背景:大B细胞淋巴瘤(LBCL)是最常见的淋巴瘤,已知是一种遗传上的生物异质性疾病,表型,和临床特征。虽然预后良好,三分之一的人患有原发性难治性或复发性疾病,这强调了开发能够识别高风险和低风险患者的预测性生物学标志物的重要性。DNA甲基化(DNAm)和端粒维持改变是癌症和衰老的标志。这两种改变都可能导致疾病的异质性,并可能影响LBCL的预后。
结果:我们使用qPCR研究了93例LBCL的DNAm谱(InfiniumMethylationEPICBeadChip)和相对端粒长度(RTL):未指明的弥漫性大B细胞淋巴瘤(DLBCL,n=66),高级别B细胞淋巴瘤(n=7),原发性中枢神经系统淋巴瘤(n=8),和惰性B细胞淋巴瘤的转化(n=12)。与正常细胞和其他B细胞肿瘤相比,DLBCL和其他LBCL实体存在大量甲基化异质性。LBCL病例具有特别异常的半甲基化模式(0.15≤β≤0.8),具有较大的肿瘤间变异和总体较低的超甲基化(β>0.8)。DNAm模式不能用于区分生发中心B细胞样(GC)和非GCDLBCL病例。在用R-CHOP样方案治疗的病例中,在多变量分析中,高比例的整体低甲基化(β<0.15)与DLBCL患者较差的疾病特异性生存期(DSS)(HR6.920,95%CI1.499-31.943)和无进展生存期(PFS)(HR4.923,95%CI1.286-18.849)以及LBCL患者较差的DSS(HR5.147,95%CI1.239-21.388)相关.这些具有高比例全局低甲基化的病例也具有较高程度的CpG岛甲基化,包括启动子相关区域中的岛,而不是低甲基化的病例。此外,端粒长度在LBCL中是异质的,DLBCL-GC病例的子集占最长的RTL。在接受R-CHOP样方案治疗的LBCL中,短RTL与较差的DSS(HR6.011,95%CI1.319-27.397)和PFS(HR4.689,95%CI1.102-19.963)独立相关。
结论:我们假设具有高整体低甲基化和高甲基化CpG岛的亚克隆可能在肿瘤进展中具有优势,例如通过失活抑癌基因或促进治疗抗性。我们的发现表明,全球低甲基化程度高,因此预后不良的病例可能是包括低甲基化药物在内的替代治疗方案的候选人。
BACKGROUND: Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL.
RESULTS: We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499-31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286-18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239-21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319-27.397) and PFS (HR 4.689, 95% CI 1.102-19.963) in LBCL treated with R-CHOP-like regimens.
CONCLUSIONS: We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.