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

• Published in: Leukemia 2019-12, Vol.33 (12), p.2867-2883
• Main Authors: Watatani, Yosaku, Sato, Yasuharu, Miyoshi, Hiroaki, Sakamoto, Kana, Nishida, Kenji, Gion, Yuka, Nagata, Yasunobu, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Zhao, Lanying, Ochi, Yotaro, Takeuchi, Yasuhide, Takeda, June, Ueno, Hiroo, Kogure, Yasunori, Shiozawa, Yusuke, Kakiuchi, Nobuyuki, Yoshizato, Tetsuichi, Nakagawa, Masahiro M., Nanya, Yasuhito, Yoshida, Kenichi, Makishima, Hideki, Sanada, Masashi, Sakata-Yanagimoto, Mamiko, Chiba, Shigeru, Matsuoka, Ryota, Noguchi, Masayuki, Hiramoto, Nobuhiro, Ishikawa, Takayuki, Kitagawa, Junichi, Nakamura, Nobuhiko, Tsurumi, Hisashi, Miyazaki, Tatsuhiko, Kito, Yusuke, Miyano, Satoru, Shimoda, Kazuya, Takeuchi, Kengo, Ohshima, Koichi, Yoshino, Tadashi, Ogawa, Seishi, Kataoka, Keisuke
• Format: Article
• Language: English
• Subjects: 45; 45/23; 631/208/212; 631/67/68; Alleles; Analysis; Biomarkers, Tumor; Cancer Research; Cluster analysis; Clustering; Computational Biology; Critical Care Medicine; DNA Copy Number Variations; Female; Gene expression; Gene Expression Profiling; Gene regulation; Gene sequencing; Genetic Association Studies - methods; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic Variation; Genomic Instability; Health aspects; Hematology; Heterogeneity; High-Throughput Nucleotide Sequencing; Histocompatibility antigen HLA; Humans; Intensive; Internal Medicine; Lymphocytes T; Lymphoma; Lymphoma, T-Cell, Peripheral - diagnosis; Lymphoma, T-Cell, Peripheral - genetics; Lymphoma, T-Cell, Peripheral - metabolism; Male; Medical colleges; Medicine; Medicine & Public Health; Mutation; Neoplasms; Non-Hodgkin's lymphomas; Oncology; p53 Protein; Pathogenesis; Phenotypes; Signal Transduction; T cells; T-cell lymphoma; Target recognition; Transcription; Tumor Escape; Tumor proteins; Whole Exome Sequencing
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-019-0473-1

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.