Peripheral T-cell lymphomas (PTCLs) represent a clinically, histologically, and molecularly heterogeneous group of non-Hodgkin lymphomas derived from mature post-thymic T cells. Among them, the most common in Western countries is PTCL, not otherwise specified (NOS), accounting for approximately 30% of all PTCLs. Combining whole-exome and deep targeted-capture sequencing of 133 cases, we delineated the entire picture of genetic alterations in PTCL, NOS. Of note is the identification of a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in PTCL, NOS without showing a T follicular helper cell phenotype. This subtype exhibited different prognosis and unique genetic features, including extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation. Among PTCLs, the most common entity in Japan is adult T-cell leukemia/lymphoma (ATL), which is an aggressive peripheral T-cell lymphoma associated with human T-cell leukemia virus type-1 (HTLV-1) infection. We previously carried out an integrated molecular study, in which whole-exome, transcriptome, and targeted resequencing, as well as array-based copy number analysis, were performed. We found recurrent genetic alterations in T-cell receptor/NF-κB signaling, T-cell trafficking, and other T cell-related pathways as well as immunosurveillance. Although our previous study discovered many driver mutations and copy number alterations, the whole-genome landscape of ATL still remains elusive. To this end, we have recently performed whole-genome sequencing (WGS) of 155 ATL samples, with a median depth of 95-fold for tumor samples. WGS presented a substantially different overview of driver alterations compared with WES: most driver genes were affected by more than one classes of somatic alterations, including structural variations (SV) and noncoding mutations. We integrated these genetic drivers using non-negative factorization clustering and identified several molecular subsets with distinct clinical features, including a leukemic subtype characterized by PLCG1 and STAT3 mutations. In addition, we newly identified several putative driver SVs and noncoding mutations (such as NOTCH1 truncations and mutations involving NFKBIZ 3′-untraslated region). Several types of SVs were linked to distinct alterations, suggesting their etiology, including associations of TP53 disruption with inversions and translocations, and inactivation of immune-related molecules with deletions. Our WGS analysis not only identifies novel somatic alterations, but also extends the overview of ATL genome, which can lead to future improvement of patient management. Taken together, our findings provide novel insights into genetic and molecular heterogeneity in PTCLs, which should help to devise a novel molecular classification and to exploit a new therapeutic strategy for these malignancies.

Citation Format: Keisuke Kataoka. Molecular classification of T-cell lymphomas [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA07.