文章：

CREBBP和STAT6共突变以及16p13和1p36缺失定义了t(14;18)阴性滤泡性淋巴瘤的弥漫型变异亚型

CREBBP and STAT6 co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

原文发布日期：2020-06-17

DOI: 10.1038/s41408-020-0335-0

类型: Article

开放获取: 是

英文摘要：

The diffuse variant of follicular lymphoma (dFL) is a rare variant of FL lacking t(14;18) that was first described in 2009. In this study, we use a comprehensive approach to define unifying pathologic and genetic features through gold-standard pathologic review, FISH, SNP-microarray, and next-generation sequencing of 16 cases of dFL. We found unique morphologic features, including interstitial sclerosis, microfollicle formation, and rounded nuclear cytology, confirmed absence of t(14;18) and recurrent deletion of 1p36, and showed a novel association with deletion/CN-LOH of 16p13 (inclusive of CREBBP, CIITA, and SOCS1). Mutational profiling demonstrated near-uniform mutations in CREBBP and STAT6, with clonal dominance of CREBBP, among other mutations typical of germinal-center B-cell lymphomas. Frequent CREBBP and CIITA codeletion/mutation suggested a mechanism for immune evasion, while subclonal STAT6 activating mutations with concurrent SOCS1 loss suggested a mechanism of BCL-xL/BCL2L1 upregulation in the absence of BCL2 rearrangements. A review of the literature showed significant enrichment for 16p13 and 1p36 loss/CN-LOH, STAT6 mutation, and CREBBP and STAT6 comutation in dFL, as compared with conventional FL. With this comprehensive approach, our study demonstrates confirmatory and novel genetic associations that can aid in the diagnosis and subclassification of this rare type of lymphoma.
 

摘要翻译： 

滤泡性淋巴瘤弥漫性变异型（dFL）是一种罕见的缺乏t(14;18)的FL亚型，于2009年首次被描述。本研究采用综合方法，通过金标准病理会诊、FISH、SNP微阵列及16例dFL的新一代测序，明确了其统一的病理学和遗传学特征。我们发现其独特的形态学特征（包括间质硬化、微滤泡形成和圆形核细胞学），确认了t(14;18)缺失和1p36反复缺失，并首次揭示了16p13缺失/拷贝数中性杂合性缺失（涉及CREBBP、CIITA和SOCS1）的新型关联。突变谱分析显示几乎所有病例均存在CREBBP和STAT6突变，其中CREBBP呈克隆优势，并伴有其他生发中心B细胞淋巴瘤典型突变。频繁出现的CREBBP与CIITA共缺失/突变提示免疫逃逸机制，而STAT6激活突变伴随SOCS1缺失则提示在缺乏BCL2重排情况下BCL-xL/BCL2L1上调机制。文献综述显示与传统FL相比，dFL中16p13和1p36缺失/CN-LOH、STAT6突变以及CREBBP与STAT6共突变显著富集。通过这种综合研究方法，我们证实了新的遗传学关联，有助于这种罕见淋巴瘤的诊断与亚分类。

原文链接：

CREBBP and STAT6 co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma