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Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas
Author(s) -
Ferreri Andrés J. M.,
Dell'Oro Stefania,
Capello Daniela,
Ponzoni Maurilio,
Iuzzolino Paolo,
Rossi Davide,
Pasini Felice,
Ambrosetti Achille,
Orvieto Enrico,
Ferrarese Fabio,
Arrigoni Gianluigi,
Foppoli Marco,
Reni Michele,
Gaidano Gianluca
Publication year - 2004
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2004.05109.x
Subject(s) - primary central nervous system lymphoma , methylation , diffuse large b cell lymphoma , lymphoma , cytarabine , cpg site , chemotherapy , cancer research , dna methylation , medicine , methotrexate , biology , gene , genetics , gene expression
Summary We investigated the prevalence and prognostic role of CpG island methylation of the reduced folate carrier ( RFC ) gene promoter region in primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Genomic DNA from 40 PCNSL was used for methylation‐specific polymerase chain reaction and bisulphite genomic sequencing of the RFC promoter region. Human immunodeficiency virus‐negative systemic diffuse large B‐cell lymphomas (DLBCL) were used as controls ( n = 50). The impact on outcome of RFC promoter methylation was assessed in 37 PCNSL patients treated with high‐dose methotrexate (HD‐MTX)‐based chemotherapy ± radiotherapy. RFC promoter methylation occurred in 12 of 40 (30%) PCNSL and in four of 50 (8%) DLBCL ( P = 0·01). Of 37 PCNSL treated with HD‐MTX‐based chemotherapy, methylation occurred in nine cases (24%, M‐PCNSL), while 28 cases (76%, U‐PCNSL) were negative. Three M‐PCNSL (33%) and 15 U‐PCNSL (54%) achieved complete remission (CR) after primary chemotherapy. Logistic regression confirmed the independent association between CR rate and International Extranodal Lymphoma Study Group score ( P = 0·03), RFC promoter methylation ( P = 0·07) and use of cytarabine ( P = 0·08). The 3‐year failure‐free survival (FFS) and overall survival for M‐PCNSL and U‐PCNSL was 0% vs. 31 ± 9% ( P = 0·34) and 0% vs. 31 ± 9% ( P = 0·35) respectively. This is the first study to assess the methylation status of the RFC promoter in human tumour samples. RFC methylation is more common in PCNSL compared with systemic DLBCL, and is associated with a lower CR rate to HD‐MTX‐based chemotherapy. If confirmed in prospective trials on PCNSL treated with HD‐MTX alone, these data may suggest the necessity for alternative strategies in M‐PCNSL considering the increased risk of MTX resistance by tumour cells.