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Hypermethylation of the Death-Associated Protein (DAP) Kinase Promoter and Aggressiveness in Stage I Non-Small-Cell Lung Cancer
Ximing Tang,
Fadlo R. Khuri,
J. Jack Lee,
Bonnie L. Kemp,
Diane Liu,
Waun Ki Hong,
Li Mao
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 (57). 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 (811). 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 (1416), 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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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 hematoxylineosin, 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 TrisHCl (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 KaplanMeier estimator. The variance of the KaplanMeier 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
.
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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Fig. 1. Hypermethylation of the CpG sites at the death-associated protein (DAP) kinase gene for 17 representative non-small-cell lung cancer tumors. Methylation-specific polymerase chain reaction (PCR) was used to detect DNA with hypermethylation at the 5` end of the DAP kinase gene. Numbers above each gel identify the primary tumor analyzed. M = DNA ladder markers; u = PCR products with the use of unmethylated-specific primer set; m = PCR products with the use of methylated-specific primer set; - = DNA from normal unmethylated tissue; + = DNA from a tissue specimen with a hypermethylated DAP kinase gene promoter. Among the tumor data shown, hypermethylation was observed in tumors 5, 7, 8, 10, 12, 16, 23, 107, 110, and 112.
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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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Fig. 2. Death-associated protein (DAP) kinase promoter hypermethylation in primary non-small-cell lung cancer and probability of survival. The KaplanMeier method was used to determine the survival probability, and the log-rank test was used to compare the survival curves between groups. A) Probability of overall survival for patients with DAP kinase hypermethylation (HyperM.) versus patients without hypermethylation (No HyperM.). At year 5, for the group with DAP kinase promoter hypermethylation, the 95% confidence interval (CI) is .35.60 for 27 patients at risk; for the group with no hypermethylation, the 95% CI is .59.80 for 52 patients at risk. At year 10, for the group with the DAP kinase promoter hypermethylation, the 95% CI is .17-.44 for nine patients at risk; for the group with no hypermethylation, the 95% CI is .27.52 for 18 patients at risk. B) Probability of disease-specific survival at various times for patients with DAP kinase hypermethylation versus patients without hypermethylation. At year 5, for the group with DAP kinase promoter hypermethylation, the 95% CI is .44.71 for 27 patients at risk; for the group with no hypermethylation, the 95% CI is .86.99 for 54 patients at risk. At year 10, for the group with DAP kinase promoter hypermethylation, the 95% CI is .24.57 for nine patients at risk; for the group with no hypermethylation, the 95% CI is .73.94 for 29 patients at risk. C) Probability of disease-specific survival at various times for patients with adenocarcinoma and DAP kinase hypermethylation versus patients with adenocarcinoma but without hypermethylation. At year 5, for the group with adenocarcinoma and DAP kinase hypermethylation, the 95% CI is .44.79 for 18 patients at risk; for the group with adenocarcinoma but without hypermethylation, the 95% CI is .851.00 for 29 patients at risk. At year 10, for the group with adenocarcinoma and DAP kinase hypermethylation, the 95% CI is .13.64 for four patients at risk; for the group with adenocarcinoma but without hypermethylation, the 95% CI is .68.98 for 20 patients at risk. D) Probability of disease-specific survival at various times for patients with squamous cell carcinoma and DAP kinase hypermethylation versus patients with squamous cell carcinoma but without hypermethylation. At year 5, for the group with squamous cell carcinoma and DAP kinase hypermethylation, the 95% CI is .42.95 for nine patients at risk; for the group with squamous cell carcinoma but without hypermethylation, the 95% CI is .841.00 for 28 patients at risk. At year 10, for the group with squamous cell carcinoma and DAP kinase hypermethylation, the 95% CI is .31.91 for six patients at risk; for the group with squamous cell carcinoma but without hypermethylation, the 95% CI is .741.00 for 15 patients at risk. All P values are from two-sided tests.
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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 (2123). 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 (2631). 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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REFERENCES
|
---|
1
Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999;49:3364, 1.[Abstract/Free Full Text]
2
Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:629.[Abstract/Free Full Text]
3
Williams DE, Pairolero PC, Davis CS, Bernatz PE, Payne WS, Taylor WF, et al. Survival of patients surgically treated for stage I lung cancer. J Thorac Cardiovasc Surg 1981;82:706.[Abstract]
4
Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99105.[Medline]
5
Virmani AK, Fong KM, Kodagoda D, McIntire D, Hung J, Tonk V, et al. Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types. Genes Chromosomes Cancer 1998;21: 30819.[Medline]
6
Minna JD. Genetic events in the pathogenesis of lung cancer. Chest 1989; 96(1 Suppl):17S23S.[Medline]
7
Thiberville L, Payne P, Vielkinds J, LeRiche J, Horsman D, Nouvet G, et al. Evidence of cumulative gene losses with progression of premalignant epithelial lesions to carcinoma of the bronchus. Cancer Res 1995;55:51339.[Abstract]
8
Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 1994;54:4855 78.[Medline]
9
Reissmann PT, Koga H, Takahashi R, Figlin RA, Holmes C, Piantadosi S, et al. Inactivation of the retinoblastoma susceptibility gene in non-small-cell lung cancer. The Lung Cancer Study Group. Oncogene 1993;8:19139.[Medline]
10
Rosell R, Monzo M, Molina F, Martinez E, Pifarre A, Moreno I, et al. K-ras genotypes and prognosis in non-small-cell lung cancer. Ann Oncol 1995;6 Suppl 3:S1520.[Medline]
11
Kelley MJ, Nakagawa K, Steinberg SM, Mulshine JL, Kamb A, Johnson BE. Differential inactivation of CDKN2 and Rb protein in non-small-cell and small-cell lung cancer cell lines. J Natl Cancer Inst 1995;87:75661.[Abstract]
12
Feinstein E, Druck T, Kastury K, Berissi H, Goodart SA, Overhauser J, et al. Assignment of DAP1 and DAPKgenes that positively mediate programmed cell death triggered by IFN-gammato chromosome regions 5p12.2 and 9q34.1, respectively. Genomics 1995;29:3057.[Medline]
13
Inbal B, Cohen O, Polak-Charcon S, Kopolovic J, Vadai E, Eisenbach L, et al. DAP kinase links the control of apoptosis to metastasis. Nature 1997;390:1804.[Medline]
14
Katzenellenbogen RA, Baylin SB, Herman JG. Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 1999;93:434753.[Abstract/Free Full Text]
15
Kissil JL, Feinstein E, Cohen O, Jones PA, Tsai YC, Knowles MA, et al. DAP-kinase loss of expression in various carcinoma and B-cell lymphoma cell lines: possible implications for role as tumor suppressor gene. Oncogene 1997;15:4037.[Medline]
16
Esteller M, Sanchez-Cespedes M, Rosell R, Sidransky D, Baylin SB, Herman JG. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res 1999;59:6770.[Abstract/Free Full Text]
17
Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:17107.[Abstract/Free Full Text]
18
Kim SK, Ro JY, Kemp BL, Lee JS, Kwon TJ, Fong KM, et al. Identification of three distinct tumor suppressor loci on the short arm of chromosome 9 in small cell lung cancer. Cancer Res 1997;57:4003.[Abstract]
19
Mao L, Lee JS, Fan YH, Ro JY, Batsakis JG, Lippman S, et al. Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nat Med 1996;2:6825.[Medline]
20
Mountain CF. Value of the new TNM staging system for lung cancer. Chest 1989;96(1 Suppl):47S49S.[Medline]
21
Laster SM, Wood JG, Gooding LR. Tumor necrosis factor can induce both apoptotic and necrotic forms of cell lysis. J Immunol 1988;141:262934.[Abstract/Free Full Text]
22
Novelli F, Di Pierro F, Francia di Celle P, Bertini S, Affaticati P, Garotta G, et al. Environmental signals influencing expression of the IFN-gamma receptor on human T cells control whether IFN-gamma promotes proliferation or apoptosis. J Immunol 1994;152:496504.[Abstract/Free Full Text]
23
Lin JK, Chou CK. In vitro apoptosis in the human hepatoma cell line induced by transforming growth factor beta 1. Cancer Res 1992;52:3858.[Abstract]
24
Schwarz LC, Wright JA, Gingras MC, Kondaiah P, Danielpour D, Pimentel M, et al. Aberrant TGF-beta production and regulation in metastatic malignancy. Growth Factors 1990;3:11527.[Medline]
25
Cohen O, Feinstein E, Kimchi A. DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity. EMBO J 1997;16:9981008.[Abstract/Free Full Text]
26
Miyake M, Adachi M, Huang C, Higashiyama M, Kodama K, Taki T. A novel molecular staging protocol for non-small cell lung cancer. Oncogene 1999;18:2397404.[Medline]
27
Graziano SL, Gamble GP, Newman NB, Abbott LZ, Rooney M, Mookherjee S, et al. Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer. J Clin Oncol 1999;17:66875.[Abstract/Free Full Text]
28
Kwiatkowski DJ, Harpole DH Jr, Godleski J, Herndon JE 2nd, Shieh DB, Richards W, et al. Molecular pathologic substaging in 244 stage I non-small-cell lung cancer patients: clinical implications. J Clin Oncol 1998;16:246877.[Abstract]
29
Rosell R, Li S, Skacel Z, Mate JL, Maestre J, Canela M, et al. Prognostic impact of mutated K-ras gene in surgically resected non-small cell lung cancer patients. Oncogene 1993;8:240712.[Medline]
30
Zhou X, Kemp BL, Khuri FR, Liu D, Lee JJ, Wu W, et al. Prognostic implication of microsatellite alteration profiles in early-stage non-small cell lung cancer. Clin Cancer Res 2000;6:55965.[Abstract/Free Full Text]
31
Herbst RS, Yano S, Kuniyasu H, Khuri FR, Bucana CD, Guo F, et al. Differential expression of E-cadherin and type IV collagenase genes predicts outcome in patients with stage I non-small cell lung carcinoma. Clin Cancer Res 2000;6:7907.[Abstract/Free Full Text]
32
Apolinario RM, van der Valk P, de Jong JS, Deville W, van Ark-Otte J, Dingemans AM, et al. Prognostic value of the expression of p53, bcl-2, and bax oncoproteins, and neovascularization in patients with radically resected non-small cell lung cancer. J Clin Oncol 1997;15:245666.[Abstract]
33
Pastorino U, Andreola S, Tagliabue E, Pezzella F, Incarbone M, Sozzi G, et al. Immunocytochemical markers in stage I lung cancer: relevance to prognosis. J Clin Oncol 1997;15:285865.[Abstract]
34
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 1996;93:98216.[Abstract/Free Full Text]
35
Cohen O, Inbal B, Kissil JL, Raveh T, Berissi H, Spivak-Kroizaman T, et al. DAP-kinase participates in TNF-alpha- and Fas-induced apoptosis and its function requires the death domain. J Cell Biol 1999;146:1418.[Abstract/Free Full Text]
36
Jiang SX, Kameya T, Sato Y, Yanase N, Yoshimura H, Kodama T. Bcl-2 protein expression in lung cancer and close correlation with neuroendocrine differentiation. Am J Pathol 1996;148:83746.[Abstract]
37
Pezzella F, Turley H, Kuzu I, Tungekar MF, Dunnill MS, Pierce CB, et al. bcl-2 protein in non-small-cell lung carcinoma. N Engl J Med 1993;329:6904.[Abstract/Free Full Text]
Manuscript received January 24, 2000;
revised June 26, 2000;
accepted July 10, 2000.
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-
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-
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[Full Text]
-
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[Full Text]
-
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[Abstract]
[Full Text]
-
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[Abstract]
[Full Text]
-
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[Full Text]
-
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[Abstract]
[Full Text]
-
Shohat, G., Spivak-Kroizman, T., Cohen, O., Bialik, S., Shani, G., Berrisi, H., Eisenstein, M., Kimchi, A.
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[Abstract]
[Full Text]
-
Toyooka, S., Toyooka, K. O., Maruyama, R., Virmani, A. K., Girard, L., Miyajima, K., Harada, K., Ariyoshi, Y., Takahashi, T., Sugio, K., Brambilla, E., Gilcrease, M., Minna, J. D., Gazdar, A. F.
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1: 61-67
[Abstract]
[Full Text]
-
Velentza, A. V., Schumacher, A. M., Weiss, C., Egli, M., Watterson, D. M.
(2001). A Protein Kinase Associated with Apoptosis and Tumor Suppression. STRUCTURE, ACTIVITY, AND DISCOVERY OF PEPTIDE SUBSTRATES. J. Biol. Chem.
276: 38956-38965
[Abstract]
[Full Text]
-
Yuan, Y., Mendez, R., Sahin, A., Dai, J. L.
(2001). Hypermethylation Leads to Silencing of the SYK Gene in Human Breast Cancer. Cancer Res
61: 5558-5561
[Abstract]
[Full Text]
-
Ng, M. H. L., To, K. W., Lo, K. W., Chan, S., Tsang, K. S., Cheng, S. H., Ng, H. K.
(2001). Frequent Death-associated Protein Kinase Promoter Hypermethylation in Multiple Myeloma. Clin Cancer Res
7: 1724-1729
[Abstract]
[Full Text]
-
Costello, J. F, Plass, C.
(2001). Methylation matters. J. Med. Genet.
38: 285-303
[Abstract]
[Full Text]
-
Zöchbauer-Müller, S., Fong, K. M., Maitra, A., Lam, S., Geradts, J., Ashfaq, R., Virmani, A. K., Milchgrub, S., Gazdar, A. F., Minna, J. D.
(2001). 5' CpG Island Methylation of the FHIT Gene Is Correlated with Loss of Gene Expression in Lung and Breast Cancer. Cancer Res
61: 3581-3585
[Abstract]
[Full Text]
-
Esteller, M., Corn, P. G., Baylin, S. B., Herman, J. G.
(2001). A Gene Hypermethylation Profile of Human Cancer. Cancer Res
61: 3225-3229
[Abstract]
[Full Text]
-
Hoon Kang, G., Shim, Y.-H., Jung, H.-Y., Ho Kim, W., Y. Ro, J., Rhyu, M.-G.
(2001). CpG Island Methylation in Premalignant Stages of Gastric Carcinoma. Cancer Res
61: 2847-2851
[Abstract]
[Full Text]
-
Baylin, S. B., Esteller, M., Rountree, M. R., Bachman, K. E., Schuebel, K., Herman, J. G.
(2001). Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet
10: 687-692
[Abstract]
[Full Text]
-
Baylin, S. B., Belinsky, S. A., Herman, J. G.
(2000). Aberrant Methylation of Gene Promoters in Cancer--Concepts, Misconcepts, and Promise. J Natl Cancer Inst
92: 1460-1461
[Full Text]
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