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Molecular Biology and Genetics |
Departments of Surgery [C. A. E., R. V. L., T. I. L., S. K. K., J. H. P., S. R. D., T. R. D., K. A. S., P. W. L.], Biochemistry and Molecular Biology [C. A. E., T. I. L., P. W. L.], Pathology [K. W.], and Preventive Medicine [L. B.], University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California 90089-9176
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The incidence of EAC3 has increased rapidly in the Western World over the past three decades (8 , 9) . EAC arises from a multistep process whereby normal squamous mucosa undergoes metaplasia to specialized columnar epithelium (IM or Barrett‘s esophagus), which then ultimately progresses to DYS and subsequent malignancy (10 , 11) . Epigenetic studies of this model have thus far been limited to the DNA methylation analysis of a few genes (12, 13, 14) . Most studies of epigenetic alterations in cancer have focused primarily on either a very small set of known genes (1 , 15) or on the global analysis of unknown CpG islands (2) . We have previously used a targeted approach to show that hypermethylation of the genes APC, CDKN2A, and ESR1 occur as early as the premalignant Barrett‘s esophagus stage (14) . However, this study was limited to six patients. The general frequency with which these methylation changes occurred could not be accurately resolved.
It has previously been reported that a subset of colorectal and gastric tumors display a CIMP, whereby aberrant hypermethylation changes are widespread, affecting multiple loci in a single tumor (16 , 17) . This is reflected in a bimodal distribution of the frequency of the number of genes methylated in a group of tumors (16) . CIMP tumors are a distinct group of tumors that are defined by a high degree of concordant CpG island hypermethylation of genes exclusively methylated in cancer, or type C genes. CIMP is now thought to be a new, distinct, yet major pathway of tumorigenesis (16 , 17) . The role of the CIMP pathway in the tumor evolution of EAC is still unknown because the previous epigenetic studies analyzed only one (12 , 13) or only a few genes (14) .
In this report, we have now combined the advantages of both the targeted and the comprehensive approaches by analyzing 20 different genes (see Table 1
) using a quantitative, high-throughput methylation assay, MethyLight (14
, 18
, 19)
: (a) to more extensively characterize the methylation changes in EAC; (b) to generate epigenomic fingerprints for the different histological stages of EAC; (c) to identify epigenetic biomarkers useful in disease diagnosis and prevention; and (d) to determine whether CIMP is a contributor to the tumorigenesis of EAC tumors. We screened 104 tissue specimens from 51 patients with different stages of Barrett‘s esophagus and/or associated adenocarcinoma. We found that the 20 genes segregated into classes of similar epigenetic behavior. Each class undergoes unique epigenetic changes at different steps of disease progression of EAC suggesting a step-wise loss of multiple protective barriers against CpG island hypermethylation. These epigenetic profiles may prove to be useful as a clinical tool to monitor or diagnose Barrett‘s esophagus or EAC. Furthermore, we found no clear evidence of a CIMP in the esophageal tumors analyzed.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Nucleic Acid Isolation.
Genomic DNA was isolated from the frozen-tissue biopsies by a simplified proteinase K digestion method (20)
. The DNA from the paraffin tissues was extracted in lysis buffer [Tris-HCl (100 mM; pH 8), EDTA (10 mM), proteinase K (1 mg/ml)] overnight at 50°C (21)
.
Sodium Bisulfite Conversion.
Sodium bisulfite conversion of genomic DNA was performed as described previously (22)
. The beads were incubated for 14 h at 50°C to ensure complete conversion.
MethyLight Analysis.
After sodium bisulfite conversion, the methylation analysis was performed by the fluorescence-based, real-time PCR assay MethyLight as described previously (14
, 18
, 19)
. Two sets of primers and probes, designed specifically for bisulfite-converted DNA, were used: a methylated set for the gene of interest and a reference set, ß-actin (ACTB), to normalize for input DNA. Specificity of the reactions for methylated DNA were confirmed separately using human sperm DNA (with very low levels of CpG island methylation) and SssI (New England Biolabs)-treated sperm DNA (heavily methylated) as described previously (14)
. The percentage of fully methylated molecules at a specific locus was calculated by dividing the GENE:ACTB ratio of a sample by the GENE:ACTB ratio of SssI-treated sperm DNA and multiplying by 100. We use the abbreviation PMR to indicate this measurement. The methylation analysis on the paraffin-microdissected samples was performed after bisulfite treatment as described above by an investigator (C. A. E.) blind to the associated DYS status of the samples. The primers and probes used in the methylation analysis are listed in Table 2
.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Refs. 1
, 6
, 15
, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39
). We included a region located in the MTHFR gene as a control for a single-copy sequence that does not satisfy the criteria of a CpG island. CpG dinucleotides outside of an island are presumably normally methylated, unlike CpG dinucleotides within CpG islands.
Fig. 1
illustrates the quantitative methylation data of the 20 genes from our screen of 84 tissue specimens from 31 patients with different stages of Barrett‘s esophagus and/or associated adenocarcinoma. There is a general increase in the frequency and in the quantitative level of CpG island hypermethylation at progressively advanced stages of disease. However, the propensity for aberrant methylation of the genes is not uniform. Genes differ both in their frequency and in their levels of hypermethylation in various tissues. Accordingly, genes can be grouped by their methylation behavior, as indicated in Fig. 1
. This allows for a visual assessment of concordant methylation of the different genes. We provide a rationale for each of the gene classes in the following section.
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). To equalize the quantitative impact of methylated genes within each class, we collapsed the methylation values that were used to generate Fig. 1
into a binary variable with a dichotomization point of 4 PMR (see "Materials and Methods"). This dichotomization moderates the effect of highly methylated genes, simplifies cross-gene comparisons of methylation frequencies, as shown in Fig. 2
, and allows the calculation of class averages of methylation frequencies, as shown in Fig. 3
. We based the 4-PMR-dichotomization point on previous work (13)
, and on its ability to discriminate between the different tissue types, as shown in Fig. 1
.
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, 2
, and 3
).
Class A consists of the genes CDKN2A, ESR1, and MYOD1 (Figs. 1
, 2
, and 3
). There is a statistically significant difference in the methylation frequency of ESR1 (P = 0.0001) and MYOD1 (P = 0.0038) of NE, as compared with IM tissue, but not for CDKN2A (P = 0.097). The frequency of CDKN2A methylation increases significantly in the more advanced stages of the adenocarcinoma (T) (P < 0.0001). Class B consists of the genes CALCA, MGMT, and TIMP3. In contrast to Class A, this class exhibits methylation in the NE mucosa and stomach (S) tissue (Figs. 1
and 2
). Only TIMP3 shows a significant difference in methylation frequency between the NE and the IM (P = 0.0074).
Class C consists of the gene APC, which is, in contrast to Classes A and B, methylated in all of the normal stomach samples (Figs. 1
and 2
). This confirms our previous documentation of APC methylation in normal stomach tissue (14)
. The mechanism that protects APC from methylation in the normal esophageal tissues but not in normal stomach tissues is not clear. Class D consists of the genes ARF, CDH1, CDKN2B, GSTP1, MLH1, PTGS2, and THBS1, which are infrequently methylated (Figs. 1
and 2
). There is a slight increase in the frequency of this class of genes in adenocarcinoma, but this does not approach statistical significance (Fig. 3)
. Interestingly, with the exception of PTGS2, which has not yet been investigated in other systems, the remaining Class D genes are frequently hypermethylated in other tumor types (Table 2)
. Class E genes (CTNNB1, RB1, TGFBR2, and TYMS1) are unmethylated at each stage in the progression of EAC. Similar to most Class D genes, RB1 and TGFBR2 have been found to be hypermethylated in other tumors types (Refs. 1
, 15
, 36
, 37
; Table 1
).
It should be noted that all of the samples scored positive for DNA input as measured by the control gene (ACTB). Therefore, the lack of detectable DNA methylation cannot be attributed to a lack of input DNA. We verified that the control reaction was sufficient in each sample such that a level as low as 1 PMR for a given gene could be detected. The integrity and specificity of all of the methylation reactions was confirmed using in vitro methylated human DNA.
The Class F gene (HIC1) is completely methylated, regardless of tissue type (Figs. 1
and 2
). HIC1 is commonly methylated in other types of cancers (1
, 15)
, and has been shown to be methylated in normal breast ductal tissue and bone marrow samples of breast cancer and acute myelogenous leukemia patients, respectively (6
, 40)
. Nevertheless, the finding of ubiquitous methylation of a CpG island in normal tissues was unexpected. Therefore, we confirmed the validity of the HIC1 MethyLight results using a different technique (HpaII-PCR; Ref. 41
; data not shown). Interestingly, the ubiquitous HIC1 methylation pattern is similar to the non-CpG island MTHFR control (Class G); however the percentage of methylated molecules is quantitatively higher (Fig. 1).
Epigenetic Profiles of EAC Progression.
Each tissue type shows a unique epigenetic profile that changes during disease progression (Fig. 3A)
. Classes A, B, and C are methylated at a significantly higher frequency in IM tissue than in normal esophageal mucosa (NE; Fig. 3, A and B
). Furthermore, the transition from IM to DYS or malignancy (T) is associated with an additional increase in Class A methylation (Fig. 3, A and B)
. The lack of a significant difference between DYS and adenocarcinoma for any of the gene classes or when all of the 19 genes are combined (Fig. 3, A and B)
suggests that most of these abnormal epigenetic alterations occur early in the progression of EAC.
Hypermethylation and EAC Tumor Grade and Stage.
We investigated whether the grade or stage of an EAC correlates with a higher frequency of CpG island hypermethylation. Moderately differentiated tumors have significantly less frequent Class A methylation compared with poorly differentiated tumors (P = 0.045; data not shown). Fig. 4A
shows that there is a significantly higher mean number of Class A genes methylated in stage II, III, and IV tumors relative to less advanced, stage I tumors. The differences between stage I tumors and stage II, III, and IV tumors did not reach statistical significance for any of the other classes.
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, NO) or whether they had associated DYS and/or adenocarcinoma present in a different region of the esophagus (Fig. 1
, YES). We found that the frequency of Class B methylation in the NE is indeed significantly higher in patients with associated DYS/tumor (P = 0.0037; Fig. 1
). In addition, we found that Class A methylation is more frequent in IM samples from patients with concurrent DYS or cancer, than in IM samples from patients without any evidence of further progression (P < 0.0001; Fig. 1
). A potential criticism of this analysis is that the same set of samples was used to delineate the class of genes as was used to test the association with a clinical parameter. Therefore, we performed a follow-up study of 20 additional cases of IM, entirely independent of this first data set. Our initial study had revealed that all of the IM samples that were associated with further disease progression had at least two Class A genes methylated, whereas all of the IM samples without associated DYS or adenocarcinoma did not show any methylation of Class A genes (Fig. 1)
. Therefore, we defined two or more Class A genes methylated as an indicator of increased risk for the presence of associated DYS or cancer. The data from our first series gives a P of 0.0048 in a Fisher‘s exact test of this association (Fig. 5A)
. Our new series of 20 independent cases gives a P of 0.018 (Fig. 5B)
. We conclude that the positive association between hypermethylation of Class A genes and the presence of associated DYS or cancer is significant. It should be noted that the IM samples without associated DYS in this follow-up study show a low frequency of samples with at least two genes methylated, which is in contrast to the absence of methylation in the first study (Figs. 1
and 5
). This may be attributed to the fact that the samples in the second series were microdissected from paraffin sections. Therefore, there is a lower background of unmethylated stromal cells in the sample. In this case, the methylation signal is not as diluted by other normal cells, and, consequently, the ratio of methylated molecules:total DNA may rise above the 4 PMR threshold. Alternatively, dysplastic or malignant tissue may have been missed during the endoscopic survey in some of the cases scored as free of further disease progression because of the sampling limitations of endoscopy. This is a well-documented problem in the detection of EAC (42)
.
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; Ref. 17
). Similar results are observed when we also include Class D genes (Fig. 6)
, which also exhibit type C methylation, and when we combine Classes A, B, C, and D genes (Fig. 6)
. Classes E and F genes are not included because they do not exhibit any methylation variation between the different tissue types. We did find a single sample with 10 of 14 Class A-D genes methylated (Fig. 1
, Case 3, and Fig. 6
). However, this sample only stands out when we include Class B genes, which are methylated in normal esophageal mucosa and, therefore, do not satisfy the definition of type C genes that constitute the CIMP phenotype (16
, 17)
. Therefore, we tentatively conclude that there is no clear evidence of a separate group of CIMP tumors in our study of EAC, as previously defined for colorectal and gastric cancer (16
, 17)
. We do find, however, that CpG island hypermethylation in EAC does occur across multiple loci in a given sample. Furthermore, the number of loci hypermethylated in a single sample increases as the disease progresses through different histological stages (Fig. 6)
. The bimodal distributions seen in IM tissues (Fig. 6)
can be fully attributed to the concurrent association with DYS or cancer described above.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We dichotomized the methylation data to equalize the quantitative impact of methylated genes within each class, simplifying cross-gene comparisons of methylation frequencies. However, the dichotomization point does not significantly affect the statistics or alter the conclusions. For instance, there is still a statistically significant difference in the mean percentage of genes methylated (of 19 genes) between the normal esophageal mucosa and the IM (P = 0.0003), DYS (P < 0.0001), and adenocarcinoma (T) (P < 0.0001) tissues when the data are dichotomized at 10 PMR. In addition, all of the statistically significant findings of the NE and IM methylation frequency with or without associated DYS remain significant at a dichotomization point of 10 PMR, instead of 4 PMR. It is important to note that 4 PMR is not comparable with a 4% methylation level of a single CpG dinucleotide. Rather, it indicates that in this sample, 4% of the DNA molecules had complete methylation at all of the CpG dinucleotides covered by the three MethyLight primers (usually about eight CpGs). The nature of the MethyLight assay is such that it is oblivious to any other methylation patterns that may be present (19) . Therefore, 4 PMR is likely to represent a higher mean level of methylation than 4%. The extensively methylated molecules that are assayed by MethyLight are likely to represent alleles that have been completely silenced by CpG island hypermethylation, although this was not investigated in this study.
This genomic approach to DNA methylation changes (as opposed to a functional approach) leads us to several interesting findings and conclusions. It is now clear that DNA hypermethylation is an early epigenetic alteration in the multistep progression of EAC. The premalignant IM is already significantly more methylated than the normal tissue. We report, for the first time, frequent hypermethylation of five additional genes in this tumor system: MYOD1, MGMT, CALCA, TIMP3, and HIC1. The methylation observed for MGMT, TIMP3, and HIC1 in normal tissues may be attributed to the region of the gene in which we analyzed methylation levels (43, 44, 45)
. These three genes were analyzed at CpG islands located at, or downstream of, the transcription start site (Table 2)
. However, this does not account for the CALCA methylation that we observed because we analyzed the promoter region of this gene. Low levels of CALCA methylation has been previously reported in normal bone marrow samples of acute myelogenous leukemia patients (6)
, which suggests that this locus may have a higher propensity to be methylated in the normal tissues of cancer patients.
It is of particular interest to note that dysplastic tissues are more frequently methylated than stage I tumors for both Class A (P < 0.0001) and B (P = 0.0174; Fig. 1
). This is similar to the finding of genetic abnormalities (loss of heterozygosity, deletions, and mutations) present in Barrett‘s esophagus with high-grade DYS but not present in the adjacent invasive EAC (10)
. Because stage II-IV tumors appear to be methylated in Class A genes at a similar frequency as DYS, this suggests that stage I tumors may actually evolve from an origin different from that of the dysplastic tissue and higher-staged tumors or may diverge after DYS independently from stage II-IV tumors during clonal expansion. Alternatively, stage I tumors could undergo a transient reversal of hypermethylation, although we consider that to be rather unlikely. Tumor development in Barrett‘s esophagus is proposed to evolve clonally through the linear multistep pathway of metaplasia-DYS-tumor (11)
. However, the occurrence of genetic and, now, epigenetic alterations in a nonlinear order suggests that the clonal evolution of EAC is more complex than originally predicted (10)
. A similar observation has been described for different stages of bladder tumors (46)
.
We did not find clear evidence, aside from one tumor with 10 genes methylated, for a separate cluster of tumors with extensive concordant methylation, which would be indicative of a CIMP. Similar results are obtained even if we examine only type C genes, as defined for CIMP (methylated in cancer, not methylated in normal tissues; Refs. 16 , 17 ). Interestingly, the type C genes in EAC differ from those described for colorectal cancer (16 , 17) . For example, ESR1 is classified as a type A gene (defined as methylated in aging normal tissues) rather than a type C gene in colorectal cancer, because it is frequently methylated in the normal colonic epithelium of aging individuals (16 , 17) . However, in EAC, ESR1 clearly behaves like a type C gene. This may be attributed to the difference in the technology used to measure hypermethylation or more likely may be attributable to differences in tissue types.
There is clearly a tissue-specific and tumor-specific propensity for particular genes to become hypermethylated. For instance, APC is hypermethylated in normal stomach, but not in normal esophageal mucosa. The tumor-specificity of hypermethylation is illustrated by the lack of detectable methylation of the two Class E genes TGFBR2 and RB1, which are frequently hypermethylated in gastric and lung tumors, and retinoblastoma tumors, respectively (3 , 36 , 37) . The tumor-specificity of CpG island hypermethylation suggests that there may be tissue-specific trans-acting factors that modulate methylation changes of these CpG islands during tumorigenesis and that differ between EACs and other tumor types. Alternatively, there may be a lack of selective advantage to the silencing of these genes in EACs by DNA methylation. There are two scenarios in which this would be the case. One is if the gene in question has been inactivated by a different, genetic mechanism, rendering hypermethylation of no further selective advantage. The other is if the gene does not play a role in tumor suppression in this particular tumor system.
Although alterations in DNA methylation changes are common events in tumorigenesis, the underlying mechanism is unclear. We have shown previously in colorectal tumors that abnormal methylation is not attributable to a mere up-regulation of the DNA methyltransferase genes, which suggests that other major players are involved (18)
. Our data do provide some first glimpses into the process underlying these abnormal methylation changes. We find that different, functionally unrelated, genes can behave in distinct classes with respect to their methylation changes within various tissues of EAC progression. The CpG island hypermethylation does not appear to be a random, stochastic process (although there is a stochastic component), but rather a step-wise process that involves multiple, distinct groups of alterations. This is consistent with the existence of several different mechanisms that protect against CpG island hypermethylation. In this scenario, the concerted changes seen at different CpG islands would be the result of the loss of a different type of protective element at different stages of disease progression. This finding does not appear to be dependent on the location of the CpG island relative to the gene, because both promoter and internal CpG islands were observed in all of the gene classes. We also examined the structural features of these CpG islands by analyzing the percentage of GC content, the observed/expected CpG ratio, and the CpG:GpC ratio, and we found no association with gene class (Table 2)
.
We show that the IM or NE samples themselves, with or without associated DYS or cancer, were histologically indistinguishable, yet molecularly distinct. NE and IM samples derived from individuals with concurrent, distally located DYS or malignancy show a statistically higher incidence of CpG island hypermethylation. We confirmed this finding in the IM tissues in a completely independent study (Fig. 5B)
. This suggests that epigenetic markers, particularly Class A and B genes, may be used as disease screening tools and perhaps ultimately as predictive markers for the progression of more advanced-stage disease. However, because this was not a longitudinal study, we cannot distinguish whether the methylation seen in the preneoplastic tissues represents a predisposing event in the field of cells that give rise to the DYS, or whether the methylation in the preneoplastic tissue develops concurrently with the DYS or adenocarcinoma. Regardless, these methylation profiles could be of profound significance in the early detection of this disease. A molecular diagnostic approach using normal and/or premalignant tissues that might identify patients with cancer or at elevated risk for developing cancer would provide an opportunity for early intervention. Furthermore, a benefit of using CpG island hypermethylation as a diagnostic marker is that it can easily be detected in a field of normal cell contamination as a gain of signal, unlike loss of gene expression, loss of heterozygosity, and deletion analysis, which are difficult to resolve in a sample with contaminating normal cells. A prospective longitudinal study should help reveal whether these epigenetic alterations in normal or early-stage tissues are predictive of imminent dysplastic/malignant disease. A concern in this part of our study is the potential for the presence of contaminating tumor cells in the NE and IM tissue. If the methylation that we observe in nondysplastic tissues were indeed attributable to admixture of dysplastic or malignant tissues, then the level of contamination would have to be at least 4 PMR, because we use a 4-PMR dichotomization point. Although the presence of contaminating dysplastic/tumor cells can never be fully excluded, this is unlikely to be the case, because not only were the NE and IM samples separated by large distances (
10 cm in the case of the normal tissue) or microdissected (IM samples in the second study) from the malignant and dysplastic areas, but each sample was also very carefully reviewed by a pathologist for any signs of malignancy or DYS in both of the studies.
In summary, the 19 CpG islands segregate into six classes of epigenetic patterns in the various tissue types. Each class undergoes unique epigenetic changes at different steps of disease progression of EAC. We propose that these unique epigenomic profiles arise from an interplay between gene-specific cis-acting factors and tissue- and tumor-specific trans-acting factors. Additional studies such as this one will help to clarify this picture and identify clusters of CpG islands that behave concordantly in different systems. The next step will then be to identify the molecular mechanisms and factors affecting the various CpG island clusters.
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FOOTNOTES |
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1 Supported by NIH Grant R01 CA 75090 from the National Cancer Institute (to P. W. L.). 
2 To whom requests for reprints should be addressed, at USC/Norris Comprehensive Cancer Center, Room 6418, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176. Phone: (323) 865-0650; Fax: (323) 865-0158; E-mail: plaird{at}hsc.usc.edu
3 The abbreviations used are: EAC, esophageal adenocarcinoma; CIMP, CpG island methylator phenotype; IM, intestinal metaplasia; NE, normal esophagus; DYS, dysplasia; PMR, percentage of methylated reference; PLSD, protected least significant difference.
Received 8/29/00. Accepted 2/13/01.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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 J. K. Stephen, L. E. Vaught, K. M. Chen, V. Shah, V. G. Schweitzer, G. Gardner, M. S. Benninger, and M. J. Worsham An Epigenetically Derived Monoclonal Origin for Recurrent Respiratory Papillomatosis Arch Otolaryngol Head Neck Surg, July 1, 2007; 133(7): 684 - 692. [Abstract] [Full Text] [PDF]
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 S. Ogino, T. Kawasaki, G. J. Kirkner, P. Kraft, M. Loda, and C. S. Fuchs Evaluation of Markers for CpG Island Methylator Phenotype (CIMP) in Colorectal Cancer by a Large Population-Based Sample J. Mol. Diagn., July 1, 2007; 9(3): 305 - 314. [Abstract] [Full Text] [PDF]
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I. Zighelboim, P. J. Goodfellow, A. P. Schmidt, K. C. Walls, M. A. Mallon, D. G. Mutch, P. S. Yan, T. H.-M. Huang, and M. A. Powell Differential Methylation Hybridization Array of Endometrial Cancers Reveals Two Novel Cancer-Specific Methylation Markers Clin. Cancer Res., May 15, 2007; 13(10): 2882 - 2889. [Abstract] [Full Text] [PDF]
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D. R. Yates, I. Rehman, M. F. Abbod, M. Meuth, S. S. Cross, D. A. Linkens, F. C. Hamdy, and J. W.F. Catto Promoter Hypermethylation Identifies Progression Risk in Bladder Cancer Clin. Cancer Res., April 1, 2007; 13(7): 2046 - 2053. [Abstract] [Full Text] [PDF]
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C. A. Righini, F. de Fraipont, J.-F. Timsit, C. Faure, E. Brambilla, E. Reyt, and M.-C. Favrot Tumor-Specific Methylation in Saliva: A Promising Biomarker for Early Detection of Head and Neck Cancer Recurrence Clin. Cancer Res., February 15, 2007; 13(4): 1179 - 1185. [Abstract] [Full Text] [PDF]
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C. Zhang, Z. Li, Y. Cheng, F. Jia, R. Li, M. Wu, K. Li, and L. Wei CpG Island Methylator Phenotype Association with Elevated Serum {alpha}-Fetoprotein Level in Hepatocellular Carcinoma Clin. Cancer Res., February 1, 2007; 13(3): 944 - 952. [Abstract] [Full Text] [PDF]
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 R. Tetzner, D. Dietrich, and J. Distler Control of carry-over contamination for PCR-based DNA methylation quantification using bisulfite treated DNA Nucleic Acids Res., January 12, 2007; 35(1): e4 - e4. [Abstract] [Full Text] [PDF]
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M. Wallner, A. Herbst, A. Behrens, A. Crispin, P. Stieber, B. Goke, R. Lamerz, and F. T. Kolligs Methylation of Serum DNA Is an Independent Prognostic Marker in Colorectal Cancer Clin. Cancer Res., December 15, 2006; 12(24): 7347 - 7352. [Abstract] [Full Text] [PDF]
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R C Fitzgerald Molecular basis of Barrett's oesophagus and oesophageal adenocarcinoma. Gut, December 1, 2006; 55(12): 1810 - 1820. [Full Text] [PDF]
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J. P. Hamilton, F. Sato, Z. Jin, B. D. Greenwald, T. Ito, Y. Mori, B. C. Paun, T. Kan, Y. Cheng, S. Wang, et al. Reprimo Methylation Is a Potential Biomarker of Barrett's-Associated Esophageal Neoplastic Progression. Clin. Cancer Res., November 15, 2006; 12(22): 6637 - 6642. [Abstract] [Full Text] [PDF]
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S. Ogino, T. Kawasaki, G. J. Kirkner, M. Loda, and C. S. Fuchs CpG Island Methylator Phenotype-Low (CIMP-Low) in Colorectal Cancer: Possible Associations with Male Sex and KRAS Mutations J. Mol. Diagn., November 1, 2006; 8(5): 582 - 588. [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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S Ogino, M Cantor, T Kawasaki, M Brahmandam, G J Kirkner, D J Weisenberger, M Campan, P W Laird, M Loda, and C S Fuchs CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies Gut, July 1, 2006; 55(7): 1000 - 1006. [Abstract] [Full Text] [PDF]
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S. Ogino, T. Kawasaki, M. Brahmandam, M. Cantor, G. J. Kirkner, D. Spiegelman, G. M. Makrigiorgos, D. J. Weisenberger, P. W. Laird, M. Loda, et al. Precision and Performance Characteristics of Bisulfite Conversion and Real-Time PCR (MethyLight) for Quantitative DNA Methylation Analysis J. Mol. Diagn., May 1, 2006; 8(2): 209 - 217. [Abstract] [Full Text] [PDF]
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D. K. Vanaja, K. V. Ballman, B. W. Morlan, J. C. Cheville, R. M. Neumann, M. M. Lieber, D. J. Tindall, and C. Y.F. Young PDLIM4 Repression by Hypermethylation as a Potential Biomarker for Prostate Cancer Clin. Cancer Res., February 15, 2006; 12(4): 1128 - 1136. [Abstract] [Full Text] [PDF]
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 S. Hu, M. Ewertz, R. P. Tufano, M. Brait, A. L. Carvalho, D. Liu, A. P. Tufaro, S. Basaria, D. S. Cooper, D. Sidransky, et al. Detection of Serum Deoxyribonucleic Acid Methylation Markers: A Novel Diagnostic Tool for Thyroid Cancer J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 98 - 104. [Abstract] [Full Text] [PDF]
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D. J. Weisenberger, M. Campan, T. I. Long, M. Kim, C. Woods, E. Fiala, M. Ehrlich, and P. W. Laird Analysis of repetitive element DNA methylation by MethyLight Nucleic Acids Res., December 2, 2005; 33(21): 6823 - 6836. [Abstract] [Full Text] [PDF]
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E. Rosenbaum, M. O. Hoque, Y. Cohen, M. Zahurak, M. A. Eisenberger, J. I. Epstein, A. W. Partin, and D. Sidransky Promoter Hypermethylation as an Independent Prognostic Factor for Relapse in Patients with Prostate Cancer Following Radical Prostatectomy Clin. Cancer Res., December 1, 2005; 11(23): 8321 - 8325. [Abstract] [Full Text] [PDF]
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J. Bigler, C. M. Ulrich, T. Kawashima, J. Whitton, and J. D. Potter DNA Repair Polymorphisms and Risk of Colorectal Adenomatous or Hyperplastic Polyps Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2501 - 2508. [Abstract] [Full Text] [PDF]
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P. J. Bastian, J. Ellinger, A. Wellmann, N. Wernert, L. C. Heukamp, S. C. Muller, and A. von Ruecker Diagnostic and Prognostic Information in Prostate Cancer with the Help of a Small Set of Hypermethylated Gene Loci Clin. Cancer Res., June 1, 2005; 11(11): 4097 - 4106. [Abstract] [Full Text] [PDF]
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 P. W. Laird Cancer epigenetics Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R65 - R76. [Abstract] [Full Text] [PDF]
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H. Zou, N. K. Osborn, J. J. Harrington, K. K. Klatt, J. R. Molina, L. J. Burgart, and D. A. Ahlquist Frequent Methylation of Eyes Absent 4 Gene in Barrett's Esophagus and Esophageal Adenocarcinoma Cancer Epidemiol. Biomarkers Prev., April 1, 2005; 14(4): 830 - 834. [Abstract] [Full Text] [PDF]
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C. An, I.-S. Choi, J. C. Yao, S. Worah, K. Xie, P. F. Mansfield, J. A. Ajani, A. Rashid, S. R. Hamilton, and T.-T. Wu Prognostic Significance of CpG Island Methylator Phenotype and Microsatellite Instability in Gastric Carcinoma Clin. Cancer Res., January 15, 2005; 11(2): 656 - 663. [Abstract] [Full Text] [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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C. Jeronimo, R. Henrique, M. O. Hoque, E. Mambo, F. R. Ribeiro, G. Varzim, J. Oliveira, M. R. Teixeira, C. Lopes, and D. Sidransky A Quantitative Promoter Methylation Profile of Prostate Cancer Clin. Cancer Res., December 15, 2004; 10(24): 8472 - 8478. [Abstract] [Full Text] [PDF]
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H. M. Muller, S. Millinger, H. Fiegl, G. Goebel, L. Ivarsson, A. Widschwendter, E. Muller-Holzner, C. Marth, and M. Widschwendter Analysis of Methylated Genes in Peritoneal Fluids of Ovarian Cancer Patients: A New Prognostic Tool Clin. Chem., November 1, 2004; 50(11): 2171 - 2173. [Full Text] [PDF]
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M. L. Gonzalgo, S. Yegnasubramanian, G. Yan, C. G. Rogers, T. L. Nicol, W. G. Nelson, and C. P. Pavlovich Molecular Profiling and Classification of Sporadic Renal Cell Carcinoma by Quantitative Methylation Analysis Clin. Cancer Res., November 1, 2004; 10(21): 7276 - 7283. [Abstract] [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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M. O. Hoque, S. Begum, O. Topaloglu, C. Jeronimo, E. Mambo, W. H. Westra, J. A. Califano, and D. Sidransky Quantitative Detection of Promoter Hypermethylation of Multiple Genes in the Tumor, Urine, and Serum DNA of Patients with Renal Cancer Cancer Res., August 1, 2004; 64(15): 5511 - 5517. [Abstract] [Full Text] [PDF]
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M. Widschwendter, G. Jiang, C. Woods, H. M. Muller, H. Fiegl, G. Goebel, C. Marth, E. Muller-Holzner, A. G. Zeimet, P. W. Laird, et al. DNA Hypomethylation and Ovarian Cancer Biology Cancer Res., July 1, 2004; 64(13): 4472 - 4480. [Abstract] [Full Text] [PDF]
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C. Zuo, L. Ai, P. Ratliff, J. Y. Suen, E. Hanna, T. P. Brent, and C.-Y. Fan O6-Methylguanine-DNA Methyltransferase Gene: Epigenetic Silencing and Prognostic Value in Head and Neck Squamous Cell Carcinoma Cancer Epidemiol. Biomarkers Prev., June 1, 2004; 13(6): 967 - 975. [Abstract] [Full Text] [PDF]
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M. Widschwendter, K. D. Siegmund, H. M. Muller, H. Fiegl, C. Marth, E. Muller-Holzner, P. A. Jones, and P. W. Laird Association of Breast Cancer DNA Methylation Profiles with Hormone Receptor Status and Response to Tamoxifen Cancer Res., June 1, 2004; 64(11): 3807 - 3813. [Abstract] [Full Text] [PDF]
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H. M. Muller, L. Ivarsson, H. Schrocksnadel, H. Fiegl, A. Widschwendter, G. Goebel, S. Kilga-Nogler, H. Philadelphy, W. Gutter, C. Marth, et al. DNA Methylation Changes in Sera of Women in Early Pregnancy Are Similar to Those in Advanced Breast Cancer Patients Clin. Chem., June 1, 2004; 50(6): 1065 - 1068. [Full Text] [PDF]
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A. Widschwendter, C. Gattringer, L. Ivarsson, H. Fiegl, A. Schneitter, A. Ramoni, H. M. Muller, A. Wiedemair, S. Jerabek, E. Muller-Holzner, et al. Analysis of Aberrant DNA Methylation and Human Papillomavirus DNA in Cervicovaginal Specimens to Detect Invasive Cervical Cancer and Its Precursors Clin. Cancer Res., May 15, 2004; 10(10): 3396 - 3400. [Abstract] [Full Text] [PDF]
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H. Fiegl, C. Gattringer, A. Widschwendter, A. Schneitter, A. Ramoni, D. Sarlay, I. Gaugg, G. Goebel, H. M. Muller, E. Mueller-Holzner, et al. Methylated DNA Collected by Tampons--A New Tool to Detect Endometrial Cancer Cancer Epidemiol. Biomarkers Prev., May 1, 2004; 13(5): 882 - 888. [Abstract] [Full Text] [PDF]
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T.-S. Wong, D. L.-W. Kwong, J. S.-T. Sham, W. I. Wei, Y.-L. Kwong, and A. P.-W. Yuen Quantitative Plasma Hypermethylated DNA Markers of Undifferentiated Nasopharyngeal Carcinoma Clin. Cancer Res., April 1, 2004; 10(7): 2401 - 2406. [Abstract] [Full Text] [PDF]
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S. Yegnasubramanian, J. Kowalski, M. L. Gonzalgo, M. Zahurak, S. Piantadosi, P. C. Walsh, G. S. Bova, A. M. De Marzo, W. B. Isaacs, and W. G. Nelson Hypermethylation of CpG Islands in Primary and Metastatic Human Prostate Cancer Cancer Res., March 15, 2004; 64(6): 1975 - 1986. [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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A. Widschwendter, H. M. Muller, H. Fiegl, L. Ivarsson, A. Wiedemair, E. Muller-Holzner, G. Goebel, C. Marth, and M. Widschwendter DNA Methylation in Serum and Tumors of Cervical Cancer Patients Clin. Cancer Res., January 15, 2004; 10(2): 565 - 571. [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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K. Kawakami, A. Ruszkiewicz, G. Bennett, J. Moore, G. Watanabe, and B. Iacopetta The Folate Pool in Colorectal Cancers Is Associated with DNA Hypermethylation and with a Polymorphism in Methylenetetrahydrofolate Reductase Clin. Cancer Res., December 1, 2003; 9(16): 5860 - 5865. [Abstract] [Full Text] [PDF]
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H. M. Muller, A. Widschwendter, H. Fiegl, L. Ivarsson, G. Goebel, E. Perkmann, C. Marth, and M. Widschwendter DNA Methylation in Serum of Breast Cancer Patients: An Independent Prognostic Marker Cancer Res., November 15, 2003; 63(22): 7641 - 7645. [Abstract] [Full Text] [PDF]
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K. Kishi, Y. Doki, M. Yano, T. Yasuda, Y. Fujiwara, S. Takiguchi, S. Kim, I. Higuchi, and M. Monden Reduced MLH1 Expression after Chemotherapy Is an Indicator for Poor Prognosis in Esophageal Cancers Clin. Cancer Res., October 1, 2003; 9(12): 4368 - 4375. [Abstract] [Full Text] [PDF]
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J.-P. J. Issa Methylation and Prognosis: Of Molecular Clocks and Hypermethylator Phenotypes Clin. Cancer Res., August 1, 2003; 9(8): 2879 - 2881. [Full Text] [PDF]
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B. P. Whitcomb, D. G. Mutch, T. J. Herzog, J. S. Rader, R. K. Gibb, and P. J. Goodfellow Frequent HOXA11 and THBS2 Promoter Methylation, and a Methylator Phenotype in Endometrial Adenocarcinoma Clin. Cancer Res., June 1, 2003; 9(6): 2277 - 2287. [Abstract] [Full Text] [PDF]
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L. Zhang, W. Lu, X. Miao, D. Xing, W. Tan, and D. Lin Inactivation of DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relation to p53 mutations in esophageal squamous cell carcinoma Carcinogenesis, June 1, 2003; 24(6): 1039 - 1044. [Abstract] [Full Text] [PDF]
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A O-O Chan, S-K Lam, B C-Y Wong, W-M Wong, M-F Yuen, Y-H Yeung, W-M Hui, A Rashid, and Y-L Kwong Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer Gut, April 1, 2003; 52(4): 502 - 506. [Abstract] [Full Text] [PDF]
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F. Sato, D. Shibata, N. Harpaz, Y. Xu, J. Yin, Y. Mori, S. Wang, A. Olaru, E. Deacu, F. M. Selaru, et al. Aberrant Methylation of the HPP1 Gene in Ulcerative Colitis-associated Colorectal Carcinoma Cancer Res., December 1, 2002; 62(23): 6820 - 6822. [Abstract] [Full Text] [PDF]
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 B. N. Trinh, T. I. Long, A. E. Nickel, D. Shibata, and P. W. Laird DNA Methyltransferase Deficiency Modifies Cancer Susceptibility in Mice Lacking DNA Mismatch Repair Mol. Cell. Biol., May 1, 2002; 22(9): 2906 - 2917. [Abstract] [Full Text] [PDF]
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A. K. Virmani, J. A. Tsou, K. D. Siegmund, L. Y. C. Shen, T. I. Long, P. W. Laird, A. F. Gazdar, and I. A. Laird-Offringa Hierarchical Clustering of Lung Cancer Cell Lines Using DNA Methylation Markers Cancer Epidemiol. Biomarkers Prev., March 1, 2002; 11(3): 291 - 297. [Abstract] [Full Text] [PDF]
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C. A. Eads, A. E. Nickel, and P. W. Laird Complete Genetic Suppression of Polyp Formation and Reduction of CpG-Island Hypermethylation in ApcMin/+Dnmt1-Hypomorphic Mice Cancer Res., March 1, 2002; 62(5): 1296 - 1299. [Abstract] [Full Text] [PDF]
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M. Widschwendter and P. A. Jones The Potential Prognostic, Predictive, and Therapeutic Values of DNA Methylation in Cancer : Commentary re: J. Kwong et al., Promoter Hypermethylation of Multiple Genes in Nasopharyngeal Carcinoma. Clin. Cancer Res., 8: 131-137, 2002, and H-Z. Zou et al., Detection of Aberrant p16 Methylation in the Serum of Colorectal Cancer Patients. Clin. Cancer Res., 8: 188-191, 2002. Clin. Cancer Res., January 1, 2002; 8(1): 17 - 21. [Full Text] [PDF]
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D. J. Wong, T. G. Paulson, L. J. Prevo, P. C. Galipeau, G. Longton, P. L. Blount, and B. J. Reid p16INK4a Lesions Are Common, Early Abnormalities that Undergo Clonal Expansion in Barrett's Metaplastic Epithelium Cancer Res., November 1, 2001; 61(22): 8284 - 8289. [Abstract] [Full Text] [PDF]
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P. G. Corn, E. I. Heath, R. Heitmiller, F. Fogt, A. A. Forastiere, J. G. Herman, and T.-T. Wu Frequent Hypermethylation of the 5' CpG Island of E-Cadherin in Esophageal Adenocarcinoma Clin. Cancer Res., September 1, 2001; 7(9): 2765 - 2769. [Abstract] [Full Text] [PDF]
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, samples with less than 4 PMR;
, 4–20 PMR;
, 21–50 PMR; 
, samples with >50 PMR. On the left, the tissue types. On the right: numbers (1, 2, 3, and 4), TNM tumor staging; YES, presence of distally located DYS and/or adenocarcinoma in the patient; NO, absence of distally located DYS and/or adenocarcinoma in the patient. In the columns: N, an analysis for which the control gene ACTB did not reach sufficient levels to allow the detection of a minimal value of 1 PMR for that methylation reaction in that particular sample.
