Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma

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 <i>TP53</i> and <i>IRF4</i> mutations, and many copy number alterations (CNAs), including <i>PD-L1</i> amplifications and <i>CDKN2A</i> deletions, compared with indolent (chronic/smoldering) subtypes. By contrast, <i>STAT3</i> 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, <i>PRKCB</i> mutations, and <i>PD-L1</i> amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, <i>IRF4</i> mutations, <i>PD-L1</i> amplifications, and <i>CDKN2A</i> 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 <i>PD-L1</i> 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.