Pathology and Hematology Departments, Hospital Clínic, University of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Spain.
Cancer Res. 2012 Oct 15;72(20):5307-16. doi: 10.1158/0008-5472.CAN-12-1615. Epub 2012 Aug 20.
Mantle cell lymphoma (MCL) is a heterogeneous disease with most patients following an aggressive clinical course, whereas others having an indolent behavior. We conducted an integrative and multidisciplinary analysis of 177 MCL to determine whether the immunogenetic features of the clonotypic B-cell receptors (BcR) may identify different subsets of tumors. Truly unmutated (100% identity) IGHV genes were found in 24% cases, 40% were minimally/borderline mutated (99.9%-97%), 19% significantly mutated (96.9%-95%), and 17% hypermutated (<95%). Tumors with high or low mutational load used different IGHV genes, and their gene expression profiles were also different for several gene pathways. A gene set enrichment analysis showed that MCL with high and low IGHV mutations were enriched in memory and naive B-cell signatures, respectively. Furthermore, the highly mutated tumors had less genomic complexity, were preferentially SOX11-negative, and showed more frequent nonnodal disease. The best cut-off of germline identity of IGHV genes to predict survival was 97%. Patients with high and low mutational load had significant different outcome with 5-year overall survival (OS) of 59% and 40%, respectively (P = 0.004). Nodal presentation and SOX11 expression also predicted for poor OS. In a multivariate analysis, IGHV gene status and SOX11 expression were independent risk factors. In conclusion, these observations suggest the idea that MCL with mutated IGHV, SOX11-negativity, and nonnodal presentation correspond to a subtype of the disease with more indolent behavior.
套细胞淋巴瘤(MCL)是一种异质性疾病,大多数患者表现出侵袭性临床病程,而其他患者则表现出惰性行为。我们对 177 例 MCL 进行了综合和多学科分析,以确定克隆型 B 细胞受体(BcR)的免疫遗传学特征是否可以识别不同的肿瘤亚群。在 24%的病例中发现了真正未突变(100%同源性)的 IGHV 基因,40%为最小/边界突变(99.9%-97%),19%为显著突变(96.9%-95%),17%为高度突变(<95%)。高突变和低突变负荷的肿瘤使用不同的 IGHV 基因,它们的基因表达谱在几个基因途径上也不同。基因集富集分析表明,IGHV 突变高和低的 MCL 分别富集在记忆 B 细胞和幼稚 B 细胞特征中。此外,高度突变的肿瘤具有较低的基因组复杂性,优先为 SOX11 阴性,并表现出更频繁的非结外疾病。IGHV 基因的种系同一性最佳截断值为 97%,用于预测生存。高突变和低突变负荷的患者具有显著不同的预后,5 年总生存率(OS)分别为 59%和 40%(P = 0.004)。结内表现和 SOX11 表达也预测了较差的 OS。在多变量分析中,IGHV 基因状态和 SOX11 表达是独立的危险因素。总之,这些观察结果表明,IGHV 突变、SOX11 阴性和非结外表现的 MCL 对应于疾病的一个亚型,具有更惰性的行为。