© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 18, 1511-1516,
September 20, 2000
© 2000 Oxford University Press
REPORTS |
Hypermethylation of the Death-Associated Protein (DAP) Kinase Promoter and Aggressiveness in Stage I Non-Small-Cell Lung Cancer
Affiliations of authors: X. Tang, F. R. Khuri, D. Liu, W. K. Hong, L. Mao (Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology), J. J. Lee (Department of Biostatistics), B. L. Kemp (Department of Pathology), The University of Texas M. D. Anderson Cancer Center, Houston.
Correspondence to: Li Mao, M.D., Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: lmao{at}mdanderson.org).
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ABSTRACT |
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Background: Death-associated protein (DAP) kinase is a serine/threonine kinase that is important in ligand-induced programmed cell death and plays an important role in lung cancer metastasis in animal models. Hypermethylation of the promoter represses the expression of the DAP kinase gene. Our purpose was to determine whether the hypermethylation status of the DAP kinase promoter influences the prognosis of non-small-cell lung cancer (NSCLC). Methods: We retrospectively studied 135 patients with pathologic stage I NSCLC who had undergone curative surgery. Methylation-specific polymerase chain reaction was used to determine the methylation status of the DAP kinase promoter in resected specimens from patients with primary NSCLC. Statistical analyses, all two-sided, were performed to determine the prognostic effect of methylation status on various clinical parameters. Results: Hypermethylation of the DAP kinase promoter was found in 59 (44%) of the 135 tumors. Patients whose tumors exhibited such hypermethylation had a statistically significantly poorer probability of overall survival at 5 years after surgery than those without such hypermethylation (.46 versus .68; P = .007). Moreover, the groups with and without hypermethylation of the DAP kinase promoter showed a striking difference in the probability of disease-specific survival; i.e., among people who died of lung cancer-related causes specifically, the probability of 5-year survival was .56 for those with such hypermethylation and .92 for those without it (P<.001). Multivariate analysis indicated that hypermethylation of the DAP kinase promoter is the only independent predictor for disease-specific survival among clinical and histologic parameters tested. Conclusions: Hypermethylation of the DAP kinase promoter is a common abnormality in early-stage NSCLC. This abnormality is strongly associated with survival, suggesting that DAP kinase plays an important role in determining the biologic aggressiveness of early-stage NSCLC.
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INTRODUCTION |
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Worldwide, lung cancer is by far the most common cause of cancer deaths and cancer-related deaths in men (1). Lung cancer incidence has also increased statistically significantly in women in recent years (2). Despite improvements in the diagnosis and treatment of this disease in the past two decades, the survival rate remains dismal (1,2). Lung cancer can be classified into two major types, non-small-cell lung cancer (NSCLC) and small-cell lung cancer. NSCLC is much more common than small-cell lung cancer, accounting for about 80% of all lung cancer cases. NSCLC can be divided histologically into two major histologic subtypes, squamous cell carcinoma and adenocarcinoma.
For patients with early-stage NSCLC, standard treatment remains the complete surgical resection of primary tumors. Although this treatment is effective and can cure about 60% of the patients with stage I disease, the remaining 40% of patients will die of the disease within 5 years of surgery (3). With advances in the early detection of lung cancer (4), we anticipate that more patients with lung cancers will be diagnosed at earlier stages. However, current clinical means cannot predict whether a patient may be cured by surgical treatment alone or will require additional and more aggressive treatment to improve the long-term survival. It is, therefore, desirable that novel and clinically applicable strategies be developed to augment the current NSCLC staging system for better classification of early-stage disease. Subsequently, better treatments might be devised for patients with a high risk of disease recurrence or metastasis in addition to complete surgical resection of primary tumors.
The development of NSCLC is a multistep process involving accumulation of genetic and epigenetic alterations (5–7). Inactivation of tumor-suppressor genes has been shown to be important in lung tumorigenesis and to contribute to the abnormal proliferation, transformation, invasion, and metastasis of NSCLC (8–11). Death-associated protein (DAP) kinase, also known as DAP-2, is a novel serine/threonine kinase required for interferon gamma-induced apoptotic cell death (12). In murine models, lung carcinoma clones with highly aggressive metastatic behavior lack DAP kinase expression, whereas the clones with low metastatic capabilities express the protein (13). Restoration of DAP kinase to physiologic levels in highly metastatic carcinoma cells can suppress the metastatic ability of these cells (13). Thus, DAP kinase may function as a metastatic suppressor. It has been shown that the expression of DAP kinase was repressed in several types of human cancers by hypermethylation in the promoter CpG region of the gene (14–16), supporting the role of DAP kinase in tumorigenesis.
To determine whether the DAP kinase gene is frequently inactivated through hypermethylation in early lung tumorigenesis and whether such inactivation is associated with aggressive biologic behavior of the tumors, we analyzed 135 patients with pathologic stage I NSCLC for the methylation status of CpG sites located in the 5` end of the DAP kinase gene in surgically resected primary tumor specimens. Statistical analysis was performed to determine the prognostic effect of the hypermethylation status on various clinical parameters.
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SUBJECTS AND METHODS |
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TopNotesAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study population. One hundred thirty-five patients who were diagnosed with pathologic stage I NSCLC (17) and had undergone lobectomy or pneumonectomy for complete resection of their primary tumors at The University of Texas M. D. Anderson Cancer Center, Houston, during the period from 1975 through 1990 were enrolled in the study. During that period, a total of 588 patients were diagnosed as having stage I NSCLC in that institution. Patients were followed-up for at least 5 years. Tissue blocks were available for 163 of these 588 patients. Tumor tissues from 135 patients contained an adequate number of tumor cells and, therefore, were suitable for this study. The follow-up information was based on chart review and on reports from our tumor registry service. The study was reviewed and approved by the institution's Surveillance Committee to allow us to obtain tissue blocks and all pertinent follow-up information. None of the patients had received adjuvant chemotherapy or radiation therapy before or after surgery. Tissue sections (4 µm thick) were obtained from each tissue block, stained with hematoxylin–eosin, and reviewed by two pathologists (X. Tang and B. L. Kemp) to confirm the diagnosis and the presence or absence of tumor cells in these sections.
Microdissection and DNA extraction. Sections (8 µm thick) from formalin-fixed and paraffin-embedded tissue blocks were obtained. Tumor parts in each section were dissected under a stereomicroscope, as described previously (18,19). Dissected tissues were digested in 200 µL of digestion buffer containing 50 mM Tris–HCl (pH 8.0), 1% sodium dodecyl sulfate, and proteinase K (0.5 mg/mL) at 42 °C for 36 hours. The digested products were purified by extracting with phenol/chloroform twice. DNA was then precipitated by the ethanol precipitation method in the presence of glycogen (Boehringer Mannheim Biochemicals, Indianapolis, IN) and recovered in distilled water.
Methylation-specific polymerase chain reaction (PCR). Two hundred nanograms of DNA from each tumor was used in the initial step of chemical modification. Briefly, DNA was denatured by NaOH and treated with sodium bisulfite (Sigma Chemical Co., St. Louis, MO). After purification with the use of Wizard DNA purification resin (Promega Corp., Madison, WI), the DNA was treated again with NaOH. After precipitation, DNA was recovered in water and was ready to add to a PCR with the use of specific primers for either the methylated or the unmethylated DAP kinase promoter, as described previously (16). PCRs were carried out in 25 µL containing about 10 ng of modified DNA, 3% dimethyl sulfoxide, all four deoxynucleoside triphosphates (each at 200 µM), 1.5 mM MgCl2, 0.4 µM PCR primers, and 1.25 U of Taq DNA polymerase (Life Technologies, Inc. [GIBCO BRL], Gaithersburg, MD). DNA was amplified for 35 cycles at 95 °C for 30 seconds, 60 °C for 60 seconds, and 70 °C for 60 seconds, followed by a 5-minute extension at 70 °C in a temperature cycler (Hybaid; Omnigene, Woodbridge, NJ) in 500-µL plastic tubes. PCR products were separated on 2% agarose gels and visualized after staining with ethidium bromide. For each DNA sample, primer sets for methylated DNA and unmethylated DNA were used for analysis. The hypermethylation status was determined by visualizing a 98-base-pair PCR product with the methylation-specific primer set. All PCRs were repeated twice, and the results were reproducible.
Statistical analysis.
Survival probability as a function of time was computed by the Kaplan–Meier estimator. The variance of the Kaplan–Meier estimator was computed by the Greenwood formula. The 5-year survival rates were estimated and compared by the asymptotic z test between the hypermethylation and no-hypermethylation groups. The log-rank test was used to compare patients' survival time between groups. Both overall survival and disease-specific survival (i.e., survival rates among people who died of lung cancer-related causes specifically) were analyzed. The two-sided 
2 test was used to test equal proportion between groups in two-way contingency tables. Cox regression was used to model the risks of DAP kinase hypermethylation on survival time, with adjustment for clinical and histopathologic parameters (age, sex, tumor histology subgroup, tumor size, and smoking status). All statistical tests are two-sided.
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RESULTS |
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A total of 135 patients were evaluated in this study. All patients underwent only surgical treatment of their primary tumors. Ninety-one patients died, and 44 patients were still alive at the time of the last follow-up report. Among the 91 patients who died, 39 died of lung cancer, 16 died of heart diseases, 16 died of respiratory diseases, three died of other organ failures, and 17 died of unknown causes. The median follow-up time was 8.5 years among the patients remaining alive. Patient ages ranged from 41 to 82 years, with a median age of 62.8 years; this is similar to the age distribution in the large database of NSCLC from our institution (data not shown). Thirty-five (26%) of the patients were women and 100 (74%) were men, which is comparable to the gender distribution of the disease in the 1970s and 1980s (2). The probability of 5-year overall survival was 58% and the probability of disease-specific survival was 76% in our patient population, which are similar to the probabilities reported in a previous study with a large number of cases from our institution (20). The general clinical characteristics of the patients are shown in Table 1
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We analyzed the hypermethylation status of the DAP kinase CpG sites located at the 5` end untranslated region of the gene in the 135 primary tumor samples from patients with pathologic stage I NSCLC. Since tumor sections were dissected under a stereomicroscope, tumor cell populations were 70% or more of most of the specimens. The primer sets for both hypermethylated sequences and nonhypermethylated sequences were tested by use of unmodified genomic DNA, modified DNA from normal tissues, and modified DNA with hypermethylation of the CpG sites. Unmodified genomic DNA could not be amplified with either the hypermethylated primer set or the nonhypermethylated one, but modified normal or hypermethylated DNA could be effectively amplified with only the corresponding primer sets (data not shown). Modified DNA from 59 (44%) of the 135 tumors was amplified with the methylation-specific primer set. PCR products were separated on an agarose gel, and a specific 98-base-pair PCR product was visualized with a methylation-specific primer set. This product indicates the presence of tumor cells with hypermethylated CpG sites at the critical region of the DAP kinase gene in these tumors (Fig. 1
and Table 2). PCR products obtained from both methylated and unmethylated primer sets in selected cases were directly sequenced, and the expected methylated or unmethylated status was verified (data not shown). When we analyzed the status of DAP kinase hypermethylation in the tumors according to the sex and age of the corresponding patients, we did not observe any statistical association between these factors, although there was a trend toward more frequent methylation in men (P = .09). Notably, hypermethylation was found more frequently in adenocarcinoma and other histologic types (large-cell and unclassified tumors) than in squamous cell carcinoma (P = .02) (Table 2).
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We further analyzed potential associations between the hypermethylation status of the DAP kinase gene in the primary tumors and patients' survival data. We found that patients whose primary tumors exhibited hypermethylation had a statistically significantly poorer overall survival rate (P = .041, log-rank test). The probability of survival at 5 years after surgery was .68 (95% confidence interval [CI] = .59–.80) for patients with tumors that showed no hypermethylation of the DAP kinase gene compared with .46 (95% CI = .35–.60) for patients with tumors that showed hypermethylation (Fig. 2
, A). The 5-year survival rates were statistically significantly different between the nonhypermethylated and hypermethylated groups (P = .007, z test). The probability of survival at 10 years after surgery was also lower for patients with a hypermethylated DAP kinase gene in tumor DNA, but the difference decreased as the follow-up time increased, probably because of an increase in non-cancer-related deaths over time in this patient population. Strikingly, for the group of patients whose primary tumors did not show hypermethylation at the CpG sites of the DAP kinase gene, the probability of 5-year disease-specific survival was .92 (95% CI = .86–.99) compared with only .56 (95% CI = .44–.71) for the group with such hypermethylation (Fig. 2, B). The probability of 10-year disease-specific survival was similar (.83 [95% CI = .73–.94] for those without hypermethylation versus .37 [95 % CI = .24–.57] for those with hypermethylation). The disease-specific survival rate was highly statistically significantly different between the two groups (P<.001, log-rank test and z test). Unlike overall survival, the difference in disease-specific survival increased as follow-up time increased. Similar results were also obtained when the 17 patients who died of unknown causes were grouped with those who died of cancer (data not shown). We also analyzed potential associations between the hypermethylation pattern and disease-specific survival rate in histologic subgroups. We found that hypermethylation was associated with a poorer disease-specific survival for both adenocarcinoma (P<.001; Fig. 2, C) and squamous cell carcinoma (P = .011; Fig. 2, D) patients.
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To determine whether hypermethylation of the CpG sites of the DAP kinase gene is an independent factor in predicting survival time for patients with pathologic stage I NSCLC, we performed multivariate analysis using the Cox model. We found that hypermethylation of the CpG sites in the DAP kinase gene was the only independent predictor for disease-specific survival rates (P<.001) among parameters that could be tested, including age, sex, tumor histology, tumor size, and smoking status. It is interesting that, when we analyzed for overall survival rates, patients' ages turned out to be the only predictive factor for survival (P = .005). The result was not surprising because a statistically significant number of these patients die of other aging-related diseases, such as disorders in the respiratory and cardiovascular systems, over the longer follow-up period. In support of this idea, we note that DAP kinase hypermethylation rather than age was a statistically significant independent factor predicting the overall survival during the first 5 years of follow-up (P = .008 and P = .14, respectively).
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DISCUSSION |
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Many physiologic factors, such as tumor necrosis factor-
, interferon gamma, and transforming growth factor-ß (TGF-ß), can trigger apoptosis in normal cells (21–23). However, tumor cells may lose their ability to respond to these stimulators. For example, many lung cancer cell lines do not respond to TGF-ß (24), indicating the presence of defects in the TGF-ß-induced signaling pathway. DAP kinase was identified initially as a gene whose inhibition by an antisense molecule could prevent interferon gamma-induced apoptosis in HeLa cells (12). DAP kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with an apoptosis-inducing function that depends on its catalytic activity (25). Its ability to suppress the metastatic behavior of Lewis lung carcinoma cells in animal models suggests that DAP kinase might function as a metastasis suppressor by inducing apoptosis (13). Esteller et al. (16) studied primary NSCLC samples from 22 patients and found that DAP kinase was hypermethylated in five (23%) of the 22 tumors, indicating that DAP kinase hypermethylation was a frequent abnormality in lung cancer. However, the small sample size and the mixed stages of the tumors analyzed made it impossible to determine an accurate rate of the abnormality in NSCLC or the role of DAP kinase in the multistep lung tumorigenesis. In this study, we assembled a panel of 135 tumors in a single clinical stage, which allowed us to determine the rate of DAP kinase hypermethylation across a relatively small subset of patients with lung cancer. We found that 44% of the tumors were hypermethylated at the CpG sites of the DAP kinase gene. Previous studies (14,15) demonstrated that hypermethylation at the CpG sites of the DAP kinase can repress expression of the gene. Therefore, expression of DAP kinase in the tumor cells containing a hypermethylated promoter was most likely repressed. In fact, we found that the DAP kinase methylation status was closely associated with the gene expression in lung cancer cell lines and that demethylation restored DAP kinase gene expression (data not shown). The finding that the DAP kinase promoter is frequently hypermethylated in the early stage of lung cancers is important because it indicates that this epigenetic abnormality may be important in the disease. We are currently investigating how early this abnormality may occur in lung carcinogenesis by analyzing bronchial epithelium obtained from different stages of the process. It was interesting that tumors from men tend to have a higher hypermethylation status than tumors from women, and squamous cell tumors have a lower rate of hypermethylation than other tumor types. However, none of these factors turned out to be independent when the patients' outcomes were analyzed by multivariate analysis.
The most striking finding of the study is the strong association between hypermethylation of the DAP kinase promoter and adverse survival, particularly the disease-specific survival. Our multivariate analysis indicates that DAP kinase hypermethylation was the only independent factor that predicted disease-specific survival rates. Several other molecular and genetic markers have been shown to be able to predict outcome of patients with stage I NSCLC; they include loss of heterozygosity, K-ras mutations, and p53 overexpression (26–31). However, contradictory results have also been reported for some markers (32,33), suggesting that the roles of these molecules in lung cancer progression are complicated. Our study provides promising results that demonstrate, to our knowledge, for the first time that inactivation of DAP kinase might be an important biomarker for the molecular classification of stage I NSCLC. These findings add one more step toward the development of a model for molecular classification of lung cancer.
The advantages of methylation-specific PCR are its simplicity, its specificity for each gene, and its high sensitivity, allowing investigators to detect one altered molecule in more than 1000 normal copies (34). In contrast to many other methods of genetic testing, this assay is easy to carry out and is cost-effective. Furthermore, data interpretation is straightforward, making it possible to compare results across investigators and institutions. It is possible that only a small percentage of cells in a particular tumor are capable of metastasis. Therefore, the high sensitivity of methylation-specific PCR may help to identify these abnormal cells among large numbers of cells without such an abnormality. Although our data are very promising, double-blinded, prospective studies are necessary to validate these findings. Furthermore, the DAP kinase gene may be inactivated by other mechanisms in addition to hypermethylation. Therefore, research into the mechanisms of DAP kinase inactivation in lung tumorigenesis should continue.
The association between DAP kinase hypermethylation and poor survival rates suggests that DAP kinase plays an important role in tumor invasion and metastasis of lung cancer, which is consistent with previous results from an animal model (13). NSCLC cells lacking DAP kinase or having reduced levels of DAP kinase appear to be more invasive and more metastatic. Along these lines, recent data indicate that the death domain of DAP kinase is critical in ligand-induced apoptosis (35). Cohen et al. (35) have found that DAP kinase is also involved in tumor necrosis factor- and Fas-induced apoptosis and, furthermore, that DAP kinase apoptotic function can be blocked by bcl-2 as well as by p35 inhibitors of caspases. Because bcl-2 is frequently overexpressed in lung cancer (36,37), it would be interesting to see whether bcl-2 overexpression and DAP kinase hypermethylation are associated with or play a synergistic role in promoting invasion and metastasis. These results suggest that DAP kinase should be an ideal therapeutic target in the treatment of NSCLC patients who have a high probability of disease recurrence and metastasis.
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NOTES |
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Supported in part by American Cancer Society grant RPG-98-054 (to L. Mao); by American Cancer Society-Clinical Oncology Career Development Award No. 96-41 (to F. R. Khuri); and by Public Health Service grants U19CA68437 (to W. K. Hong) and P30CA16620 (to The University of Texas M. D. Anderson Cancer Center) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. W. K. Hong is an American Cancer Society Clinical Research Professor.
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Manuscript received January 24, 2000; revised June 26, 2000; accepted July 10, 2000.
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J. A. Hutt, B. R. Vuillemenot, E. B. Barr, M. J. Grimes, F. F. Hahn, C. H. Hobbs, T. H. March, A. P. Gigliotti, S. K. Seilkop, G. L. Finch, et al. Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways Carcinogenesis, November 1, 2005; 26(11): 1999 - 2009. [Abstract] [Full Text] [PDF]
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S. A. Belinsky Silencing of genes by promoter hypermethylation: key event in rodent and human lung cancer Carcinogenesis, September 1, 2005; 26(9): 1481 - 1487. [Abstract] [Full Text] [PDF]
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F. Jiang, N. P. Caraway, B. Nebiyou Bekele, H.-Z. Zhang, A. Khanna, H. Wang, R. Li, R. L. Fernandez, T. M. Zaidi, D. A. Johnston, et al. Surfactant Protein A Gene Deletion and Prognostics for Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., August 1, 2005; 11(15): 5417 - 5424. [Abstract] [Full Text] [PDF]
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A. M. Safar, H. Spencer III, X. Su, M. Coffey, C. A. Cooney, L. D. Ratnasinghe, L. F. Hutchins, and C.-Y. Fan Methylation Profiling of Archived Non-Small Cell Lung Cancer: A Promising Prognostic System Clin. Cancer Res., June 15, 2005; 11(12): 4400 - 4405. [Abstract] [Full Text] [PDF]
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S. Singhal, A. Vachani, D. Antin-Ozerkis, L. R. Kaiser, and S. M. Albelda Prognostic Implications of Cell Cycle, Apoptosis, and Angiogenesis Biomarkers in Non-Small Cell Lung Cancer: A Review Clin. Cancer Res., June 1, 2005; 11(11): 3974 - 3986. [Abstract] [Full Text] [PDF]
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K. Fujiwara, N. Fujimoto, M. Tabata, K. Nishii, K. Matsuo, K. Hotta, T. Kozuki, M. Aoe, K. Kiura, H. Ueoka, et al. Identification of Epigenetic Aberrant Promoter Methylation in Serum DNA Is Useful for Early Detection of Lung Cancer Clin. Cancer Res., February 1, 2005; 11(3): 1219 - 1225. [Abstract] [Full Text] [PDF]
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L. C. Pulling, B. R. Vuillemenot, J. A. Hutt, T. R. Devereux, and S. A. Belinsky Aberrant Promoter Hypermethylation of the Death-Associated Protein Kinase Gene Is Early and Frequent in Murine Lung Tumors Induced by Cigarette Smoke and Tobacco Carcinogens Cancer Res., June 1, 2004; 64(11): 3844 - 3848. [Abstract] [Full Text] [PDF]
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S. A. Belinsky, D. M. Klinge, K. C. Liechty, T. H. March, T. Kang, F. D. Gilliland, N. Sotnic, G. Adamova, G. Rusinova, and V. Telnov Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma Carcinogenesis, June 1, 2004; 25(6): 1063 - 1067. [Abstract] [Full Text] [PDF]
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D. Levy, G. Plu-Bureau, Y. Decroix, D. Hugol, W. Rostene, A. Kimchi, and A. Gompel Death-Associated Protein Kinase Loss of Expression Is a New Marker for Breast Cancer Prognosis Clin. Cancer Res., May 1, 2004; 10(9): 3124 - 3130. [Abstract] [Full Text] [PDF]
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K. Terasawa, S. Sagae, M. Toyota, K. Tsukada, K. Ogi, A. Satoh, H. Mita, K. Imai, T. Tokino, and R. Kudo Epigenetic Inactivation of TMS1/ASC in Ovarian Cancer Clin. Cancer Res., March 15, 2004; 10(6): 2000 - 2006. [Abstract] [Full Text] [PDF]
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Y. Liu, Q. An, L. Li, D. Zhang, J. Huang, X. Feng, S. Cheng, and Y. Gao Hypermethylation of p16INK4a in Chinese lung cancer patients: biological and clinical implications Carcinogenesis, December 1, 2003; 24(12): 1897 - 1901. [Abstract] [Full Text] [PDF]
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A. N. Reddy, W. W. Jiang, M. Kim, N. Benoit, R. Taylor, J. Clinger, D. Sidransky, and J. A. Califano Death-Associated Protein Kinase Promoter Hypermethylation in Normal Human Lymphocytes Cancer Res., November 15, 2003; 63(22): 7694 - 7698. [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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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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S. Toyooka, K. O. Toyooka, K. Miyajima, J. L. Reddy, M. Toyota, U. G. Sathyanarayana, A. Padar, M. S. Tockman, S. Lam, N. Shivapurkar, et al. Epigenetic Down-Regulation of Death-associated Protein Kinase in Lung Cancers Clin. Cancer Res., August 1, 2003; 9(8): 3034 - 3041. [Abstract] [Full Text] [PDF]
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K. Kozar, R. Kaminski, T. Switaj, T. Oldak, E. Machaj, P. J. Wysocki, A. Mackiewicz, W. Lasek, M. Jakobisiak, and J. Golab Interleukin 12-based Immunotherapy Improves the Antitumor Effectiveness of a Low-Dose 5-Aza-2'-Deoxycitidine Treatment in L1210 Leukemia and B16F10 Melanoma Models in Mice Clin. Cancer Res., August 1, 2003; 9(8): 3124 - 3133. [Abstract] [Full Text] [PDF]
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S. V. Harden, Y. Tokumaru, W. H. Westra, S. Goodman, S. A. Ahrendt, S. C. Yang, and D. Sidransky Gene Promoter Hypermethylation in Tumors and Lymph Nodes of Stage I Lung Cancer Patients Clin. Cancer Res., April 1, 2003; 9(4): 1370 - 1375. [Abstract] [Full Text] [PDF]
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C. Balana, J. L. Ramirez, M. Taron, Y. Roussos, A. Ariza, R. Ballester, C. Sarries, P. Mendez, J. J. Sanchez, and R. Rosell O6-methyl-guanine-DNA methyltransferase Methylation in Serum and Tumor DNA Predicts Response to 1,3-Bis(2-Chloroethyl)-1-Nitrosourea but not to Temozolamide Plus Cisplatin in Glioblastoma Multiforme Clin. Cancer Res., April 1, 2003; 9(4): 1461 - 1468. [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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Y. S. Chang, L. Wang, D. Liu, L. Mao, W. K. Hong, F. R. Khuri, and H.-Y. Lee Correlation between Insulin-like Growth Factor-binding Protein-3 Promoter Methylation and Prognosis of Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., December 1, 2002; 8(12): 3669 - 3675. [Abstract] [Full Text] [PDF]
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E. C. Chan, S. Y. Lam, K. W. Tsang, B. Lam, J. C. M. Ho, K. H. Fu, W. K. Lam, and Y. L. Kwong Aberrant Promoter Methylation in Chinese Patients with Non-Small Cell Lung Cancer: Patterns in Primary Tumors and Potential Diagnostic Application in Bronchoalevolar Lavage Clin. Cancer Res., December 1, 2002; 8(12): 3741 - 3746. [Abstract] [Full Text] [PDF]
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M. D. Brundage, D. Davies, and W. J. Mackillop Prognostic Factors in Non-small Cell Lung Cancer* : A Decade of Progress Chest, September 1, 2002; 122(3): 1037 - 1057. [Abstract] [Full Text] [PDF]
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Y. Tada, M. Wada, K.-i. Taguchi, Y. Mochida, N. Kinugawa, M. Tsuneyoshi, S. Naito, and M. Kuwano The Association of Death-associated Protein Kinase Hypermethylation with Early Recurrence in Superficial Bladder Cancers Cancer Res., July 15, 2002; 62(14): 4048 - 4053. [Abstract] [Full Text] [PDF]
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Y. Huang, M. Tan, M. Gosink, K. K. W. Wang, and Y. Sun Histone Deacetylase 5 Is Not a p53 Target Gene, But Its Overexpression Inhibits Tumor Cell Growth and Induces Apoptosis Cancer Res., May 1, 2002; 62(10): 2913 - 2922. [Abstract] [Full Text] [PDF]
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S. A. Belinsky, W. A. Palmisano, F. D. Gilliland, L. A. Crooks, K. K. Divine, S. A. Winters, M. J. Grimes, H. J. Harms, C. S. Tellez, T. M. Smith, et al. Aberrant Promoter Methylation in Bronchial Epithelium and Sputum from Current and Former Smokers Cancer Res., April 1, 2002; 62(8): 2370 - 2377. [Abstract] [Full Text] [PDF]
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M. W. Y. Chan, L. W. Chan, N. L. S. Tang, J. H. M. Tong, K. W. Lo, T. L. Lee, H. Y. Cheung, W. S. Wong, P. S. F. Chan, F. M. M. Lai, et al. Hypermethylation of Multiple Genes in Tumor Tissues and Voided Urine in Urinary Bladder Cancer Patients Clin. Cancer Res., February 1, 2002; 8(2): 464 - 470. [Abstract] [Full Text] [PDF]
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J.-C. Soria, M. Rodriguez, D. D. Liu, J. J. Lee, W. Ki Hong, and L. Mao Aberrant Promoter Methylation of Multiple Genes in Bronchial Brush Samples from Former Cigarette Smokers Cancer Res., January 1, 2002; 62(2): 351 - 355. [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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A. V. Velentza, A. M. Schumacher, C. Weiss, M. Egli, and D. M. Watterson A Protein Kinase Associated with Apoptosis and Tumor Suppression. STRUCTURE, ACTIVITY, AND DISCOVERY OF PEPTIDE SUBSTRATES J. Biol. Chem., October 12, 2001; 276(42): 38956 - 38965. [Abstract] [Full Text] [PDF]
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Y. Yuan, R. Mendez, A. Sahin, and J. L. Dai Hypermethylation Leads to Silencing of the SYK Gene in Human Breast Cancer Cancer Res., July 1, 2001; 61(14): 5558 - 5561. [Abstract] [Full Text] [PDF]
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M. H. L. Ng, K. W. To, K. W. Lo, S. Chan, K. S. Tsang, S. H. Cheng, and H. K. Ng Frequent Death-associated Protein Kinase Promoter Hypermethylation in Multiple Myeloma Clin. Cancer Res., June 1, 2001; 7(6): 1724 - 1729. [Abstract] [Full Text] [PDF]
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S. Zöchbauer-Müller, K. M. Fong, A. Maitra, S. Lam, J. Geradts, R. Ashfaq, A. K. Virmani, S. Milchgrub, A. F. Gazdar, and J. D. Minna 5' CpG Island Methylation of the FHIT Gene Is Correlated with Loss of Gene Expression in Lung and Breast Cancer Cancer Res., May 1, 2001; 61(9): 3581 - 3585. [Abstract] [Full Text]
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G. Hoon Kang, Y.-H. Shim, H.-Y. Jung, W. Ho Kim, J. Y. Ro, and M.-G. Rhyu CpG Island Methylation in Premalignant Stages of Gastric Carcinoma Cancer Res., April 1, 2001; 61(7): 2847 - 2851. [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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