Prognostic significance of aberrant promoter hypermethylation of CpG islands in patients with diffuse large B-cell lymphomas

Amara, Khaled; Trimeche, Mounir; Ziadi, Sonia; Laatiri, Adnen; Hachana, Mohamed Ridha; Korbi, Sadok

doi:10.1093/annonc/mdn374

Article (Scientific journals)

Prognostic significance of aberrant promoter hypermethylation of CpG islands in patients with diffuse large B-cell lymphomas

Amara, Khaled; Trimeche, Mounir; Ziadi, Sonia et al.

2008 • In Annals of Oncology, 19 (10), p. 1774-1786

Peer Reviewed verified by ORBi

Permalink
https://hdl.handle.net/2268/87469

DOI
10.1093/annonc/mdn374

PubMed
18539616

Files (1)Send to Details Statistics Bibliography Similar publications

Files

Full Text

Prognostic significance of aberrant promoter.pdf

Author preprint (356.32 kB)

Request a copy

All documents in ORBi are protected by a user license.

Send to

RIS BibTex APA Chicago Permalink X Linkedin

Details

Keywords :

diffuse large B-cell lymphomas; hypermethylation; prognosis; tumor suppressor genes

Abstract :

[en] Background: Diffuse large B-cell lymphoma (DLBCL) exhibits heterogeneous clinical features and a marked variable response to treatment. Patients and methods: We investigated the prognostic significance of the methylation status of DAPK, GSTP1, P14, P15, P16, P33, RB1, SHP1, CDH1, APC, BLU, VHL, TIMP3, and RASSF1A genes in 46 DLBCL specimens from Tunisian patients. Methylation status of each gene was correlated with clinicopathological parameters including the International Prognostic Index (IPI), the germinal center immunophenotype, and response to treatment and survival. Overall survival (OS) and disease-free survival (DFS) rates were calculated by the Kaplan–Meier method and differences were compared with the log-rank test. Results: Hypermethylation of SHP1 was associated with elevated lactate dehydrogenase level (P = 0.031). P16 and VHL were frequently hypermethylated in patients with high IPI scores (P = 0.006 and 0.004) and a performance status of two or more (P = 0.007 and 0.047). In addition, hypermethylation of P16 was significantly associated with advanced clinical stages and B symptoms (P = 0.041 and 0.012). Interestingly, hypermethylation of DAPK was significantly correlated with resistance to treatment (P = 0.023). With regard to survival rates, promoter hypermethylation of DAPK, P16, and VHL were significantly associated with shortened OS (P = 0.003, 0.001, and 0.017, respectively) and DFS (P = 0.006, 0.003, and 0.046, respectively). In multivariate analysis, hypermethylation of DAPK remains an independent prognostic factor in predicting shortened OS (P = 0.001) and DFS (P = 0.024), as well as the IPI and the germinal center status. Conclusions: This study demonstrates that DLBCLs with hypermethylated P16, VHL, DAPK, and SHP1 commonly show a biologically aggressive phenotype and worse prognosis. Interestingly, hypermethylation of DAPK was found to be an independent prognostic factor that may be used in conjunction with the conventional prognostic factors such as the IPI and the germinal center status.

Research Center/Unit :

Departments of Pathology and Clinical Hematology, Farhat-Hached Hospital of Sousse, Tunisia

Disciplines :

Hematology

Author, co-author :

Amara, Khaled

Trimeche, Mounir

Ziadi, Sonia

Laatiri, Adnen

Hachana, Mohamed Ridha ; Université de Liège - ULiège > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén.

Korbi, Sadok

Language :

English

Title :

Prognostic significance of aberrant promoter hypermethylation of CpG islands in patients with diffuse large B-cell lymphomas

Publication date :

October 2008

Journal title :

Annals of Oncology

ISSN :

0923-7534

eISSN :

1569-8041

Publisher :

Oxford University Press, London, United Kingdom

Volume :

Issue :

Pages :

1774-1786

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 22 March 2011

Statistics

Number of views

142 (0 by ULiège)

Number of downloads

0 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer Press, 2001; 171-174.
Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: Clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 1998; 16: 2780-2795.
Lossos IS, Morgensztern D. Prognostic biomarkers in diffuse large B-cell lymphoma. J Clin Oncol 2006; 24: 995-1007.
Alizadeh AA, Eisen MB, Davis RE et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503-511.
Rosenwald A, Wright G, Chan WC et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 1937-1947.
Hans CP, Weisenburger DD, Greiner TC et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103: 275-282.
Chang CC, McClintock S, Cleveland RP et al. Immunohistochemical expression patterns of germinal center and activation B-cell markers correlate with prognosis in diffuse large B-cell lymphoma. Am J Surg Pathol 2004; 28: 464-470.
Amara K, Trimeche M, Ziadi S et al. Presence of Simian virus 40 in diffuse large B-cell lymphomas in Tunisia correlates with germinal center B-cell immunophenotype, t(14;18) translocation, and P53 accumulation. Mod Pathol 2008; 21: 282-296.
Colomo L, Lopez-Guillermo A, Perales M et al. Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma. Blood 2003; 101: 78-84.
Moskowitz CH, Zelenetz AD, Kewalramani T et al. Cell of origin, germinal center versus nongerminal center, determined by immunohistochemistryon tissue microarray, does not correlate with outcome in patients with relapsed and refractory DLBCL. Blood 2005; 106: 3383-3385.
Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003; 349: 2042-2054.
Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev 2002; 3: 415-428.
Toyota M, Issa JP. The role of DNA hypermethylation in human neoplasia. Electrophoresis 2000; 21: 329-333.
Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: Pathophysiology and therapeutic implications. Ann Intern Med 2001; 134: 573-586.
Chim CS, Liang R, Kwong YL. Hypermethylation of gene promoters in hematological neoplasia. Hematol Oncol 2002; 20: 167-176.
Paz MF, Fraga MF, Avila S et al. A systematic profile of DNA methylation in human cancer cell lines. Cancer Res 2003; 63: 1114-1121.
Issa JP, Garcia-Manero G, Giles FJ et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 2004; 103: 1635-1640.
Kantarjian HM, O'Brien S, Cortes J et al. Results of decitabine (5-aza-2′deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer 2003; 98: 522-528.
Baur AS, Shaw P, Burri N et al. Frequent methylation silencing of p15(INK4b)(MTS2) and p16(INK4a) (MTS1) in B-cell and T-cell ymphomas. Blood 1999; 94: 1773-1781.
Shiozawa E, Takimoto M, Makino R et al. Hypermethylation of CpG islands in p16 as a prognostic factor for diffuse large B-cell lymphoma in a high-risk group. Leuk Res 2006; 30: 859-867.
Esteller M, Gaidano G, Goodman SN et al. Hypermethylation of the DNA repair gene O6-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. J Natl Cancer Inst 2002; 94: 26-32.
Al-Kuraya K, Narayanappa R, Siraj AK et al. High frequency and strong prognostic relevance of O6-methylguanine DNA methyltransferase silencing in diffuse large B-cell lymphomas from the Middle East. Human Pathology 2006; 37: 742-748.
Ropero S. Epigenetic pathways in hematological malignancies. Haematol Rep 2006; 2: 7-10.
Takahashi T, Shivapurkar N, Reddy J et al. DNA methylation profiles of lymphoid and hematopoietic malignancies. Clin Cancer Res 2004; 10: 2928-2935.
Wong N, Li L, Tsang K et al. Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma. J Hepatol 2002; 37: 633-639.
Agathanggelou A, Dallol A, Zochbauer-Muller S et al. Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers. Oncogene 2003; 22: 1580-1588.
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 USA 1994; 91: 9700-9704.
Esteller M, Sparks A, Toyota M et al. Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res 2000; 60: 4366-4371.
Herman JG, Graff JR, Myohanen S et al. Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996; 93: 9821-9826.
Katzenellenbogen RA, Baylin SB, Herman JG. Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 1999; 93: 4347-4353.
Esteller M, Corn PG, Urena JM et al. Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res 1998; 58: 4515-4518.
Oka T, Ouchida M, Koyama M et al. Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res 2002; 62: 6390-6394.
Shen DH, Chan KY, Khoo US et al. Epigenetic and genetic alterations of p33ING1b in ovarian cancer. Carcinogenesis 2005; 26: 855-863.
Bachman KE, Herman JG, Corn PG et al. Methylation associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers. Cancer Res 1999; 59: 798-802.
Amara K, Trimeche M, Ziadi S et al. Presence of simian virus 40 DNA sequences in diffuse large B-cell lymphomas in Tunisia correlates with aberrant promoter hypermethylation of multiple tumor suppressor genes. Int J Cancer 2007; 121: 2693-2702.
Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17: 1244-1253.
Man Y, Moinfar F, Bratthauer GL et al. An improved method for DNA extraction from paraffin sections. Pathol Res Pract 2001; 197: 635-642.
Singal R, Ferdinand L, Reis IM, Schlesselman JJ. Methylation of multiple genes in prostate cancer and the relationship with clinicopathological features of disease. Oncol Rep 2004; 12: 631-637.
Roman-Gomez J, Jimenez-Velasco A, Castillejo JA et al. Promoter hypermethylation of cancer-related genes: A strong independent prognostic factor in acute lymphoblastic leukemia. Blood 2004; 104: 2492-2498.
Koh J, Enders GH, Dynlacht BD, Harlow E. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature (Lond) 1995; 375: 506-510.
Cairns P, Polascik JT, Eby Y et al. Frequency of homozygous deletion at p16/CDKN2 in primary human tumors. Nat Genet 2001; 11: 210-212.
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: 4525-4530.
Kim JR, Kim SY, Kim MJ, Kim JH. Alterations of CDKN2 (MTS1/p16INK4A) gene in paraffin-embedded tumor tissues of human stomach, lung, cervix and liver cancers. Exp Mol Med 1998; 30: 109-114.
Lee M, Han WS, Kim OK et al. Prognostic value of p16INK4a and p14ARF gene hypermethylation in human colon cancer. Pathol Res Pract 2006; 202: 415-424.
Wang J, Lee JJ, Wang L et al. Value of p16INK4a and RASSF1A promoter hypermethylation in prognosis of patients with resectable non-small cell lung cancer. Clin Cancer Res 2004; 10: 6119-6125.
Lo KW, Cheung ST, Leung SF et al. Hypermethylation of the p16 gene in nasopharyngeal carcinoma. Cancer Res 1996; 56: 2721-2725.
Garcia MJ, Martinez-Delgado B, Cebrian A et al. Different incidence and pattern of p15INK4b and p16INK4a promoter region hypermethylation in Hodgkin's and CD30-positive non-Hodgkin's lymphomas. Am J Pathol 2002; 161: 1007-1013.
Sanchez-Beato M, Saez AI, Navas IC. Overall survival in aggressive B-cell lymphomas is dependent on the accumulation of alterations in p53, p16, and p27. Am J Pathol 2001; 159: 205-213.
Pinyol M, Cobo F, Bea S et al. p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas. Blood 1998; 91: 2977-2984.
Huang Q, AI L, Zhang ZY et al. Promoter hypermethylation and protein expression of the p16 gene: Analysis of 43 cases of B-cell primary gastric lymphomas from China. Mod Pathol 2004; 17: 416-422.
Latif F, Tory K, Gnarra J et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993; 260: 1317-1320.
Linehan WM, Lerman MI, Zbar B. Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer. Jama 1995; 273: 564-570.
Los M, Jansen GH, Kaelin WG et al. Expression pattern of the von Hippel-Lindau protein in human tissues. Lab Invest 1996; 75: 231-238.
Sakashita N, Takeya M, Kishida T et al. Expression of von Hippel-Lindau protein in normal and pathological human tissues. Histochem J 1999; 31: 133-144.
Kuroki T, Trapasso F, Yendamuri S et al. Allele loss and promoter hypermethylation of VHL, RAR-β, RASSF1A, and FHIT tumor suppressor genes on chromosome 3p in esophageal squamous cell carcinoma. Cancer Res 2003; 63: 3724-3728.
Yu J, Zhang HY, Ma ZZ et al. Methylation profiling of twenty four genes and the concordant methylation behaviours of nineteen genes that may contribute to hepatocellular carcinogenesis. Cell Res 2003; 13: 319-333.
Fung MKL, Au WY, Liang R et al. Aberrant promoter methylation in gastric lymphomas. Haematologica 2003; 88: 231-232.
Deiss LP, Feinstein E, Berissi H et al. Identification of a novel serine/ threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev 2005; 9: 15-30.
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.
Ng MH. Death associated protein kinase: From regulation of apoptosis to tumor suppressive functions and B cell malignancies. Apoptosis 2002; 7: 261-270.
Inbal B, Cohen O, Polak-Charcon S et al. DAP kinase links the control of apoptosis to metastasis. Nature 1997; 390: 180-184.
Kim DH, Nelson HH, Wiencke JK et al. Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer. Oncogene 2001; 20: 1765-1770.
Mittag F, Kuester K, Vieth M et al. DAPK promotor methylation is an early event in colorectal carcinogenesis. Cancer Lett 2006; 240: 69-75.
Tozawa T, Tamura G, Honda T et al. Promoter hypermethylation of DAP-kinase is associated with poor survival in primary biliary tract carcinoma patients. Cancer Sci 2004; 95: 736-740.
Voso MT, Gumiero D, D'Alo' F et al. DAP-kinase hypermethylation in the bone marrow of patients with follicular lymphoma. Haematologica 2006; 91: 1252-1256.
Fischera JR, Ohnmachtc U, Riegerb N et al. Promoter methylation of RASSF1A, RAŘ and DAPK predict poor prognosis of patients with malignant mesotheliomas. Lung Cancer 2006; 54: 109-116.
Rossi D, Capello D, Gloghini A et al. Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia. Haematologica 2004; 89: 154-164.
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: 892-895.
Matsumoto H, Nagao M, Ogawa S et al. Prognostic significance of death-associated protein-kinase expression in hepatocellular carcinomas. Anticancer Res 2003; 23: 1333-1341.
Pani G, Kozlowski M, Cambier JC et al. Identification of the tyrosine phosphatase PTP1C as a B cell antigen receptor-associated protein involved in the regulation of B cell signaling. J Exp Med 1995; 181: 2077-2084.
Cyster JG, Goodnow CC. Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection. Immunity 1995; 2: 13-24.
Koyama M, Oka T, Ouchida M et al. Activated proliferation of B-cell lymphomas/leukemias with the SHP1 gene silencing by aberrant CpG methylation. Lab Invest 2003; 83: 1849-1858.