Genetic Subtyping and Phenotypic Characterization of the Immune Microenvironment and MYC/BCL2 Double Expression Reveal Heterogeneity in Diffuse Large B-cell Lymphoma.
Genetic Subtyping and Phenotypic Characterization of the Immune Microenvironment and MYC/BCL2 Double Expression Reveal Heterogeneity in Diffuse Large B-cell Lymphoma.
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DOI：
10.1158/1078-0432.ccr-21-2949
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发表时间：
2022-03-01
影响因子：
11.5
通讯作者：
Young, Ken H.
中科院分区：
文献类型：
--
作者：
Xu-Monette, Zijun Y.;Wei, Li;Fang, Xiaosheng;Au, Qingyan;Nunns, Harry;Nagy, Mate;Tzankov, Alexandar;Zhu, Feng;Visco, Carlo;Bhagat, Govind;Dybkaer, Karen;Chiu, April;Tam, Wayne;Zu, Youli;Hsi, Eric D.;Hagemeister, Fredrick B.;Sun, Xiaoping;Han, Xin;Go, Heounjeong;Ponzoni, Maurilio;Ferreri, Andres J. M.;Moller, Michael B.;Parsons, Benjamin M.;van Krieken, J. Han;Piris, Miguel A.;Winter, Jane N.;Li, Yong;Xu, Bing;Albitar, Maher;You, Hua;Young, Ken H.
弥漫性大B细胞淋巴瘤（DLBCL）在分子和临床上是异质性的，并且可以使用DNA或RNA水平上的高通量基因组数据根据遗传改变、来源的B细胞或微环境特征进行亚型分型。虽然高通量蛋白质组学分析尚未用于DLBCL亚型分型，但MYC/BCL 2蛋白双表达（DE）是DLBCL中确定的预后生物标志物。本研究的目的是揭示DLBCL遗传、表型和微环境生物标志物的相对预后作用。我们在一个大型DLBCL队列中进行了靶向下一代测序，MYC，BCL 2和FN 1的免疫组织化学，以及微环境标志物的荧光多重免疫组织化学。我们在DLBCL基因亚型和MYC/BCL 2双表达者之间进行了相关性和预后分析。我们发现MYC/BCL 2双高表达（DhE）在EZB基因亚型和LymphGen未分类的DLBCL病例中具有显著的不良预后影响，但在MCD和ST 2基因亚型中没有。相反，KMT 2D突变显著分层DhE DLBCL，但非DhE DLBCL不分层。T细胞浸润在BN 2、MCD和DhE中显示出有利的预后作用，但在ST 2和LymphGen未分类病例中显示出不利的预后作用。FN 1和PD-1高表达在多个DLBCL遗传/表型亚组中具有显著的不良预后影响。DLBCL基因亚型中DhE和免疫生物标志物的预后作用是独立的，尽管在LymphGen未分类病例中DhE和高Ki-67与较低的T细胞浸润显著相关。总之，这些结果证明了表型MYC/BCL 2和微环境生物标志物以及DLBCL分类中的遗传亚型的独立和累加预后作用，这对于改善DLBCL分类和识别预后决定因素和治疗靶点很重要。
Diffuse large B-cell lymphoma (DLBCL) is molecularly and clinically heterogeneous, and can be subtyped according to genetic alterations, B cell-of-origin or microenvironmental signatures using high-throughput genomic data at the DNA or RNA level. Although high-throughput proteomic profiling has not been available for DLBCL subtyping, MYC/BCL2 protein double-expression (DE) is an established prognostic biomarker in DLBCL. The purpose of this study is to reveal the relative prognostic roles of DLBCL genetic, phenotypic, and microenvironmental biomarkers. We performed targeted next-generation sequencing, immunohistochemistry for MYC, BCL2, and FN1, and fluorescent multiplex immunohistochemistry for microenvironmental markers in a large cohort of DLBCL. We performed correlative and prognostic analyses within and across DLBCL genetic subtypes and MYC/BCL2 double-expressors. We found that MYC/BCL2 double-high-expression (DhE) had significant adverse prognostic impact within the EZB genetic subtype and LymphGen-unclassified DLBCL cases but not within MCD and ST2 genetic subtypes. Conversely, KMT2D mutations significantly stratified DhE but not non-DhE DLBCL. T-cell infiltration showed favorable prognostic effects within BN2, MCD, and DhE but unfavorable within ST2 and LymphGen-unclassified cases. FN1 and PD-1-high expression had significant adverse prognostic effects within multiple DLBCL genetic/phenotypic subgroups. The prognostic effects of DhE and immune biomarkers within DLBCL genetic subtypes were independent although DhE and high Ki-67 were significantly associated with lower T-cell infiltration in LymphGen-unclassified cases. Together, these results demonstrated independent and additive prognostic effects of phenotypic MYC/BCL2 and microenvironment biomarkers and genetic subtyping in DLBCL prognostication, important for improving DLBCL classification and identifying prognostic determinants and therapeutic targets.