演題詳細

一般口演 / Oral Session

【E】一般口演 13 (Oral Session 13) :Malignant Lymphoma:Genomic Alteration

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日程
2013年10月11日(金)
時間
09:30 - 10:30
会場
第9会場 / Room No.9 (ロイトン札幌 1F キャッスル)
座長・司会
渡邊 俊樹 (Toshiki Watanabe):1
1:Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Japan
 
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Prognostic impact of EZH2 expression, H3K27 trimethylation and DNA methylation in diffuse large B cell lymphoma

演題番号 : OS-1-64

Shih-Chiang Lin (林 世強):1、Chien-Chen Tsai:2、Shih-Sung Chuang:3、Chou Wen-Chien:4

1:Department of Internal Medicine, Devision of Oncology and Hematology , Far Eastern Memorial Hospital, New Taipei City、2:Department of Anatomical Pathology, Far Eastern Memorial Hospital, New Taipei City、3:Department of Pathology, Chi Mei Medical Center, Tainan、4:Department of Internal Medicine, Devision of Hematology, National Taiwan University Hospital, Taipei City

 

Background: International Prognostic Index (IPI) score is used to predict the prognosis in diffuse large B cell lymphoma (DLBCL) for around 20 years. However, few molecular prognostic factors were proposed. Overexpression of Enhancer of zeste homolog 2 (EZH2) and decreased histone 3-lysine 27 tri-methylation (H3K27me3) are associated with poor prognosis in many cancers. Promoter CpG island hypermethylation of tumor-suppressor genes is a common hallmark of all human cancers. 5-methylcytosine (5-mC) levels in cancer cells can reflect the DNA hypermethylation status and measurement of 5-hydroxymethylcytosine (5-hmC) levels may estimate the DNA demethylation status in cancer cells. A unique EZH2 Tyr 641 somatic mutation was detected in DLBCL and follicular lymphoma. However, the clinical implications of DNA methylation status, DNA hydroxymethylation, EZH2 expression, the extent of H3K27me3 and EZH2 Tyr 641 somatic mutation in DLBCL patients have not been studied in a comprehensive or integrated way.Aims: We aim to see significant impact of DNA methylation, DNA hydroxymethylation, EZH2 expression levels and mutation status, and H3K27 trimethylation on the clinical and biological presentation of DLBCL.Methods: We enrolled the 110 DLBCL patients with complete remission (CR) after standard chemotherapy. These patients included 45 consecutive patients in Far Eastern Memorial Hospital and 65 consecutive patients in Chi Mei Medical Center (diagnosed between 2002 and 2009). The demographic data, treatment regimens, and response of disease were reviewed retrospectively. Immunohistochemistry (IHC) was used to examine 5-mC, 5-hmC, EZH2 expression and the extent of H3K27me3 in formalin-fixed, paraffin-embedded biopsy specimens of DLBCL. DNA extraction from the tissues was examined for EZH2 Tyr641 mutation. Statistical analysis was performed with the Stata statistical software (Small Stata, version 11.0, Stata Corp, College Station, TX). Results: Statistical analysis was performed in 110 CR patients with Rituximab-CHOP (R-CHOP) and CHOP regimen. Totally we recruited 70 male (64%) and 40 female (36%) with a median age 57 years. Sixty-three percent of the patients had stage I/II disease. According to the IPI, 76% of the patients were classified as low/low-intermediate risk (IPI=0-2). Thirty patients received CHOP-like regimen and eighty patients received R-CHOP-like regimen as first-line chemotherapy. The median observation time for overall survival (OS) in the 110 patients was 49 mo. The clinical parameter of IPI score was correlated with OS. None of 48 patients harbored EZH2 mutation at Tyr641. Low expression 5-mC tended to have lower H3K27me3 expression (P=0.019). And low expression 5-mC tended to have lower 5-hmC expression (P=0.002). There was no obvious relationship between the expression of EZH2 and degree of H3K27me3 in DLBCL tumor cells. There was no significant prognostic impact in single epigenetic marker. Then we subdivide the patients by combination H3K27me3 with 5-hmC. In this new-classification analysis, the high H3K27me3/ low 5-hmC patients were associated with longer OS in univariate (P=0.013) and multivariate analysis (P=0.017). Summary / Conclusion: High H3K27me3/ low 5-hmC expression was a possible favorable prognostic factor in DLBCL patients with CR after standard chemotherapy. The incidence of EZH2 mutation at Tyr641 in our cohort is much lower compared with western countries. Low expression 5-mC tended to have lower H3K27me3 expression and low expression 5-mC tended to have lower 5-hmC in DLBCL tumor cells. Our study suggests epigenetic markers may be an informative biomarker for prognosis prediction in DLBCL.

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