DNA methylation markers: A versatile diagnostic tool for routine clinical use

Current Opinion in Molecular Therapeutics

Volumn 9, Issue 3, 2007, Pages 222-230

  Lesche, R ^a   Eckhardt, F ^a  

^a EPIGENOMICS AG   (Germany)

Author keywords

Biomarker; Cancer; DNA methylation; Drug response; Molecular diagnostics; Outcome prediction

Indexed keywords

ALKYLATING AGENT; ALPHA INTERFERON; CISPLATIN; CYCLOPHOSPHAMIDE; DAUNORUBICIN; DNA; EPIRUBICIN; ETOPOSIDE; PLATINUM; TAMOXIFEN; TAXANE DERIVATIVE; TEMOZOLOMIDE; VINCRISTINE;

BREAST CANCER; CANCER STAGING; CLINICAL TRIAL; COLON CANCER; DNA METHYLATION; GLIOMA; HORMONE RELEASE; HUMAN; LEUKEMIA; NONHUMAN; PREDICTION; REVIEW; TREATMENT OUTCOME;

BREAST NEOPLASMS; COLONIC NEOPLASMS; DNA METHYLATION; FEMALE; GLIOMA; HUMANS; MALE; NEOPLASMS; OVARIAN NEOPLASMS; TUMOR MARKERS, BIOLOGICAL;

EID: 34250784471     PISSN: 14648431     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (105)

1. Inoue S, Oishi M: Effects of methylation of non-CpG sequence in the promoter region on the expression of human synaptotagmin XI (syt11). Gene (2005) 348:123-34.
2. Jaenisch R, Bird A: Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet (2003) 33(Suppl):245-254.
3. Takai D, Jones PA: Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci USA (2002) 99(6):3740-3745.
4. International Human Genome Sequencing Consortium: Initial sequencing and analysis of the human genome. Nature (2001) 409(6822):860- 921.
5. Antequera F, Bird A: Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci USA (1993) 90(24):11995-11999.
6. Strathdee G, Sim A, Brown R: Control of gene expression by CpG island methylation in normal cells. Biochem Soc Trans (2004) 32(6):913-915.
7. Murayama A, Sakura K, Nakama M, Yasuzawa-Tanaka K, Fujita E, Tateishi Y, Wang Y, Ushijima T, Baba T, Shibuya K, Shibuya A et al: A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory. EMBO J (2006) 25(5):1081-1092.
8. mCpG methylation. Gene (1997) 195(1):67-71.
9. Prendergast GC, Ziff EB: Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science (1991) 251(4990):186-189.
10. Klose RJ, Bird AP: Genomic DNA methylation: The mark and its mediators. Trends Biochem Sci (2006) 31(2):89-97.
11. Eckhardt F, Lewin J, Cortese R, Rakyan V, Attwood J, Burger M, Burton J, Cox T, Davies R, Down TA, Haefliger C et al: Large-scale DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet (2006) 38(12):1378-1385. •• This is the most comprehensive analysis of DNA methylation to date. 1.9 Million CpG methylation values were obtained from 12 different tissues. These data suggest that DNA methylation is ontogenetically more stable than previously thought.
12. Jones PA, Laird PW: Cancer epigenetics comes of age. Nat Genet (1999) 21(2):163-167.
13. Ehrlich M: DNA methylation in cancer: Too much, but also too little. Oncogene (2002) 21(35):5400-5413.
14. Yamada Y, Jackson-Grusby L, Linhart H, Meissner A, Eden A, Lin H, Jaenisch R: Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc Natl Acad Sci USA (2005) 102(38):13580- 13585.
15. Laird PW, Jackson-Grusby L, Fazeli A, Dickinson SL, Jung WE, Li E, Weinberg RA, Jaenisch R: Suppression of intestinal neoplasia by DNA hypomethylation. Cell (1995) 81(2):197-205.
16. Feinberg AP, Vogelstein B: Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature (1983) 301(5895):89-92.
17. Issa JP, Kantarjian H: Azacitidine. Nat Rev Drug Discov (2005) Suppl:S6-7.
18. Lieb JD, Beck S, Bulyk ML, Farnham P, Hattori N, Henikoff S, Liu XS, Okumura K, Shiota K, Ushijima T, Greally JM: Applying whole-genome studies of epigenetic regulation to study human disease. Cytogenet Genome Res (2006) 114(1):1-15.
19. Harden SV, Sanderson H, Goodman SN, Partin AA, Walsh PC, Epstein JI, Sidransky D: Quantitative GSTP1 methylation and the detection of prostate adenocarcinoma in sextant biopsies. J Natl Cancer Inst (2003) 95(21):1634-1637.
20. Bremnes RM, Sirera R, Camps C: Circulating tumour-derived DNA and RNA markers in blood: A tool for early detection, diagnostics, and follow-up? Lung Cancer (2005) 49(1):1-12.
21. Muller HM, Oberwalder M, Fiegl H, Morandell M, Goebel G, Zitt M, Muhlthaler M, Ofner D, Margreiter R, Widschwendter M: Methylation changes in faecal DNA: A marker for colorectal cancer screening? Lancet (2004) 363(9417):1283-1285.
22. Jubb AM, Quirke P, Oates AJ: DNA methylation, a biomarker for colorectal cancer: Implications for screening and pathological utility. Ann N Y Acad Sci (2003) 983:251-267.
23. Belinsky SA: Gene-promoter hypermethylation as a biomarker in lung cancer. Nat Rev Cancer (2004) 4(9):707-717.
24. Lofton-Day C, Model F, Tetzner R, DeVos T, Schuster M, Lesche R, Sledziewski A, Day RW: A real-time PCR test for septin 9 gene methylation identifies early stage colorectal cancer in plasma. Proc Am Assoc Cancer Res (2006) 47:LB-224.
25. Fiegl H, Millinger S, Mueller-Holzner E, Marth C, Ensinger C, Berger A, Klocker H, Goebel G, Widschwendter M: Circulating tumor-specific DNA: A marker for monitoring efficacy of adjuvant therapy in cancer patients. Cancer Res (2005) 65(4):1141-1145.
26. Lapidus RG, Ferguson AT, Ottaviano YL, Parl FF, Smith HS, Weitzman SA, Baylin SB, Issa JP, Davidson NE: Methylation of estrogen and progesterone receptor gene 5′ CpG islands correlates with lack of estrogen and progesterone receptor gene expression in breast tumors. Clin Cancer Res (1996) 2(5):805-810.
27. Lapidus RG, Nass SJ, Davidson NE: The loss of estrogen and progesterone receptor gene expression in human breast cancer. J Mammary Gland Biol Neoplasia (1998) 3(1):85-94.
28. Chang HG, Kim SJ, Chung KW, Noh DY, Kwon Y, Lee ES, Kang HS: Tamoxifen-resistant breast cancers show less frequent methylation of the estrogen receptor β but not the estrogen receptor α gene. J Mol Med (2004) 83(2):132-139. • In this study, DNA methylation and mRNA expression of estrogen receptors α and β were analyzed from 34 tamoxifen-resistant breast cancer patients and 68 controls. Statistically significant differences between the groups were observed only for estrogen receptor β.
29. Rody A, Holtrich U, Solbach C, Kourtis K, von Minckwitz G, Engels K, Kissler S, Gatje R, Karn T, Kaufmann M: Methylation of estrogen receptor β promoter correlates with loss of ER-β expression in mammary carcinoma and is an early indication marker in premalignant lesions. Endocr Relat Cancer (2005) 12(4):903-916.
30. Rosen EM, Fan S, Pestell RG, Goldberg ID: BRCA1 in hormone-responsive cancers. Trends Endocrinol Metab (2003) 14(8):378-385.
31. Rice JC, Ozcelik H, Maxeiner P, Andrulis I, Futscher BW: Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis (2000) 21(9):1761- 1765.
32. Widschwendter M, Siegmund KD, Muller HM, Fiegl H, Marth C, Muller-Holzner E, Jones PA, Laird PW: Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen. Cancer Res (2004) 64(11):3807-3813.
33. Schlegel A, Wang C, Katzenellenbogen BS, Pestell RG, Lisanti MP: Caveolin-1 potentiates estrogen receptor α (ERα) signaling. Caveolin-1 drives ligand-independent nuclear translocation and activation of ERα. J Biol Chem (1999) 274(47):33551-33556.
34. Schlegel A, Wang C, Pestell RG, Lisanti MP: Ligand-independent activation of oestrogen receptor α by caveolin-1. Biochem J (2001) 359(1):203-210.
35. Chen ST, Lin SY, Yeh KT, Kuo SJ, Chan WL, Chu YP, Chang JG: Mutational, epigenetic and expressional analyses of caveolin-1 gene in breast cancers. Int J Mol Med (2004) 14(4):577-582.
36. Ferguson AT, Lapidus RG, Baylin SB, Davidson NE: Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res (1995) 55(11):2279-2283.
37. Sharma D, Saxena NK, Davidson NE, Vertino PM: Restoration of tamoxifen sensitivity in estrogen receptor-negative breast cancer cells: Tamoxifen-bound reactivated ER recruits distinctive corepressor complexes. Cancer Res (2006) 66(12):6370-6378.
38. van Agthoven T, van Agthoven TL, Dekker A, Foekens JA, Dorssers LC: Induction of estrogen independence of ZR-75-1 human breast cancer cells by epigenetic alterations. Mol Endocrinol (1994) 8(11):1474-1483.
39. Rio MC, Bellocq JP, Gairard B, Rasmussen UB, Krust A, Koehl C, Calderoli H, Schiff V, Renaud R, Chambon P: Specific expression of the pS2 gene in subclasses of breast cancers in comparison with expression of the estrogen and progesterone receptors and the oncogene ERBB2. Proc Natl Acad Sci USA (1987) 84(24):9243-9247.
40. Nunez AM, Berry M, Imler JL, Chambon P: The 5′ flanking region of the pS2 gene contains a complex enhancer region responsive to oestrogens, epidermal growth factor, a tumour promoter (TPA), the c-Ha-ras oncoprotein and the c-jun protein. EMBO J (1989) 8(3):823-829.
41. Foekens JA, Rio MC, Seguin P, van Putten WL, Fauque J, Nap M, Klijn JG, Chambon P: Prediction of relapse and survival in breast cancer patients by pS2 protein status. Cancer Res (1990) 50(13):3832-3837.
42. Koerner FC, Goldberg DE, Edgerton SM, Schwartz LH: pS2 expression and response to hormonal therapy in patients with advanced breast cancer. Cancer Res (1991) 51(2):624-628.
43. Martin V, Ribieras S, Song-Wang X, Rio MC, Dante R: Genomic sequencing indicates a correlation between DNA hypomethylation in the 5′ region of the pS2 gene and its expression in human breast cancer cell lines. Gene (1995) 157(1-2):261-264.
44. Martin V, Ribieras S, Song-Wang XG, Lasne Y, Frappart L, Rio MC, Dante R: Involvement of DNA methylation in the control of the expression of an estrogen-induced breast-cancer-associated protein (pS2) in human breast cancers. J Cell Biochem (1997) 65(1):95-106.
45. Leu YW, Yan PS, Fan M: Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer. Cancer Res (2004) 64(22):8184-8192.
46. Badia E, Duchesne MJ, Semlali A, Fuentes M, Giamarchi C, Richard-Foy H, Nicolas JC, Pons M: Long-term hydroxytamoxifen treatment of an MCF-7-derived breast cancer cell line irreversibly inhibits the expression of estrogenic genes through chromatin remodeling. Cancer Res (2000) 60(15):4130- 4138.
47. Martens JW, Nimmrich I, Koenig T, Look MP, Harbeck N, Model F, Kluth A, Bolt-de Vries J, Sieuwerts AM, Portengen H, Meijer-Van Gelder ME et al: Association of DNA methylation of phosphoserine aminotransferase with response to endocrine therapy in patients with recurrent breast cancer. Cancer Res (2005) 65(10):4101-4117. • This comprehensive study used a microarray approach to analyze the methylation status of 117 genes in 200 steroid hormone receptor-positive breast cancer specimens. Phosphoserine aminotransferase was the strongest marker associated with endocrine therapy.
48. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ: Meeting highlights: International expert consensus on the primary therapy of early breast cancer. Ann Oncol (2005) 16:1569-1583.
49. Carlson RW, McCormick B. Update: NCCN breast cancer clinical practice guidelines. J Natl Compr Canc Netw (2005) 3(Suppl 1):S7-11.
50. Maier S, Nimmrich I, Koenig T, Eppenberger-Castori S, Bohlmann I, Paradiso A, Spyratos F, Thomssen C, Mueller V, Nährig J, Schittulli F et al: DNA-methylation status of the homeodomain transcription factor PITX2 reliably predicts risk of distant disease recurrence in tamoxifen-treated, node-negative breast cancer patients - technical and clinical validation in a multicenter setting in collaboration with the EORTC PathoBiology Group. Eur J Cancer (2007): in press. • In this study, a DNA methylation marker, PITX2, was identified and confirmed to reliably predict risk of distant disease recurrence in estrogen receptor-positive, node-negative, tamoxifen-treated breast cancer patients. Biomarkers that address this question are considered of high clinical relevance.
51. Harbeck N, Bohlmann I, Ross JS, Gruetzmann R, Kristiansen G, Margossian A, Hartmann A, Cufer T, Paradiso A, Maier S, EpiBreast Group: Multicenter study validates PITX2 DNA methylation for risk prediction in tamoxifen-treated, node-negative breast cancer using paraffin-embedded tumor tissue. ASCO Annual Meeting Proceedings J Clin Oncol (2005) 23(16S):505. •• This paper describes a multicenter validation of the DNA methylation marker PITX2 in 400 specimens from estrogen receptor-positive, nodenegative, tamoxifen-treated patient samples. In this study, the analysis of formalin-fixed paraffin embedded specimens demonstrated the clinical utility of the DNA methylation marker.
52. Martens JW, Maier S, Schwope I, Koenig T, Hartmann O, Kluth A, Look MP, Harbeck N, Bolt-de Vries J, Sieuwerts AM, Portengen H et al: DNA-hypermethylation of PITX2 and risk of cancer recurrence in lymph node-negative hormone receptor-positive breast cancer patients. Am Assoc Cancer Res (2005) 96: Abs 2762.
53. Seidman AD: Systemic treatment of breast cancer. Two decades of progress. Oncology (2006) 20(9):983-990.
54. Quinn JE, Kennedy RD, Mullan PB, Gilmore PM, Carty M, Johnston PG, Harkin DP: BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res (2003) 63(19):6221-6228.
55. Egawa C, Miyoshi Y, Takamura Y, Taguchi T, Tamaki Y, Noguchi S: Decreased expression of BRCA2 mRNA predicts favorable response to docetaxel in breast cancer. Int J Cancer (2001) 95(4):255-259.
56. Egawa C, Motomura K, Miyoshi Y, Takamura Y, Taguchi T, Tamaki Y, Inaji H, Koyama H, Noguchi S: Increased expression of BRCA1 mRNA predicts favorable response to anthracycline-containing chemotherapy in breast cancers. Breast Cancer Res Treat (2003) 78(1):45-50.
57. Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E et al: Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst (2000) 92(7):564-569.
58. Matros E, Wang ZC, Lodeiro G, Miron A, Iglehart JD, Richardson AL: BRCA1 promoter methylation in sporadic breast tumors: Relationship to gene expression profiles. Breast Cancer Res Treat (2005) 91(2):179-186.
59. 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(7):3105-3109.
60. Liu L, Tommasi S, Lee DH, Dammann R, Pfeifer GP: Control of microtubule stability by the RASSF1A tumor suppressor. Oncogene (2003) 22(50):8125-8136.
61. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN et al: PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell (2004) 6(2):117-127. • The molecular nature of trastuzumab resistance despite a positive HER2/neu status is among the most relevant clinical questions to date. This study suggests that loss of PTEN predicts trastuzumab resistance in patients.
62. Garcia JM, Silva J, Pena C, Garcia V, Rodriguez R, Cruz MA, Cantos B, Provencio M, Espana P, Bonilla F: Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer (2004) 41(2):117-124.
63. Strathdee G, MacKean MJ, Illand M, Brown R: A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene (1999) 18(14):2335-2341.
64. Gifford G, Paul J, Vasey PA, Kaye SB, Brown R: The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin Cancer Res (2004) 10(13):4420- 4426.
65. Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, Mok SC, D'Andrea AD: Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med (2003) 9(5):568-574.
66. Snyder ER, Ricker JL, Chen Z, Waes CV: Variation in cisplatinum sensitivity is not associated with Fanconi Anemia/BRCA pathway inactivation in head and neck squamous cell carcinoma cell lines. Cancer Lett (2007) 245(1-2):75-80.
67. Chiang JW, Karlan BY, Cass L, Baldwin RL: BRCA1 promoter methylation predicts adverse ovarian cancer prognosis. Gynecol Oncol (2006) 101(3):403-410.
68. Wiley A, Katsaros D, Fracchioli S, Yu H: Methylation of the insulin-like growth factor binding protein-3 gene and prognosis of epithelial ovarian cancer. Int J Gynecol Cancer (2006) 16(1):210-218.
69. Veeck J, Niederacher D, An H, Klopocki E, Wiesmann F, Betz B, Galm O, Camara O, Durst M, Kristiansen G, Huszka C et al: Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis. Oncogene (2006) 25(24):3479-3488.
70. Wei SH, Balch C, Paik HH, Kim YS, Baldwin RL, Liyanarachchi S, Li L, Wang Z, Wan JC, Davuluri RV, Karlan BY et al: Prognostic DNA methylation biomarkers in ovarian cancer. Clin Cancer Res (2006) 12(9):2788-2794.
71. Wiley A, Katsaros D, Chen H, Rigault de la Longrais IA, Beeghly A, Puopolo M, Singal R, Zhang Y, Amoako A, Zelterman D, Yu H: Aberrant promoter methylation of multiple genes in malignant ovarian tumors and in ovarian tumors with low malignant potential. Cancer (2006) 107(2):299-308.
72. Chan MW, Wei SH, Wen P, Wang Z, Matei DE, Liu JC, Liyanarachchi S, Brown R, Nephew KP, Yan PS, Huang TH: Hypermethylation of 18S and 28S ribosomal DNAs predicts progression-free survival in patients with ovarian cancer. Clin Cancer Res (2005) 11(20):7376-7383.
73. 6-methylguanine. Oncogene (2006) 26(2):186-197.
74. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG: Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med (2000) 343(19):1350-1354.
75. Paz MF, Yaya-Tur R, Rojas-Marcos I, Reynes G, Pollan M, Aguirre-Cruz L, Garcia-Lopez JL, Piquer J, Safont MJ, Balana C, Sanchez-Cespedes M et al: CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res (2004) 10(15):4933-4938.
76. Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R: Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res (2004) 10(6):1871-1874.
77. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med (2005) 352(10):997-1003. •• This study, conducted in a clinical trial setting, confirmed MGMT methylation as a biomarker for temozolomide response. When comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide, only glioblastoma patients with a methylated MGMT promoter benefited from temozolomide.
78. Yang HJ, Liu VW, Wang Y, Tsang PC, Ngan HY: Differential DNA methylation profiles in gynecological cancers and correlation with clinico-pathological data. BMC Cancer (2006) 6:212.
79. Judson H, Stewart A, Leslie A, Pratt N, Baty D, Steele R, Carey F: Relationship between point gene mutation, chromosomal abnormality, and tumour suppressor gene methylation status in colorectal adenomas. J Pathol (2006) 210(3):344-350
80. Hoque MO, Begum S, Topaloglu O, Chatterjee A, Rosenbaum E, Van Criekinge W, Westra WH, Schoenberg M, Zahurak M, Goodman SN, Sidransky D: Quantitation of promoter methylation of multiple genes in urine DNA and bladder cancer detection. J Natl Cancer Inst (2006) 98(14):996-1004.
81. Weaver KD, Grossman SA, Herman JG: Methylated tumor-specific DNA as a plasma biomarker in patients with glioma. Cancer Invest (2006) 24(1):35-40.
82. 6-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 (2003) 9(4):1461-1468.
83. Colon Cancer (PDQ) - Treatment. National Cancer Institute, NIH, Bethesda, MD, USA (2007). http://www.cancer.gov/cancertopics/pdq/treatment/ colon/healthprofessional
84. Aebi S, Fink D, Gordon R, Kim HK, Zheng H, Fink JL, Howell SB: Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells. Clin Cancer Res (1997) 3(10):1763-1767.
85. Brown R, Hirst GL, Gallagher WM, McIlwrath AJ, Margison GP, van der Zee AG, Anthoney DA: hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents. Oncogene (1997) 15(1):45-52.
86. Toft NJ, Winton DJ, Kelly J, Howard LA, Dekker M, te Riele H, Arends MJ, Wyllie AH, Margison GP, Clarke AR: Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. Proc Natl Acad Sci USA (1999) 96(7):3911-3915.
87. Arnold CN, Goel A, Boland CR: Role of hMLH1 promoter hypermethylation in drug resistance to 5 fluorouracil in colorectal cancer cell lines. Int J Cancer (2003) 106(1):66-73.
88. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF et al: Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA (1998) 95(12):6870-6875.
89. Ricciardiello L, Ceccarelli C, Angiolini G, Pariali M, Chieco P, Paterini P, Biasco G, Martinelli GN, Roda E, Bazzoli F: High thymidylate synthase expression in colorectal cancer with microsatellite instability: Implications for chemotherapeutic strategies. Clin Cancer Res (2005) 11(11):4234-4240.
90. Benatti P, Gafa R, Barana D, Marino M, Scarselli A, Pedroni M, Maestri I, Guerzoni L, Roncucci L, Menigatti M, Roncari B et al: Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res (2005) 11(23):8332-8340.
91. Issa JP: CpG island methylator phenotype in cancer. Nat Rev Cancer (2004) 4(12):988-993.
92. Van Rijnsoever M, Elsaleh H, Joseph D, McCaul K, Iacopetta B: CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer. Clin Cancer Res (2003) 9(8):2898-2903.
93. Toffoli G, Cecchin E, Corona G, Russo A, Buonadonna A, D'Andrea M, Pasetto LM, Pessa S, Errante D, De Pangher V, Giusto M et al: The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol (2006) 24(19):3061-3068.
94. Gagnon JF, Bernard O, Villeneuve L, Tetu B, Guillemette C: Irinotecan inactivation is modulated by epigenetic silencing of UGT1A1 in colon cancer. Clin Cancer Res (2006) 12(6):1850-1858. • This paper describes an interesting proof-of-concept study of colon cancer cell lines, the findings of which suggest that drug response to irinotecan might be regulated by epigenetic silencing of UGT1A1, an enzyme involved in irinotecan metabolism.
95. Glavinas H, Krajcsi P, Cserepes J, Sarkadi B: The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv (2004) 1(1):27-42.
96. Nakayama M, Wada M, Harada T, Nagayama J, Kusaba H, Ohshima K, Kozuru M, Komatsu H, Ueda R, Kuwano M: Hypomethylation status of CpG sites at the promoter region and overexpression of the human MDR1 gene in acute myeloid leukemias. Blood (1998) 92(11):4296-4307.
97. Roman-Gomez J, Jimenez-Velasco A, Castillejo JA, Agirre X, Barrios M, Navarro G, Molina FJ, Calasanz MJ, Prosper F, Heiniger A, Torres A: Promoter hypermethylation of cancer-related genes: A strong independent prognostic factor in acute lymphoblastic leukemia. Blood (2004) 104(8):2492- 2498.
98. Roman-Gomez J, Jimenez-Velasco A, Agirre X, Castillejo JA, Navarro G, Garate L, Jose-Eneriz ES, Cordeu L, Barrios M, Prosper F, Heiniger A et al: Promoter hypermethylation and global hypomethylation are independent epigenetic events in lymphoid leukemogenesis with opposing effects on clinical outcome. Leukemia (2006) 20(8):1445-1448. • This paper describes a comprehensive study that analyzed more than 250 patient specimens from acute lymphoblastic leukemia patients. The results suggest that DNA methylation profiling may be used as a biomarker of risk prediction in ALL.
99. FDA's Critical Path Initiative. FDA, Rockville, MD, USA (2007). http://www.fda.gov/oc/initiatives/criticalpath/ •• This web site provides information on the critical path initiative issued by the FDA, which is expected to spur biomarker research, especially in the context of clinical trials.
100. Balch C, Huang TH, Brown R, Nephew KP: The epigenetics of ovarian cancer drug resistance and resensitization. Am J Obstet Gynecol (2004) 191(5):1552-1572.
101. Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R: Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res (2000) 60(21):6039-6044.
102. Efferth T, Futscher BW, Osieka R: 5-Azacytidine modulates the response of sensitive and multidrug-resistant K562 leukemic cells to cytostatic drugs. Blood Cells Mol Dis (2001) 27(3):637-648.
103. Roman-Gomez J, Castillejo JA, Jimenez A, Cervantes F, Boque C, Hermosin L, Leon A, Granena A, Colomer D, Heiniger A, Torres A: Cadherin-13, a mediator of calcium-dependent cell-cell adhesion, is silenced by methylation in chronic myeloid leukemia and correlates with pretreatment risk profile and cytogenetic response to interferon α. J Clin Oncol (2003) 21(8):1472-1479.
104. Satoh A, Toyota M, Itoh F, Sasaki Y, Suzuki H, Ogi K, Kikuchi T, Mita H, Yamashita T, Kojima T, Kusano M et al: Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer. Cancer Res (2003) 63(24):8606-8613.
105. Koul S, McKiernan JM, Narayan G, Houldsworth J, Bacik J, Dobrzynski DL, Assaad AM, Mansukhani M, Reuter VE, Bosl GJ, Chaganti RS et al: Role of promoter hypermethylation in cisplatin treatment response of male germ cell tumors. Mol Cancer (2004) 3:16.