Simpson Haley M, Khan Rashid Z, Song Chang, Sharma Deva, Sadashivaiah Kavitha, Furusawa Aki, Liu Xinyue, Nagaraj Sushma, Sengamalay Naomi, Sadzewicz Lisa, Tallon Luke J, Chen Qing C, Livak Ferenc, Rapoport Aaron P, Kimball Amy, Banerjee Arnob
Program in Oncology, Greenebaum Cancer Center, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
Center for Stem Cell Research and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
PLoS One. 2015 Nov 4;10(11):e0141906. doi: 10.1371/journal.pone.0141906. eCollection 2015.
Peripheral T cell lymphoma (PTCL) is a heterogeneous malignancy with poor response to current therapeutic strategies and incompletely characterized genetics. We conducted whole exome sequencing of matched PTCL and non-malignant samples from 12 patients, spanning 8 subtypes, to identify potential oncogenic mutations in PTCL. Analysis of the mutations identified using computational algorithms, CHASM, PolyPhen2, PROVEAN, and MutationAssessor to predict the impact of these mutations on protein function and PTCL tumorigenesis, revealed 104 somatic mutations that were selected as high impact by all four algorithms. Our analysis identified recurrent somatic missense or nonsense mutations in 70 genes, 9 of which contained mutations predicted significant by all 4 algorithms: ATM, RUNX1T1, WDR17, NTRK3, TP53, TRMT12, CACNA2D1, INTS8, and KCNH8. We observed somatic mutations in ATM (ataxia telangiectasia-mutated) in 5 out of the 12 samples and mutations in the common gamma chain (γc) signaling pathway (JAK3, IL2RG, STAT5B) in 3 samples, all of which also harbored mutations in ATM. Our findings contribute insights into the genetics of PTCL and suggest a relationship between γc signaling and ATM in T cell malignancy.
外周T细胞淋巴瘤（PTCL）是一种异质性恶性肿瘤，对当前治疗策略反应不佳，其遗传学特征也不完全清楚。我们对12例患者的配对PTCL样本和非恶性样本进行了全外显子组测序，涵盖8个亚型，以确定PTCL中潜在的致癌突变。使用计算算法CHASM、PolyPhen2、PROVEAN和MutationAssessor对所鉴定的突变进行分析，以预测这些突变对蛋白质功能和PTCL肿瘤发生的影响，结果显示有104个体细胞突变被所有四种算法选为高影响突变。我们的分析在70个基因中鉴定出复发性体细胞错义或无义突变，其中9个基因的突变被所有4种算法预测为具有显著性：ATM、RUNX1T1、WDR17、NTRK3、TP53、TRMT12、CACNA2D1、INTS8和KCNH8。我们在12个样本中的5个样本中观察到ATM（共济失调毛细血管扩张症突变）的体细胞突变，在3个样本中观察到共同γ链（γc）信号通路（JAK3、IL2RG、STAT5B）的突变，所有这些样本也都含有ATM的突变。我们的研究结果有助于深入了解PTCL的遗传学，并提示γc信号与T细胞恶性肿瘤中ATM之间的关系。
