Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling

Yosaku Watatani, Yasuharu Sato, Hiroaki Miyoshi, Kana Sakamoto, Kenji Nishida, Yuka Gion, Yasunobu Nagata, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Lanying Zhao, Yotaro Ochi, Yasuhide Takeuchi, June Takeda, Hiroo Ueno, Yasunori Kogure, Yusuke Shiozawa, Nobuyuki Kakiuchi, Tetsuichi Yoshizato, Masahiro M. NakagawaYasuhito Nanya, Kenichi Yoshida, Hideki Makishima, Masashi Sanada, Mamiko Sakata-Yanagimoto, Shigeru Chiba, Ryota Matsuoka, Masayuki Noguchi, Nobuhiro Hiramoto, Takayuki Ishikawa, Junichi Kitagawa, Nobuhiko Nakamura, Hisashi Tsurumi, Tatsuhiko Miyazaki, Yusuke Kito, Satoru Miyano, Kazuya Shimoda, Kengo Takeuchi, Koichi Ohshima, Tadashi Yoshino, Seishi Ogawa, Keisuke Kataoka

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.

Original languageEnglish
Pages (from-to)2867-2883
Number of pages17
JournalLeukemia
Volume33
Issue number12
DOIs
Publication statusPublished - Dec 1 2019

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Watatani, Y., Sato, Y., Miyoshi, H., Sakamoto, K., Nishida, K., Gion, Y., Nagata, Y., Shiraishi, Y., Chiba, K., Tanaka, H., Zhao, L., Ochi, Y., Takeuchi, Y., Takeda, J., Ueno, H., Kogure, Y., Shiozawa, Y., Kakiuchi, N., Yoshizato, T., ... Kataoka, K. (2019). Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. Leukemia, 33(12), 2867-2883. https://doi.org/10.1038/s41375-019-0473-1