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 language | English |
|---|---|
| Journal | Leukemia |
| DOIs | |
| Publication status | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research
Cite this
Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. / 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.
In: Leukemia, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling
AU - Watatani, Yosaku
AU - Sato, Yasuharu
AU - Miyoshi, Hiroaki
AU - Sakamoto, Kana
AU - Nishida, Kenji
AU - Gion, Yuka
AU - Nagata, Yasunobu
AU - Shiraishi, Yuichi
AU - Chiba, Kenichi
AU - Tanaka, Hiroko
AU - Zhao, Lanying
AU - Ochi, Yotaro
AU - Takeuchi, Yasuhide
AU - Takeda, June
AU - Ueno, Hiroo
AU - Kogure, Yasunori
AU - Shiozawa, Yusuke
AU - Kakiuchi, Nobuyuki
AU - Yoshizato, Tetsuichi
AU - Nakagawa, Masahiro M.
AU - Nanya, Yasuhito
AU - Yoshida, Kenichi
AU - Makishima, Hideki
AU - Sanada, Masashi
AU - Sakata-Yanagimoto, Mamiko
AU - Chiba, Shigeru
AU - Matsuoka, Ryota
AU - Noguchi, Masayuki
AU - Hiramoto, Nobuhiro
AU - Ishikawa, Takayuki
AU - Kitagawa, Junichi
AU - Nakamura, Nobuhiko
AU - Tsurumi, Hisashi
AU - Miyazaki, Tatsuhiko
AU - Kito, Yusuke
AU - Miyano, Satoru
AU - Shimoda, Kazuya
AU - Takeuchi, Kengo
AU - Ohshima, Koichi
AU - Yoshino, Tadashi
AU - Ogawa, Seishi
AU - Kataoka, Keisuke
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065962774&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065962774&partnerID=8YFLogxK
U2 - 10.1038/s41375-019-0473-1
DO - 10.1038/s41375-019-0473-1
M3 - Article
AN - SCOPUS:85065962774
JO - Leukemia
JF - Leukemia
SN - 0887-6924
ER -