Biological and clinical relevance of quantitative global methylation of repetitive DNA sequences in chronic lymphocytic leukemia
Biological and clinical relevance of quantitative global methylation of repetitive DNA sequences in chronic lymphocytic leukemia
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DOI：
10.4161/epi.6.2.13528
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发表时间：
2011-02-01
期刊：
影响因子：
3.7
通讯作者：
Baccarelli, Andrea
中科院分区：
文献类型：
--
作者：
Fabris, Sonia;Bollati, Valentina;Baccarelli, Andrea
据报道，在不同的癌症类型中，整体 DNA 低甲基化会影响重复序列。在此，我们研究了慢性淋巴细胞白血病 (CLL) 中重复 DNA 元件的甲基化水平、它们与主要细胞遗传学和分子特征的相关性以及预测无治疗生存 (TFS) 的临床相关性。使用定量亚硫酸氢盐-PCR 焦磷酸测序方法评估 77 名未经治疗的早期 (Binet A) CLL 患者的 Alu、长散布核元件-1 (LINE-1) 和卫星-α (SAT-α) 序列的甲基化。来自 7 名健康捐赠者的外周 B 细胞用作对照。与对照组相比，B-CLL 中的甲基化水平（中位数 % 5mC）较低（Alu、LINE-1 和 SAT-alpha 分别为 21.4 vs. 25.9；66.8 vs. 85.7；84.0 vs. 88.2）（p < 0.001）。在 CLL 患者中，观察到 17p13.1 缺失（对于 Alu、LINE-1 和 SAT-α，分别为 16.8 vs. 22.4；51.2 vs. 68.5；52.6 vs. 85.0）存在显着相关性，但与其他主要遗传病变、IgV(H) 突变状态、CD38 或 ZAP-70 表达无关。后续分析表明，较低的 SAT-α 甲基化水平似乎是一个独立的预后标志物，与较短的 TFS 显着相关。我们的研究扩展了先前关于 CLL 重复序列甲基化的有限证据，表明该疾病具有重要的生物学和临床相关性。
Global DNA hypomethylation affecting repeat sequences has been reported in different cancer types. Herein, we investigated the methylation levels of repetitive DNA elements in chronic lymphocytic leukemia (CLL), their correlation with the major cytogenetic and molecular features and clinical relevance in predicting therapy-free survival (TFS). A quantitative bisulfite-PCR pyrosequencing method was used to evaluate methylation of Alu, long interspersed nuclear elements-1 (LINE-1) and satellite-alpha (SAT-alpha) sequences in 77 untreated early-stage (Binet A) CLL patients. Peripheral B cells from seven healthy donors were used as controls. Methylation levels (median % 5mC) were lower in B-CLLs compared with controls (21.4 vs. 25.9; 66.8 vs. 85.7; 84.0 vs. 88.2 for Alu, LINE-1 and SAT-alpha, respectively) (p < 0.001). Among CLL patients, a significant association was observed with 17p13.1 deletion (16.8 vs. 22.4; 51.2 vs. 68.5; 52.6 vs. 85.0, for Alu, LINE-1 and SAT-alpha) but not with other major genetic lesions, IgV(H) mutation status, CD38 or ZAP-70 expression. Follow-up analyses showed that lower SAT-alpha methylation levels appeared to be an independent prognostic marker significantly associated with shorter TFS. Our study extended previous limited evidences in methylation of repetitive sequences in CLL suggesting an important biological and clinical relevance in the disease.