Promoter hypermethylation of the bone morphogenetic protein-6 gene in malignant lymphoma
Promoter hypermethylation of the bone morphogenetic protein-6 gene in malignant lymphoma
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DOI：
10.1158/1078-0432.ccr-06-2766
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发表时间：
2007-06-15
影响因子：
11.5
通讯作者：
Taguchi, Hirokuni
中科院分区：
文献类型：
--
作者：
Daibata, Masanori;Nemoto, Yuiko;Taguchi, Hirokuni
目的：骨形态发生蛋白（BMP）属于转化生长因子β超家族，是细胞生长、分化和凋亡的重要调节因子。然而，BMPs对恶性淋巴瘤的生物学效应仍不清楚。BMP-6基因启动子甲基化在淋巴瘤investigated. ExperimentalDesign：我们研究了BMP-6启动子甲基化及其基因表达在各种组织学类型的90个原发性淋巴瘤和30个淋巴瘤细胞系。BMP-6启动子甲基化对临床结局的影响也evaluated.Results：BMP-6在淋巴瘤亚群中表观遗传学失活。这种沉默在弥漫性大B细胞淋巴瘤（DLBCL）和伯基特淋巴瘤中发生频率很高，与BMP-6启动子异常甲基化有关。在60%（21/35）的DLBCL病例和100%（7/7）的DLBCL细胞系中，以及在83%（5/6）的伯基特淋巴瘤病例和86%（12/14）的伯基特淋巴瘤细胞系中观察到甲基化。相比之下，其他组织学类型的原发性淋巴瘤研究有很少或没有检测到甲基化（1/49; 2%）。在DLBCL中BMP-6启动子高甲基化的存在与无病生存期（P = 0.014）和总生存期（P = 0.038）的降低具有统计学相关性。多因素分析显示，BMP-6基因甲基化是预测无病生存期（P = 0.022）和总生存期（P = 0.046）的独立预后因素。结论：侵袭性淋巴瘤中BMP-6基因启动子区高甲基化发生率较高，甲基化程度可能与淋巴瘤的组织学类型有关。BMP-6基因启动子甲基化可能成为预测DLBCL风险的一个新的生物标志物。
Purpose: Bone morphogenetic proteins (BMP), belonging to the transforming growth factor-beta superfamily, are important regulators of cell growth, differentiation, and apoptosis. The biological effects of BMPs on malignant lymphoma, however, remain unknown. Promoter methylation of the BMP-6 gene in lymphomas was investigated.Experimental Design: We investigated BMP-6 promoter methylation and its gene expression in various histologic types of 90 primary lymphomas and 30 lymphoma cell lines. The effect of BMP-6 promoter hypermethylation on clinical outcome was also evaluated.Results: BMP-6 was epigenetically inactivated in subsets of lymphomas. The silencing occurred with high frequency in diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma in association with aberrant BMP-6 promoter methylation. The methylation was observed in 60% (21 of 35) of DLBCL cases and 100% (7 of 7) of DLBCL cell lines, and in 83% (5 of 6) of Burkitt's lymphoma cases and 86% (12 of 14) of Burkitt's lymphoma cell lines. In contrast, other histologic types of primary lymphomas studied had little or no detectable methylation (1 of 49; 2%). The presence of BMP-6 promoter hypermethylation in DLBCL statistically correlated with a decrease in disease-free survival (P = 0.014) and overall survival (P = 0.038). Multivariate analysis showed that the methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.022) and overall survival (P = 0.046).Conclusion: BMP-6 promoter was hypermethylated more often in aggressive types of lymphomas, and the hypermethylation is likely to be related to the histologic type of lymphomas. BMP-6 promoter methylation may be a potential new biomarker of risk prediction in DLBCL.