眼附属器黏膜相关淋巴组织淋巴瘤的遗传学特征揭示了 NFAT 和 MEF2B 信号通路的频繁异常。
The Genetic Landscape of Ocular Adnexa MALT Lymphoma Reveals Frequent Aberrations in NFAT and MEF2B Signaling Pathways.
机构信息
Division of Hematology, Department of Medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL.
Center for Genomic and Computational Biology and Department of Medicine, University, Duke Durham, NC.
出版信息
Cancer Res Commun. 2021 Oct;1(1):1-16. doi: 10.1158/2767-9764.crc-21-0022. Epub 2021 Oct 13.
A comprehensive constellation of somatic non-silent mutations and copy number (CN) variations in ocular adnexa marginal zone lymphoma (OAMZL) is unknown. By utilizing whole-exome sequencing in 69 tumors we define the genetic landscape of OAMZL. Mutations and CN changes in CABIN1 (30%), RHOA (26%), TBL1XR1 (22%), and CREBBP (17%) and inactivation of TNFAIP3 (26%) were among the most common aberrations. Candidate cancer driver genes cluster in the B-cell receptor (BCR), NFkB, NOTCH and NFAT signaling pathways. One of the most commonly altered genes is CABIN1, a calcineurin inhibitor acting as a negative regulator of the NFAT and MEF2B transcriptional activity. CABIN1 deletions enhance BCR-stimulated NFAT and MEF2B transcriptional activity, while CABIN1 mutations enhance only MEF2B transcriptional activity by impairing binding of mSin3a to CABIN1. Our data provide an unbiased identification of genetically altered genes that may play a role in the molecular pathogenesis of OAMZL and serve as therapeutic targets.
眼部附属器边缘区淋巴瘤（OAMZL）的体细胞非沉默突变和拷贝数（CN）变异的综合特征尚不清楚。通过对 69 个肿瘤进行全外显子组测序，我们定义了 OAMZL 的遗传景观。CABIN1（30%）、RHOA（26%）、TBL1XR1（22%）和 CREBBP（17%）的突变和 CN 变化以及 TNFAIP3 的失活（26%）是最常见的异常之一。候选癌症驱动基因聚集在 B 细胞受体（BCR）、NFkB、NOTCH 和 NFAT 信号通路中。最常改变的基因之一是 CABIN1，它是一种钙调神经磷酸酶抑制剂，作为 NFAT 和 MEF2B 转录活性的负调节剂。CABIN1 缺失增强了 BCR 刺激的 NFAT 和 MEF2B 转录活性，而 CABIN1 突变仅通过削弱 mSin3a 与 CABIN1 的结合来增强 MEF2B 转录活性。我们的数据提供了一个公正的鉴定，确定了可能在 OAMZL 的分子发病机制中发挥作用的遗传改变基因，并作为治疗靶点。
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