Adult T-cell leukemia/lymphoma (ATL) is a deadly neoplasm that resembles regulatory T cells immunophenotypically and is caused by the human T-cell leukemia virus type 1. For a study, researchers used whole-genome sequencing (WGS) to uncover the overall landscape of genetic changes in ATL patients. Previous exome-centric analyses of several cancer types had ignored numerous (33%) loss-of-function changes primarily targeting the CIC long isoform. In vivo, long isoform-specific inactivation of Cic selectively enhanced CD4+CD25+Foxp3+ T cells but not short isoform-specific inactivation. They also discovered frequent (13%) 3′-truncations of REL, which cause transcriptional upregulation and the production of gain-of-function proteins. REL truncations were also prevalent in diffuse large B-cell lymphoma, particularly in the germinal center B-cell–like subtype (12%).
They discovered recurrent mutations in regulatory regions, notably splice sites, of multiple driver genes in the non-coding genome. Furthermore, they identified the mutational enrichment at the binding sites of host and viral transcription factors, implying their activities in ATL, and characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes. They detected 56 recurrently changed driver genes, including 11 unique ones, by combining analysis for coding and non-coding mutations, structural variations, and copy number changes. Finally, based on the driver alteration profile, ATL patients were divided into two molecular groups with unique clinical and genetic features.