Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response
Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response
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DOI：
10.1182/blood-2004-07-2947
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发表时间：
2005-03-01
期刊：
影响因子：
20.3
通讯作者：
Shipp, MA
中科院分区：
文献类型：
--
作者：
Monti, S;Savage, KJ;Shipp, MA
弥漫性大B细胞淋巴瘤（DLBCL）是一种异质性疾病，在临床结局、遗传特征和起源细胞方面具有公认的变异性。迄今为止，转录谱已被用于突出DLBCL肿瘤细胞和正常B细胞亚型之间的相似性，并将基因和途径与不利的结果相关联。为了鉴定具有全面转录特征的稳健且高度可重复的DLBCL亚型，我们使用了大量新诊断的DLBCL、全基因组阵列和多种聚类方法。还分析了肿瘤中DLBCL中已知的常见遗传异常。存在DLBCL的3个离散子集-“氧化磷酸化”、“B细胞受体/增殖”和“宿主应答”（HR-鉴定），其使用基因集富集分析表征并在独立系列中确认。HR肿瘤的T/自然杀伤细胞受体和活化途径组分、补体级联成员、巨噬细胞树突状细胞标志物和炎症介质的表达增加。HR DLB-CL还含有显著更高数量的形态学上不同的CD 2（+）/CD 3（+）肿瘤浸润淋巴细胞和交错的S100（+）/γ干扰素诱导的溶酶体转移酶阳性（GILT（+））CD 1a（-）/CD 123（-）树突状细胞。HR群集具有组织学定义的富含T细胞/组织细胞的B细胞淋巴瘤的共同特征，包括较少的遗传异常，出现时年龄较小，以及频繁的脾脏和骨髓受累。这些研究将肿瘤微环境和宿主炎症反应确定为DLBCL的定义特征，并提出了特定DLBCL亚群的合理治疗靶点。
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with recognized variability in clinical outcome, genetic features, and cells of origin. To date, transcriptional profiling has been used to highlight similarities between DLBCL tumor cells and normal B-cell subtypes and associate genes and pathways with unfavorable outcome. To identify robust and highly reproducible DLBCL subtypes with comprehensive transcriptional signatures, we used a large series of newly diagnosed DLBCLs, whole genome arrays, and multiple clustering methods. Tumors were also analyzed for known common genetic abnormalities in DLBCL. There were 3 discrete subsets of DLBCL-"oxidative phosphorylation," "B-cell receptor/proliferation," and "host response" (HR-Identified characterized using gene set enrichment analysis and confirmed in an independent series. HR tumors had increased expression of T/natural killer cell receptor and activation pathway components, complement cascade members, macrophageldendritic cell markers, and inflammatory mediators. HR DLB-CLs also contained significantly higher numbers of morphologically distinct CD2(+)/CD3(+) tumor-infiltrating lymphocytes and interdigitating S100(+)/gamma interferon-induced lysosomal transferase-positive (GILT(+)) CD1a(-)/CD123(-) dendritic cells. The HR cluster shared features of histologically defined T-cell/histiocyte-rich B-cell lymphoma, including fewer genetic abnormalities, younger age at presentation, and frequent splenic and bone marrow involvement. These studies identity tumor microenvironment and host inflammatory response as defining features in DLBCL and suggest rational treatment targets in specific DLBCL subsets.