Notable Patterns in the Genomic Landscape of Adult T-Cell Leukemia/Lymphoma Encountered in HTLV-1 Endemic Western World Regions

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.810-810
• Main Authors: Gru, Alejandro Ariel, Snowden, Caroline, Williams, Eli, Barrionuevo, Carlos, Sanches, Jose, Battistella, Maxime, Mo, Samuel, Pulitzer, Melissa, Bhagat, Govind, Servitje, Octavio, Miyashiro, Denis, Climent, Fina, Dueñas, Daniela, Casavilca, Sandro, Guyton-Ringbloom, KImberly, Beltran, Brady E, Castro, Denisse, Toomey, Ngoc L, Barreto, Luciana, Saul, Eduardo, Plate, Thomas, Chapman, Jennifer R, Choi, Jaehyuk, Ramos, Juan Carlos
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-154275

Background: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with dismal prognosis and associated with clonal T-cell expansion driven by Human T-Lymphotropic Virus 1 (HTLV-1) infection. Comprehensive genomic studies in Japan have identified recurrent alterations affecting TCR-NF-kB signaling (i.e. PRKCB, PLCG1, CARD11, VAV1, and IRF4), T-cell trafficking pathways (i.e. CCR4 and CCR7), and the tumor suppressor genes CDKN2A and TP53. HTLV-1 endemic regions include Africa, the Caribbean, and South America in addition to Japan. Retrospective studies from the Western population have reported distinctive features from the Japanese cohort, e.g. younger age, more common lymphomatous presentation, and worse outcomes. Our group sought to evaluate the unique molecular features of ATLL in a large cohort of patients from the Caribbean and South America. Methods: We performed a multimodal genomic study on specimens from 169 patients encountered in the United States (Miami), Peru, Brazil, France, and Spain. Data types included Oncoscan/Copy Number Variation (CNV) data for 129 patients, RNA-seq data for 97 patients, and whole exome sequencing (WES) data for 125 patients. Patients were ethnically classified based upon single nucleotide polymorphisms, under 3 main groups: African (n=80), native American (n= 32), or South Asian/Islander (n=12). 46 specimens without WES data could not be ethnically classified. Somatic variants were called using Mutect. Putative driver mutations were identified by frequency-based criteria. CNV significance was determined using GISTIC2.0. Data were compared to whole exome and targeted sequencing data published by Kataoka et al. Results: Our cohort replicated trends reported in Japanese datasets but included several distinctive findings. South American and Caribbean patients had fewer mutations in CCR4 and CD58. Three putative tumor suppressors not previously implicated in ATLL were identified based on recurrent damaging mutations. These included ANKRD11 (n=3), DGKZ (n=3), and PTPN6 (n=3). Both ANKRD11 and PTPN6 were only mutated in Afro-Caribbean patients with aggressive (acute and lymphomatous) cases. CNV analysis revealed ANKRD11 deletions in a significant portion of cases (n=16). As previously reported, STAT3 mutations were more common in indolent subtypes. IRF4 mutations (n=14) or amplifications (n=19) were only observed in aggressive ATLL subtypes. L70V was the most common IRF4 variant (n=5). Among Japanese samples, K59R m