Adult T-cell leukemia/lymphoma (ATL) is a heterogeneous group of peripheral T-cell malignancies characterized by human T-cell leukemia virus type-1 infection, whose genetic profile has recently been fully investigated. However, it is still poorly understood how these alterations affect clinical features and prognosis. We investigated the effects of genetic alterations commonly found in ATL on disease phenotypes and clinical outcomes, based on genotyping data obtained from 414 and 463 ATL patients using targeted-capture sequencing and single nucleotide polymorphism array karyotyping, respectively. Aggressive (acute/lymphoma) subtypes were associated with an increased burden of genetic and epigenetic alterations, higher frequencies of TP53 and IRF4 mutations, and many copy number alterations (CNAs), including PD-L1 amplifications and CDKN2A deletions, compared with indolent (chronic/smoldering) subtypes. By contrast, STAT3 mutations were more characteristic of indolent ATL. Higher numbers of somatic mutations and CNAs significantly correlated with worse survival. In a multivariate analysis incorporating both clinical factors and genetic alterations, the Japan Clinical Oncology Group prognostic index high-risk, older age, PRKCB mutations, and PD-L1 amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions were significantly associated with shorter survival, although the chronic subtype with unfavorable clinical factors was only marginally significant. Thus, somatic alterations characterizing aggressive diseases predict worse prognosis in indolent ATL, among which PD-L1 amplifications are a strong genetic predictor in both aggressive and indolent ATL. ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic profiling might contribute to improved prognostication and management of ATL patients.

中文翻译：

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成人 T 细胞白血病/淋巴瘤中综合遗传分析的预后相关性

成人 T 细胞白血病/淋巴瘤 (ATL) 是一组异质性外周 T 细胞恶性肿瘤，其特征是人类 T 细胞白血病病毒 1 型感染，其遗传特征最近已得到充分研究。然而，人们对这些改变如何影响临床特征和预后仍知之甚少。我们基于分别使用靶向捕获测序和单核苷酸多态性阵列核型分析从 414 和 463 名 ATL 患者获得的基因分型数据，研究了 ATL 中常见的遗传改变对疾病表型和临床结果的影响。侵袭性（急性/淋巴瘤）亚型与遗传和表观遗传改变负担增加、TP53 和 IRF4 突变频率更高以及许多拷贝数改变 (CNA) 相关，包括 PD-L1 扩增和 CDKN2A 缺失，与惰性（慢性/闷烧）亚型相比。相比之下，STAT3 突变更具有惰性 ATL 的特征。较高数量的体细胞突变和 CNA 与较差的生存率显着相关。在纳入临床因素和遗传改变的多变量分析中，日本临床肿瘤学组预后指数高风险、年龄较大、PRKCB 突变和 PD-L1 扩增是侵袭性 ATL 的独立不良预后因素。在惰性 ATL 中，IRF4 突变、PD-L1 扩增和 CDKN2A 缺失与较短的生存期显着相关，尽管具有不利临床因素的慢性亚型仅具有轻微意义。因此，表征侵袭性疾病的体细胞改变预示着惰性 ATL 的预后较差，其中 PD-L1 扩增是侵袭性和惰性 ATL 的强遗传预测因子。ATL 亚型进一步分为分子不同的亚型，具有不同的预后。基因分析可能有助于改善 ATL 患者的预后和管理。