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Whole-genome landscape of adult T-cell leukemia/lymphoma.


ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform-specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3'-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell-like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.

SUBMITTER: Kogure Y 

PROVIDER: S-EPMC8854674 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Whole-genome landscape of adult T-cell leukemia/lymphoma.

Kogure Yasunori Y   Kameda Takuro T   Koya Junji J   Yoshimitsu Makoto M   Nosaka Kisato K   Yasunaga Jun-Ichirou JI   Imaizumi Yoshitaka Y   Watanabe Mizuki M   Saito Yuki Y   Ito Yuta Y   McClure Marni B MB   Tabata Mariko M   Shingaki Sumito S   Yoshifuji Kota K   Chiba Kenichi K   Okada Ai A   Kakiuchi Nobuyuki N   Nannya Yasuhito Y   Kamiunten Ayako A   Tahira Yuki Y   Akizuki Keiichi K   Sekine Masaaki M   Shide Kotaro K   Hidaka Tomonori T   Kubuki Yoko Y   Kitanaka Akira A   Hidaka Michihiro M   Nakano Nobuaki N   Utsunomiya Atae A   Sica R Alejandro RA   Acuna-Villaorduna Ana A   Janakiram Murali M   Shah Urvi U   Ramos Juan Carlos JC   Shibata Tatsuhiro T   Takeuchi Kengo K   Takaori-Kondo Akifumi A   Miyazaki Yasushi Y   Matsuoka Masao M   Ishitsuka Kenji K   Shiraishi Yuichi Y   Miyano Satoru S   Ogawa Seishi S   Ye B Hilda BH   Shimoda Kazuya K   Kataoka Keisuke K  

Blood 20220201 7


Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not s  ...[more]

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