Gene Silencing in Cancer in Association with Promoter Hypermethylation

New England Journal of Medicine

Volumn 349, Issue 21, 2003, Pages 2042-2054

  Herman, James G ^a,b   Baylin, Stephen B ^b  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b DEPARTMENT OF PATHOLOGY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CORE PROTEIN; CYTOSINE; HISTONE; HISTONE DEACETYLASE;

CANCER; CANCER PREVENTION; CANCER THERAPY; DNA METHYLATION; FUNCTIONAL ASSESSMENT; GENE SILENCING; GENETIC TRANSCRIPTION; HUMAN; MONITORING; NUCLEOSOME; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN BINDING; REVIEW; RISK ASSESSMENT;

ACETYLATION; CPG ISLANDS; DNA (CYTOSINE-5-)-METHYLTRANSFERASE; DNA METHYLATION; GENE SILENCING; HISTONES; HUMANS; NEOPLASMS; PROMOTER REGIONS (GENETICS); TUMOR MARKERS, BIOLOGICAL;

EID: 0345357773     PISSN: 00284793     EISSN: None     Source Type: Journal    
DOI: 10.1056/NEJMra023075     Document Type: Review

References (130)

1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.
2. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002;16:6-21.
3. Russo VEA, Martienssen RA, Riggs AD, eds. Epigenetic mechanisms of gene regulation. Plainview, N.Y.: Cold Spring Harbor Laboratory Press, 1996.
4. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999;21:163-7.
5. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415-28.
6. Herman JG. Hypermethylation of tumor suppressor genes in cancer. Semin Cancer Biol 1999;9:359-67.
7. Holliday R. Epigenetic inheritance based on DNA methylation. EXS 1993;64:452-68.
8. Bird AP, Wolffe AP. Methylation-induced repression - belts, braces, and chromatin. Cell 1999;99:451-4.
9. Jenuwein T, Allis CD. Translating the histone code. Science 2001;293:1074-80.
10. Rideout WM III, Coetzee GA, Olumi AF, Jones PA. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 1990;249:1288-90.
11. Antequera F, Bird A. CpG islands. EXS 1993;64:169-85.
12. Bestor TH. DNA methylation: evolution of a bacterial immune function into a regulator of gene expression and genome structure in higher eukaryotes. Philos Trans R Soc Lond B Biol Sci 1990;326:179-87.
13. Idem. The host defence function of genomic methylation patterns. Novartis Found Symp 1998;214:187-99, 228-32.
14. Csankovszki G, Nagy A, Jaenisch R. Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol 2001; 153:773-84.
15. Feinberg AP, Vogelstein B. Alterations in DNA methylation in human colon neoplasia. Semin Surg Oncol 1987;3:149-51.
16. Idem. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 1983;301:89-92.
17. Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 1985;228:187-90.
18. Walsh CP, Chaillet JR, Bestor TH. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 1998;20:116-7.
19. Cui H, Cruz-Correa M, Giardiello FM, et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 2003; 299:1753-5.
20. Xu GL, Bestor TH, Bourc'his D, et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 1999; 402:187-91.
21. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999;99:247-57.
22. Narayan A, Ji W, Zhang XY, et al. Hypomethylation of pericentromeric DNA in breast adenocarcinomas. Int J Cancer 1998; 77:833-8.
23. Gaudet F, Hodgson JG, Eden A, et al. Induction of tumors in mice by genomic hypomethylation. Science 2003;300:489-92.
24. Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 2003;300:455.
25. Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001;1:157-62.
26. Esteller M, Fraga MF, Guo M, et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 2001;10:3001-7.
27. Merlo A, Herman JG, Mao L, et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1995;1:686-92.
28. Herman JG, Latif F, Weng Y, et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A 1994;91:9700-4.
29. Esteller M, Tortola S, Toyota M, et al. Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res 2000;60:129-33.
30. Herman JG, Merlo A, Mao L, et al. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 1995;55:4525-30.
31. Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 1998;95:6870-5.
32. Hedenfalk I, Duggan D, Chen Y, et al. Gene-expression profiles in hereditary breast cancer. N Engl J Med 2001;344:539-48.
33. Wessels LF, van Welsem T, Hart AA, van't Veer LJ, Reinders MJ, Nederlof PM. Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. Cancer Res 2002;62:7110-7.
34. Burbee DG, Forgacs E, Zochbauer-Muller S, et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 2001;93:691-9.
35. Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 2000;25:315-9.
36. Dammann R, Yang G, Pfeifer GP. Hypermethylation of the CpG island of Ras association domain family 1A (RASSF1A), a putative tumor suppressor gene from the 3p21.3 locus, occurs in a large percentage of human breast cancers. Cancer Res 2001;61:3105-9.
37. Bachman KE, Herman JG, Corn PG, et al. Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggests a suppressor role in kidney, brain, and other human cancers. Cancer Res 1999; 59:798-802.
38. Corn PG, Kuerbitz SJ, van Noesel MM, et al. Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5′ CpG island methylation. Cancer Res 1999;59: 3352-6.
39. Suzuki H, Gabrielson E, Chen W, et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 2002;31:141-9.
40. Costello JF, Fruhwald MC, Smiraglia DJ, et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 2000;24:132-8.
41. Zardo G, Tiirikainen MI, Hong C, et al. Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat Genet 2002;32:453-8.
42. Wales MM, Biel MA, el Deiry W, et al. p53 Activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med 1995;1:570-7.
43. Chen WY, Zeng X, Carter MG, et al. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet 2003;33:197-202.
44. Carter MG, Johns MA, Zeng X, et al. Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome. Hum Mol Genet 2000;9:413-9.
45. Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 1998;19:219-20.
46. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 1992;69: 915-26.
47. Li E, Beard C, Jaenisch R. Role for DNA methylation in genomic imprinting. Nature 1993;366:362-5.
48. Laird PW, Jackson-Grusby L, Fazeli A, et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 1995;81:197-205.
49. Eads CA, Nickel AE, Laird PW. Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in Apc(Min/+) Dnmt1-hypomorphic mice. Cancer Res 2002;62:1296-9.
50. Rhee I, Jair KW, Yen RW, et al. CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 2000;404:1003-7.
51. Rhee I, Bachman KE, Park BH, et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002; 416:552-6.
52. Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 2001;10:687-92.
53. Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 2000;25:269-77.
54. Bachman KE, Rountree MR, Baylin SB. Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. J Biol Chem 2001;276:32282-7.
55. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 2000;25:338-42.
56. Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 2000;24:88-91.
57. Burgers WA, Fuks F, Kouzarides T. DNA methyltransferases get connected to chromatin. Trends Genet 2002;18:275-7.
58. Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T. Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J 2001; 20:2536-44.
59. Di Croce L, Raker VA, Corsaro M, et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 2002; 295:1079-82.
60. Jones PA. The DNA methylation paradox. Trends Genet 1999;15:34-7.
61. Kass SU, Pruss D, Wolffe AP. How does DNA methylation repress transcription? Trends Genet 1997;13:444-9.
62. Kuzmichev A, Reinberg D. Role of histone deacetylase complexes in the regulation of chromatin metabolism. Curr Top Microbiol Immunol 2001;254:35-58.
63. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 403:41-5.
64. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 1999;21:103-7.
65. Nakayama J, Rice JC, Strahl BD, Allis CD, Grewal SI. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 2001;292:110-3.
66. Litt MD, Simpson M, Gaszner M, Allis CD, Felsenfeld G. Correlation between histone lysine methylation and developmental changes at the chicken beta-globin locus. Science 2001;293:2453-5.
67. Noma K, Allis CD, Grewal SI. Transitions in disfinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science 2001;293:1150-5.
68. Boggs BA, Cheung P, Heard E, Spector DL, Chinault AC, Allis CD. Differentially methylated forms of histone H3 show unique association patterns with inactive human X chromosomes. Nat Genet 2002;30:73-6.
69. Peters AH, Mermoud JE, O'Carroll D, et al. Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nat Genet 2002;30:77-80.
70. Heard E, Rougeulle C, Arnaud D, Avner P, Allis CD, Spector DL. Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation. Cell 2001;107:727-38.
71. Xin Z, Allis CD, Wagstaff J. Parent-specific complementary patterns of histone H3 lysine 9 and H3 lysine 4 methylation at the Prader-Willi syndrome imprinting center. Am J Hum Genet 2001;69:1389-94.
72. Fahrner JA, Eguchi S, Herman JG, Baylin SB. Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res 2002;62: 7213-8.
73. Nguyen CT, Weisenberger DJ, Velicescu M, et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2′-deoxycytidine. Cancer Res 2002;62:6456-61.
74. Kondo Y, Shen L, Issa JP. Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol 2003;23:206-15.
75. Ghoshal K, Datta J, Majumder S, et al. Inhibitors of histone deacetylase and DNA methyltransferase synergistically activate the methylated metallothionen I promoter by activating the transcription factor MTF-1 and forming an open chromatin structure. Mol Cell Biol 2002;22:8302-19.
76. Koizume S, Tachibana K, Sekiya T, Hirohashi S, Shiraishi M. Heterogeneity in the modification and involvement of chromatin components of the CpG island of the silenced human CDH1 gene in cancer cells. Nucleic Acids Res 2002;30:4770-80.
77. Jackson JP, Lindroth AM, Cao X, Jacobsen SE. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransfetase. Nature 2002;416:556-60.
78. Tamaru H, Selker EU. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 2001;414:277-83.
79. Bachman KE, Park BH, Khee I, et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 2003;3:89-95.
80. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000;16:168-74.
81. Lubbert M. DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol 2000; 249:135-64.
82. Taylor SM, Jones PA. Changes in phenotypic expression in embryonic and adult cells treated with 5-azacytidine. J Cell Physiol 1982;111:187-94.
83. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol 2002;20:2429-40.
84. Kornblith AB, Herndon JE II, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol 2002;20:2441-52.
85. Richon VM, O'Brien JP. Histone deacetylase inhibitors: a new class of potential therapeutic agents for cancer treatment. Clin Cancer Res 2002;8:662-4.
86. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 2001;1:194-202.
87. Momparler RL. Molecular, cellular and animal pharmacology of 5-aza-2′-deoxycytidine. Pharmacol Ther 1985;30:287-99.
88. Vesely J. Mode of action and effects of 5-azacytidine and of its derivatives in eukaryotic cells. Pharmacol Ther 1985;28:227-35.
89. Ferguson AT, Vertino PM, Spitzner JR, Baylin SB, Muller MT, Davidson NE. Role of estrogen receptor gene demethylation and DNA methyltransferase: DNA adduct formation in 5-aza-2′deoxycytidine-induced cytotoxicity in human breast cancer cells. J Biol Chem 1997;272:32260-6.
90. Jackson-Grusby L, Laird PW, Magge SN, Moeller BJ, Jaenisch R. Mutagenicity of 5-aza-2′-deoxycytidine is mediated by the mammalian DNA methyltransferase. Proc Natl Acad Sci U S A 1997;94:4681-5.
91. Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/ INK4B gene in patients with myelodysplastic syndrome by 5-aza-2′-deoxycytidine (decitabine) treatment. Blood 2002;100:2957-64.
92. Pfeifer GP, Steigerwald SD, Hansen RS, Gartler SM, Riggs AD. Polymerase chain reaction-aided genomic sequencing of an X chromosome-linked CpG island: methylation patterns suggest clonal inheritance, CpG site autonomy, and an explanation of activity state stability. Proc Natl Acad Sci U S A 1990;87:8252-6.
93. Cheng JC, Matsen CB, Gonzales FA, et al. Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst 2003;95:399-409.
94. MacLeod AR, Szyf M. Expression of antisense to DNA methyltransferase mRNA induces DNA demethylation and inhibits tumorigenesis. J Biol Chem 1995;270:8037-43.
95. Robert MF, Morin S, Beaulieu N, et al. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet 2003;33:61-5.
96. 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;93:9821-6.
97. Belinsky SA, Nikula KJ, Palmisano WA, et al. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci U S A 1998;95:11891-6.
98. Palmisano WA, Divine KK, Saccomanno G, et al. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 2000;60:5954-8.
99. Esteller M, Corn PG, Baylin SB, Herman JG. A gene hypermethylation profile of human cancer. Cancer Res 2001;61:3225-9.
100. Eads CA, Danenberg KD, Kawakami K, et al. MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 2000;28:E32.
101. Lee TL, Leung WK, Chan MW, et al. Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma. Clin Cancer Res 2002;8: 1761-6.
102. 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;59:67-70. [Erratum, Cancer Res 1999;59:3853.]
103. 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;59:67-70. [Erratum, Cancer Res 1999;59:3853.]
104. Sanchez-Cespedes M, Esteller M, Wu L, et al. Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res 2000;60:892-5.
105. Hibi K, Taguchi M, Nakayama H, et al. Molecular detection of p16 promoter methylation in the serum of patients with esophageal squamous cell carcinoma. Clin Cancer Res 2001;7:3135-8.
106. Zou HZ, Yu BM, Wang ZW, et al. Detection of aberrant p16 methylation in the serum of colorectal cancer patients. Clin Cancer Res 2002;8:188-91.
107. Brabender J, Usadel H, Danenberg KD, et al. Adenomatous polyposis coli gene promoter hypermethylation in non-small cell lung cancer is associated with survival. Oncogene 2001;20:3528-32.
108. Usadel H, Brabender J, Danenberg KD, et al. Quantitative adenomatous polyposis coli promoter methylation analysis in tumor tissue, serum, and plasma DNA of patients with lung cancer. Cancer Res 2002;62: 371-5.
109. Wong IH, Lo YM, Zhang J, et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res 1999;59:71-3.
110. Shao ZM, Nguyen M. Tumor-specific DNA in plasma of breast cancer patients. Anticancer Drugs 2002;13:353-7.
111. Grady WM, Rajput A, Lutterbaugh JD, Markowitz SD. Detection of aberrantly methylated hMLH1 promoter DNA in the serum of patients with microsatellite unstable colon cancer. Cancer Res 2001;61:900-2.
112. Ahrendt SA, Chow JT, Xu LH, et al. Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer. J Natl Cancer Inst 1999; 91:332-9.
113. Cairns P, Esteller M, Herman JG, et al. Molecular detection of prostate cancer in urine by GSTP1 hypermethylation. Clin Cancer Res 2001;7:2727-30.
114. Goessl C, Muller M, Heicappell R, Krause H, Miller K. DNA-based detection of prostate cancer in blood, urine, and ejaculates. Ann N Y Acad Sci 2001;945:51-8.
115. Evron E, Dooley WC, Umbricht CB, et al. Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR. Lancet 2001;357:1335-6.
116. Sanchez-Cespedes M, Esteller M, Hibi K, et al. Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence. Clin Cancer Res 1999;5:2450-4.
117. Jeronimo C, Usadel H, Henrique R, et al. Quantitation of GSTP1 methylation in non-neoplastic prostatic tissue and organ-confined prostate adenocarcinoma. J Natl Cancer Inst 2001;93:1747-52.
118. Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JP. Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 1998; 58:5489-94.
119. Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 1994;7:536-40.
120. Chan AO, Broaddus RR, Houlihan PS, Issa JP, Hamilton SR, Rashid A. CpG island methylation in aberrant crypt foci of the colorectum. Am J Pathol 2002;160:1823-30.
121. Swafford DS, Middleton SK, Palmisano WA, et al. Frequent aberrant methylation of p16INK4a in primary rat lung tumors. Mol Cell Biol 1997;17:1366-74.
122. Nuovo GJ, Plaia TW, Belinsky SA, Baylin SB, Herman JG. In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc Natl Acad Sci U S A 1999;96:12754-9.
123. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999;59:793-7.
124. Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to aklating agents. N Engl J Med 2000;343: 1350-4. [Erratum, N Engl J Med 2000;343: 1740.]
125. Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to aklating agents. N Engl J Med 2000;343: 1350-4. [Erratum, N Engl J Med 2000;343: 1740.]
126. Esteller M, Gaidano G, Goodman SN, et al. Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. J Natl Cancer Inst 2002;94:26-32.
127. Katzenellenbogen RA, Baylin SB, Herman JG. Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 1999;93:4347-53.
128. Cohen O, Inbal B, Kissil JL, et al. DAP-kinase participates in TNF-alpha- and Fas-induced apoptosis and its function requires the death domain. J Cell Biol 1999;146:141-8.
129. Cohen O, Kimchi A. DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer. Cell Death Differ 2001;8:6-15.
130. Tang X, Khuri FR, Lee JJ, et al. Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I non-small-cell lung cancer. J Natl Cancer Inst 2000;92:1511-6.