The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome.
The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome.
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DOI：
10.1038/ng.3442
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发表时间：
2015-12
期刊：
影响因子：
30.8
通讯作者：
Palomero T
中科院分区：
文献类型：
--
作者：
da Silva Almeida AC;Abate F;Khiabanian H;Martinez-Escala E;Guitart J;Tensen CP;Vermeer MH;Rabadan R;Ferrando A;Palomero T
Sézary综合征是一种白血病和侵袭性形式的皮肤T细胞淋巴瘤（CTCL），由皮肤归巢中央记忆CD 4阳性T细胞的恶性转化引起。在这里，我们对25名Sézary综合征和17名其他CTCL患者的肿瘤-正常样本对进行了全外显子组测序。这些分析揭示了Sézary综合征中体细胞拷贝数改变的独特模式，包括涉及TP 53、RB 1、PTEN、DNMT 3A和CDKN 1B肿瘤抑制因子的高度普遍的染色体缺失。突变分析确定了参与表观遗传调控（TET 2、CREBBP、MLL 2、MLL 3、BRD 9、SMARCA 4和CHD 3）和信号传导的关键基因中的广谱体细胞突变，包括MAPK 1、BRAF、CARD 11和PRKG 1突变，这些突变在T细胞受体刺激后驱动MAPK、NFκB和NFAT活性增加。总的来说，我们的研究结果为Sézary综合征和CTCL的遗传学提供了新的见解，并支持针对治疗这些疾病的关键致癌激活信号通路的个性化疗法的开发。
Sézary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4 positive T cells. Here we performed whole-exome sequencing of tumor-normal sample pairs from 25 Sézary syndrome and 17 other CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sézary syndrome including highly prevalent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A and CDKN1B tumor suppressors. Mutation analysis identified a broad spectrum of somatic mutations in key genes involved in epigenetic regulation (TET2, CREBBP, MLL2, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including MAPK1, BRAF, CARD11 and PRKG1 mutations driving increased MAPK, NFκB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sézary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.