo, P. G. Corn, S. J. Meltzer, K. S. Pohar, D. N. Watkins, G. Capella, M. A. Peinado, X. Matias-Guiu, J. Prat, et al. p14ARF Silencing by Promoter Hypermethylation Mediates Abnormal Intracellular Localization of MDM2 Cancer Res., April 1, 2001; 61(7): 2816 - 2821. [Abstract] [Full Text]
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M. Esteller, P. G. Corn, S. B. Baylin, and J. G. Herman A Gene Hypermethylation Profile of Human Cancer Cancer Res., April 1, 2001; 61(8): 3225 - 3229. [Abstract] [Full Text]
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I P M Tomlinson, R Roylance, and R S Houlston Two hits revisited again J. Med. Genet., February 1, 2001; 38(2): 81 - 85. [Abstract] [Full Text]
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, unmethylated CpG; •, methylated CpG. The
CpG island located in the APC promoter 1A is
unmethylated in normal lymphocytes. B,
methylation-specific PCR of APC promoter 1A in normal
tissues [colon, stomach, lung, breast, brain, esophagus
(Esoph), and kidney (Renal)]. PBR322/Msp
digest are shown at left as molecular weight markers.
The presence of a visible PCR product in those lanes marked
U indicates the presence of unmethylated genes; the
presence of product in those lanes marked M indicates
the presence of methylated genes. In vitro methylated
DNA (IVD) was used as positive control for methylation,
normal lymphocytes were used as negative control for methylation, and
water was used as negative PCR control. All of the normal tissues
analyzed are unmethylated at the APC promoter 1A.
) and antisense (
) is indicated. Each
row represents an individual cloned and sequenced allele
after sodium bisulfite DNA modification. CpG sites are marked as
circles and drawn to accurately reflect CpG density of
the region. 
