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Tumor Biology, The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [M. E., S. B. B., J. G. H.]; and Department of Otolaryngology-Head and Neck Surgery, Division of Head and Neck Cancer Research [M. S-C., D. S.], and Medical Oncology Service [R. R.], Hospital Germans Trias i Pujol, Badalona, Spain
| ABSTRACT |
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| Introduction |
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70% for patients with stage I NSCLC but drops to only 30% in patients with stage IIIa disease (3)
. Thus, earlier detection of lung cancer would facilitate more effective management of the disease. Standard diagnostic techniques rely on radiological images with a tumor size detection limit of
1 cm, which represents 109 cells or a mass of 1 g (4)
. Conventional sputum cytology and bronchoalveolar lavage have not been proven effective as screening tools. Therefore, it is important to develop new methods that provide sensitive and reliable diagnostic and prognostic markers of NSCLC.
Nanogram quantities of DNA circulating in blood are present in healthy individuals (5
, 6)
. Previous studies have proposed that tumor DNA is also released in plasma and serum (7
, 8)
. However, the serum of cancer patients is enriched in DNA, containing, on average,
4 times the amount of free DNA, compared to normal controls (9)
. On the basis of these observations, several studies have shown that is possible to identify microsatellite alterations in the plasma and serum DNA of patients with head and neck carcinoma (10)
and small cell lung carcinoma (11)
. In addition, p53 and ras gene mutations have been detected in the plasma and serum of patients with colorectal (12, 13, 14)
and pancreatic (15
, 16)
carcinomas and hematological malignancies (17)
.
In addition to the molecular genetic alterations described above, silencing of tumor suppressor genes by promoter hypermethylation is a common feature in human cancer (18) . Hypermethylation of normally unmethylated CpG islands in the promoter regions of many cancer key genes, including p16, p15, E-cadherin, VHL, and hMLH1, correlates with its loss of transcription in human tumors (19 , 20) . In primary lung carcinomas, the inactivation of the tumor suppressor gene p16 (18 , 21) , the DNA repair gene MGMT (22) , and the detoxifying gene GSTP1 (23) by promoter hypermethylation have been well described. In addition, loss of expression of the DAP kinase gene, reactivated by the demethylating agent 5'-azadeoxycytidine (24) , has also been correlated with metastatic potential in experimental lung cancer models (25) . On the basis of these observations, here, we examined 22 NSCLC patients using the sensitive MSP technique for abnormal promoter hypermethylation in p16, DAP kinase, GSTP1, and MGMT, in primary tumors and paired normal tissue and serum samples.
| Materials and Methods |
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MSP.
DNA methylation patterns in the CpG island of the MGMT gene were determined by chemical modification of unmethylated but not the methylated cytosines to uracil and subsequent PCR using primers specific for either methylated or the modified unmethylated DNA (27)
. Primer sequences of MGMT were for the unmethylated reaction 5'-ATG GTA TGG ATT TTA GTG TTG GTT-3' (sense) and 5'-ACT ATA CCT AAA CTC AAC AAA CAC CA-3' (antisense) and for the methylated reaction 5'-GTA TGG ATT TTA GCG TCG GTC-3' (sense) and 5'-TAA ACT CGA CGA ACG CCG-3' (antisense). Primer sequences of DAP kinase were for the unmethylated reaction 5'-GGA GGA TAG TTG GAT TGA GTT AAT GTT-3' (sense) and 5'-CAA ATC CCT CCC AAA CAC CAA-3' (antisense) and for the methylated reaction 5'-GGA TAG TCG GAT CGA GTT AAC GTC-3' (sense) and 5'-CCC TCC CAA ACG CCG A-3' (antisense). Primer sequences of GSTP1 were for the unmethylated reaction 5'-GAT GTT TGG GGT GTA GTG GTT GTT-3' (sense) and 5'-CCA CCC CAA TAC TAA ATC ACA ACA-3' (antisense) and for the methylated reaction 5'-TTC GGG GTG TAG CGC TCG TC-3' (sense) and 5'-GCC CCA ATA CTA AAT CAC GAC G-3' (antisense). Primer sequences for p16 have been described previously (27)
. The annealing temperatures were 60°C for p16 and DAP kinase and 59°C for MGMT and GSTP1. PCR conditions for the four genes were as follows: 95°C for 5 min; then 35 cycles of 95°C for 30 s, the specific annealing temperature for 30 s, and 72°C for 30 s; and a final extension of 4 min at 72°C. All PCR amplification was performed using an Omnigene thermocycler (Hybaid) with tube control for accurate annealing temperatures. Hot start was used. Human placental DNA was treated in vitro with excess SssI methyltransferase (New England Biolabs), to generate completely methylated DNA at all CpGs and was used as positive control for methylated alleles of each gene. DNA from normal lymphocytes was used as the control for unmethylated alleles. Some samples were analyzed for p16 methylation using 40 cycles of amplification, with concordant results.
Briefly, 1 µg of DNA was denatured by NaOH and modified by sodium bisulfite. DNA samples were then purified using Wizard DNA purification resin (Promega), again treated with NaOH, precipitated with ethanol, and resuspended in water. Controls without DNA were performed for each set of PCR. Ten µl of each PCR were directly loaded onto nondenaturing 6% polyacrylamide gels, stained with ethidium bromide, and visualized under UV illumination.
| Results |
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| Discussion |
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Methylation is the main epigenetic modification in humans (18)
, and changes in methylation patterns play an important role in tumorigenesis. In particular, hypermethylation of normally unmethylated CpG islands in many tumor suppressor genes correlates with loss of expression (18)
. The recent development of the MSP technique (27)
has simplified the study of genes inactivated by promoter hypermethylation in human cancer and its high sensitivity, approaching 1 methylated gene copy in 1000 unmethylated copies in dilution experiments (27)
, support the potential power of this approach for molecular detection. Moreover, the MSP technique has demonstrated great specificity in our study, because we did not find any abnormal methylation in serum DNA if this alteration was not present in the primary tumor (Table 1)
. In other studies, genetic alterations were sometimes detected in the serum, whereas they were absent in the primary specimens (11
, 13)
. Our approach with MSP avoids the use of expensive sequencing reagents and radioactivity, allowing the study of multiple markers by rapid analysis. Unlike some tumor suppressor gene mutations (i.e., p53), MSP allows the detection of aberrant DNA methylation as a molecular detection method without prior analysis of the primary tumor. Furthermore, the analysis of abnormal promoter methylation status of several genes in a timely and economic fashion, combined with the study of previously described genetic alterations, may allow the detection of almost all patients with circulating tumor DNA.
Some markers in serum DNA, such as p16 methylation, may be helpful in the monitoring of multiple tumor types because inactivation of p16 by methylation is a common feature in human neoplasia (18)
. However, depending upon the particular tumor type, other markers may also be detected in serum DNA. For example, promoter hypermethylation of hMLH1, present in the majority of sporadic colon and endometrial carcinomas with microsatellite instability (19
, 20)
, and GSTP1, aberrantly methylated in
90% of prostate carcinomas (18)
, may be ideal markers for these particular tumor types. In addition, the particular spectrum of genes with promoter hypermethylation in the serum DNA may provide us clues about the biological behavior of the primary tumor. For example, the finding of the inactivation of a putative metastasis tumor suppressor gene like DAP kinase may suggest the metastatic potential of a tumor (25)
. The detection of the methylation-mediated silencing of the MGMT gene (22)
, which provides resistance to alkylating agents, may modify the chemotherapeutic treatment.
Our results indicate that abnormal promoter hypermethylation of tumor suppressor genes is readily detectable in the serum DNA of cancer patients using MSP analysis. By using the right combination of target genes, MSP may detect aberrant methylated DNA across a broad spectrum of neoplasms. This approach allows sensitive and accurate detection of circulating tumor DNA and may have multiple applications in the follow-up and management of cancer patients.
| FOOTNOTES |
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1 Supported by NIH Grant 5P50CA58184. M. E. and M. S-C. are recipients of Spanish Ministerio de Educacion y Cultura Awards. J. G. H. is a Valvano Foundation Scholar. S. B. B. and J. G. H. receive research funding and are entitled to sales royalties from Oncor, which is developing products related to research described in this paper. The terms of this arrangement have been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies. ![]()
2 To whom requests for reprints should be addressed, at Tumor Biology, The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231. Phone: (410) 955-8506; Fax: (410) 614-9884; E-mail: hermanji{at}welchlink.welch.jhu.edu ![]()
3 The abbreviations used are: NSCLC, non-small cell lung carcinoma; MGMT, O6-methylguanine-DNA-methyltransferase; GSTP1, glutathione S-transferase P1; DAP kinase, death-associated protein kinase; MSP, methylation-specific PCR. ![]()
Received 9/ 9/98. Accepted 11/ 9/98.
| REFERENCES |
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
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||||
![]() |
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||||
![]() |
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||||
![]() |
R. Meuwissen and A. Berns Mouse models for human lung cancer Genes & Dev., March 15, 2005; 19(6): 643 - 664. [Abstract] [Full Text] [PDF] |
||||
![]() |
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||||
![]() |
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||||
![]() |
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||||
![]() |
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C. Lu, J.-C. Soria, X. Tang, X.-C. Xu, L. Wang, L. Mao, R. Lotan, B. Kemp, B. N. Bekele, L. Feng, et al. Prognostic Factors in Resected Stage I Non-Small-Cell Lung Cancer: A Multivariate Analysis of Six Molecular Markers J. Clin. Oncol., November 15, 2004; 22(22): 4575 - 4583. [Abstract] [Full Text] [PDF] |
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P. M. Das and R. Singal DNA Methylation and Cancer J. Clin. Oncol., November 15, 2004; 22(22): 4632 - 4642. [Abstract] [Full Text] [PDF] |
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O. Gautschi, C. Bigosch, B. Huegli, M. Jermann, A. Marx, E. Chasse, D. Ratschiller, W. Weder, M. Joerger, D. C. Betticher, et al. Circulating Deoxyribonucleic Acid As Prognostic Marker in Non-Small-Cell Lung Cancer Patients Undergoing Chemotherapy J. Clin. Oncol., October 15, 2004; 22(20): 4157 - 4164. [Abstract] [Full Text] [PDF] |
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I. I. de Caceres, C. Battagli, M. Esteller, J. G. Herman, E. Dulaimi, M. I. Edelson, C. Bergman, H. Ehya, B. L. Eisenberg, and P. Cairns Tumor Cell-Specific BRCA1 and RASSF1A Hypermethylation in Serum, Plasma, and Peritoneal Fluid from Ovarian Cancer Patients Cancer Res., September 15, 2004; 64(18): 6476 - 6481. [Abstract] [Full Text] [PDF] |
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E. Dulaimi, J. Hillinck, I. I. de Caceres, T. Al-Saleem, and P. Cairns Tumor Suppressor Gene Promoter Hypermethylation in Serum of Breast Cancer Patients Clin. Cancer Res., September 15, 2004; 10(18): 6189 - 6193. [Abstract] [Full Text] [PDF] |
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J. S. Kim, H. Lee, H. Kim, Y. M. Shim, J. Han, J. Park, and D.-H. Kim Promoter Methylation of Retinoic Acid Receptor Beta 2 and the Development of Second Primary Lung Cancers in Non-Small-Cell Lung Cancer J. Clin. Oncol., September 1, 2004; 22(17): 3443 - 3450. [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. Guo, M. G. House, C. Hooker, Y. Han, E. Heath, E. Gabrielson, S. C. Yang, S. B. Baylin, J. G. Herman, and M. V. Brock Promoter Hypermethylation of Resected Bronchial Margins: A Field Defect of Changes? Clin. Cancer Res., August 1, 2004; 10(15): 5131 - 5136. [Abstract] [Full Text] [PDF] |
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G. Gifford, J. Paul, P. A. Vasey, S. B. Kaye, and R. Brown The Acquisition of hMLH1 Methylation in Plasma DNA after Chemotherapy Predicts Poor Survival for Ovarian Cancer Patients Clin. Cancer Res., July 1, 2004; 10(13): 4420 - 4426. [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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J. W. Park, R. S. Kerbel, G. J. Kelloff, J. C. Barrett, B. A. Chabner, D. R. Parkinson, J. Peck, R. W. Ruddon, C. C. Sigman, and D. J. Slamon Rationale for Biomarkers and Surrogate End Points in Mechanism-Driven Oncology Drug Development Clin. Cancer Res., June 1, 2004; 10(11): 3885 - 3896. [Full Text] [PDF] |
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G. F. V. Woude, G. J. Kelloff, R. W. Ruddon, H.-M. Koo, C. C. Sigman, J. C. Barrett, R. W. Day, A. P. Dicker, R. S. Kerbel, D. R. Parkinson, et al. Reanalysis of Cancer Drugs: Old Drugs, New Tricks Clin. Cancer Res., June 1, 2004; 10(11): 3897 - 3907. [Full Text] [PDF] |
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Y.-H. Su, M. Wang, D. E. Brenner, A. Ng, H. Melkonyan, S. Umansky, S. Syngal, and T. M. Block Human Urine Contains Small, 150 to 250 Nucleotide-Sized, Soluble DNA Derived from the Circulation and May Be Useful in the Detection of Colorectal Cancer J. Mol. Diagn., May 1, 2004; 6(2): 101 - 107. [Abstract] [Full Text] [PDF] |
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P. Pakneshan, B. Tetu, and S. A. Rabbani Demethylation of Urokinase Promoter as a Prognostic Marker in Patients with Breast Carcinoma Clin. Cancer Res., May 1, 2004; 10(9): 3035 - 3041. [Abstract] [Full Text] [PDF] |
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J. G. Herman Epigenetics in Lung Cancer: Focus on Progression and Early Lesions Chest, May 1, 2004; 125(5_suppl): 119S - 122S. [Full Text] [PDF] |
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E. Dulaimi, R. G. Uzzo, R. E. Greenberg, T. Al-Saleem, and P. Cairns Detection of Bladder Cancer in Urine by a Tumor Suppressor Gene Hypermethylation Panel Clin. Cancer Res., March 15, 2004; 10(6): 1887 - 1893. [Abstract] [Full Text] [PDF] |
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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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A. M. Marchevsky, J. A. Tsou, and I. A. Laird-Offringa Classification of Individual Lung Cancer Cell Lines Based on DNA Methylation Markers: Use of Linear Discriminant Analysis and Artificial Neural Networks J. Mol. Diagn., February 1, 2004; 6(1): 28 - 36. [Abstract] [Full Text] |
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D. G. Pfister, D. H. Johnson, C. G. Azzoli, W. Sause, T. J. Smith, S. Baker Jr, J. Olak, D. Stover, J. R. Strawn, A. T. Turrisi, et al. American Society of Clinical Oncology Treatment of Unresectable Non-Small-Cell Lung Cancer Guideline: Update 2003 J. Clin. Oncol., January 15, 2004; 22(2): 330 - 353. [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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C. Battagli, R. G. Uzzo, E. Dulaimi, I. Ibanez de Caceres, R. Krassenstein, T. Al-Saleem, R. E. Greenberg, and P. Cairns Promoter Hypermethylation of Tumor Suppressor Genes in Urine from Kidney Cancer Patients Cancer Res., December 15, 2003; 63(24): 8695 - 8699. [Abstract] [Full Text] [PDF] |
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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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J. G. Herman and S. B. Baylin Gene Silencing in Cancer in Association with Promoter Hypermethylation N. Engl. J. Med., November 20, 2003; 349(21): 2042 - 2054. [Full Text] [PDF] |
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G. Sozzi, D. Conte, M. Leon, R. Cirincione, L. Roz, C. Ratcliffe, E. Roz, N. Cirenei, M. Bellomi, G. Pelosi, et al. Quantification of Free Circulating DNA As a Diagnostic Marker in Lung Cancer J. Clin. Oncol., November 1, 2003; 21(21): 3902 - 3908. [Abstract] [Full Text] [PDF] |
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P. A. Bunn Jr Early Detection of Lung Cancer Using Serum RNA or DNA Markers: Ready for """Prime Time""" or for Validation? J. Clin. Oncol., November 1, 2003; 21(21): 3891 - 3893. [Full Text] [PDF] |
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K M Fong, Y Sekido, A F Gazdar, and J D Minna Lung cancer * 9: Molecular biology of lung cancer: clinical implications Thorax, October 1, 2003; 58(10): 892 - 900. [Abstract] [Full Text] [PDF] |
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P. E. Jackson, S.-Y. Kuang, J.-B. Wang, P. T. Strickland, A. Munoz, T. W. Kensler, G.-S. Qian, and J. D. Groopman Prospective detection of codon 249 mutations in plasma of hepatocellular carcinoma patients Carcinogenesis, October 1, 2003; 24(10): 1657 - 1663. [Abstract] [Full Text] [PDF] |
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P. Hou, M. Ji, C. Ge, J. Shen, S. Li, N. He, and Z. Lu Detection of methylation of human p16Ink4a gene 5'-CpG islands by electrochemical method coupled with linker-PCR Nucleic Acids Res., August 15, 2003; 31(16): e92 - e92. [Abstract] [Full Text] [PDF] |
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W. A. Palmisano, K. P. Crume, M. J. Grimes, S. A. Winters, M. Toyota, M. Esteller, N. Joste, S. B. Baylin, and S. A. Belinsky Aberrant Promoter Methylation of the Transcription Factor Genes PAX5 {alpha} and {beta} in Human Cancers Cancer Res., August 1, 2003; 63(15): 4620 - 4625. [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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B M Ryan, F Lefort, R McManus, J Daly, P W N Keeling, D G Weir, and D Kelleher A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up Mol. Pathol., June 1, 2003; 56(3): 172 - 179. [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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R. Danesi, F. De Braud, S. Fogli, T. M. De Pas, A. Di Paolo, G. Curigliano, and M. Del Tacca Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer Pharmacol. Rev., March 1, 2003; 55(1): 57 - 103. [Abstract] [Full Text] [PDF] |
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I. H. N. Wong, J. Zhang, P. B. S. Lai, W. Y. Lau, and Y. M. Dennis Lo Quantitative Analysis of Tumor-derived Methylated p16INK4a Sequences in Plasma, Serum, and Blood Cells of Hepatocellular Carcinoma Patients Clin. Cancer Res., March 1, 2003; 9(3): 1047 - 1052. [Abstract] [Full Text] [PDF] |
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M. G. House, M. Guo, C. Iacobuzio-Donahue, and J. G. Herman Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas Carcinogenesis, February 1, 2003; 24(2): 193 - 198. [Abstract] [Full Text] [PDF] |
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B M Ryan, F Lefort, R McManus, J Daly, P W N Keeling, D G Weir, and D Kelleher A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up Gut, January 1, 2003; 52(1): 101 - 108. [Abstract] [Full Text] [PDF] |
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C Jeronimo, R Henrique, P F Campos, J Oliveira, O L Caballero, C Lopes, and D Sidransky Endothelin B receptor gene hypermethylation in prostate adenocarcinoma J. Clin. Pathol., January 1, 2003; 56(1): 52 - 55. [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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C. Brambilla, F. Fievet, M. Jeanmart, F. de Fraipont, S. Lantuejoul, V. Frappat, G. Ferretti, P.Y. Brichon, and D. Moro-Sibilot Early detection of lung cancer: role of biomarkers Eur. Respir. J., January 1, 2003; 21(39_suppl): 36S - 44s. [Abstract] [Full Text] [PDF] |
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A. Bearzatto, D. Conte, M. Frattini, N. Zaffaroni, F. Andriani, D. Balestra, L. Tavecchio, M. G. Daidone, and G. Sozzi p16INK4A Hypermethylation Detected by Fluorescent Methylation-specific PCR in Plasmas from Non-Small Cell Lung Cancer Clin. Cancer Res., December 1, 2002; 8(12): 3782 - 3787. [Abstract] [Full Text] [PDF] |
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H.-W. Chang, S. M. Lee, S. N. Goodman, G. Singer, S. K. R. Cho, L. J. Sokoll, F. J. Montz, R. Roden, Z. Zhang, D. W. Chan, et al. Assessment of Plasma DNA Levels, Allelic Imbalance, and CA 125 as Diagnostic Tests for Cancer J Natl Cancer Inst, November 20, 2002; 94(22): 1697 - 1703. [Abstract] [Full Text] [PDF] |
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M. E. Reid, A. J. Duffield-Lillico, L. Garland, B. W. Turnbull, L. C. Clark, and J. R. Marshall Selenium Supplementation and Lung Cancer Incidence: An Update of the Nutritional Prevention of Cancer Trial Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1285 - 1291. [Abstract] [Full Text] [PDF] |
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G.-S. Qian, S.-Y. Kuang, X. He, J. D. Groopman, and P. E. Jackson Sensitivity of Electrospray Ionization Mass Spectrometry Detection of Codon 249 Mutations in the p53 Gene Compared with RFLP Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 1126 - 1129. [Abstract] [Full Text] [PDF] |
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