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

Keisuke Kataoka, Masako Iwanaga, Jun-ichirou Yasunaga, Yasunobu Nagata, Akira Kitanaka, Takuro Kameda, Makoto Yoshimitsu, Yuichi Shiraishi, Aiko Sato-Otsubo, Masashi Sanada, Kenichi Chiba, Hiroko Tanaka, Yotaro Ochi, Kosuke Aoki, Hiromichi Suzuki, Yusuke Shiozawa, Tetsuichi Yoshizato, Yusuke Sato, Kenichi Yoshida, Kisato Nosaka, Masakatsu Hishizawa, Hidehiro Itonaga, Yoshitaka Imaizumi, Wataru Munakata, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Tsuyoshi Nakamaki, Ken Ishiyama, Shuichi Miyawaki, Ryohei Ishii, Osamu Nureki, Kensei Tobinai, Yasushi Miyazaki, Akifumi Takaori-Kondo, Tatsuhiro Shibata, Satoru Miyano, Kenji Ishitsuka, Atae Utsunomiya, Kazuya Shimoda, Masao Matsuoka, Toshiki Watanabe and Seishi Ogawa

Key points

  • ATL subtypes are further classified into molecularly distinct subsets with different prognosis by genetic profiling.

  • PD-L1 amplifications are a strong genetic predictor for worse outcome in both aggressive and indolent ATL.

Abstract

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 SNP array karyotyping, respectively. Aggressive (acute/lymphoma) subtypes were associated with an increased burden of genetic and epigenetic alterations, and higher frequencies of TP53 and IRF4 mutations, and many copy number alterations (CNAs), including PD-L1 amplifications and CDKN2A deletions, compared to indolent (chronic/smoldering) subtypes. By contrast, STAT3 mutations were more characteristic of indolent ATL. Higher numbers of somatic mutations and CNAs significantly correlated with worse survival. In multivariate analysis incorporating both clinical factors and genetic alterations, Japan Clinical Oncology Group prognostic index high-risk, older age, PRKCB mutations, and PD-L1 amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions were significantly associated with a shorter survival, although chronic subtype with unfavorable clinical factors was only marginally significant. Thus, somatic alterations characterizing aggressive diseases predict worse prognosis in indolent ATL, among which PD-L1 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.

  • Submitted January 11, 2017.
  • Accepted October 20, 2017.