3 years ago

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

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

Publisher URL: http://doi.org/10.1182/blood-2017-01-761874

DOI: 10.1182/blood-2017-01-761874

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