TP53 and CDKN2A alterations define a poor prognostic subgroup in patients with nodal T follicular helper cell lymphoma

Yuta Ito^#^{1

2}, Joji Shimono^#³, Keisuke Kawamoto^#^{4

5}, Kanako C Hatanaka⁶, Yasunori Kogure¹, Mariko Tabata^{1

7}, Yuki Saito^{1

8}, Kota Mizuno^{1

9}, Sara Horie^{1

8}, Yosuke Mizukami^{1

8}, Junji Koya¹, Koichi Murakami^{1

9}, Takanori Teshima³, Yutaka Hatanaka¹⁰, Kenichi Chiba¹¹, Ai Okada¹¹, Yuichi Shiraishi¹¹, Hiroaki Miyoshi⁴, Yoshihiro Matsuno¹², Koichi Ohshima¹³, Keisuke Kataoka^{14

15}, Masao Nakagawa¹⁶

Affiliations

¹ Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.
² Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
³ Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.
⁴ Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
⁵ Institute of Pathology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
⁶ Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Japan.
⁷ Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁸ Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
⁹ Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
¹⁰ Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan.
¹¹ Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan.
¹² Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
¹³ Department of Pathology, Kurume University School of Medicine, Kurume, Japan. ohshima_kouichi@med.kurume-u.ac.jp.
¹⁴ Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan. kkataoka-tky@umin.ac.jp.
¹⁵ Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. kkataoka-tky@umin.ac.jp.
¹⁶ Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan. nakagawam@med.hokudai.ac.jp.

^# Contributed equally.

PMID: 40316697
DOI: 10.1038/s41375-025-02631-5

TP53 and CDKN2A alterations define a poor prognostic subgroup in patients with nodal T follicular helper cell lymphoma

Yuta Ito et al. Leukemia. 2025 Jul.

. 2025 Jul;39(7):1723-1734.

doi: 10.1038/s41375-025-02631-5. Epub 2025 May 2.

Authors

Affiliations

¹ Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.
² Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
³ Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.
⁴ Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
⁵ Institute of Pathology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
⁶ Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Japan.
⁷ Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁸ Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
⁹ Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
¹⁰ Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan.
¹¹ Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan.
¹² Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
¹³ Department of Pathology, Kurume University School of Medicine, Kurume, Japan. ohshima_kouichi@med.kurume-u.ac.jp.
¹⁴ Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan. kkataoka-tky@umin.ac.jp.
¹⁵ Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. kkataoka-tky@umin.ac.jp.
¹⁶ Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan. nakagawam@med.hokudai.ac.jp.

^# Contributed equally.

PMID: 40316697
DOI: 10.1038/s41375-025-02631-5

Abstract

Nodal T follicular helper cell lymphoma (nTFHL) exhibits unique immunophenotypes and somatic alterations, while the prognostic value of these alterations remains unclear. By analyzing 173 nTFHL cases, we identified 36 driver genes, including 4 novel ones (TET3, HLA-C, NRAS, and KLF2). Then, we classified nTFHL cases into four molecular subgroups by major driver alterations. TR-I (+) and TR-I (-) were characterized by TET2 and/or RHOA mutations with and without IDH2 mutations; AC53 by TP53 and/or CDKN2A alterations and aneuploidy; and NSD with no subgroup-defining alterations (namely without any of the above alterations). AC53 exhibited the worst survival, while NSD, particularly those lacking driver alterations, showed the best prognosis. nTFHL had a better prognosis than peripheral T-cell lymphoma, not otherwise specified, when TP53 and/or CDKN2A alterations were absent. Multivariable analyses showed that AC53, the presence of driver alterations, and international prognostic index high-risk were independently associated with worse survival. Finally, we developed a simple prognostic index (mTFHL-PI), which classified patients into three risk categories with a median OS of 181, 67, and 20 months, respectively. Our study identifies novel prognostic factors, namely TP53 and/or CDKN2A alterations and the presence of driver alterations, demonstrating the clinical relevance of molecular classification in nTFHL.

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Conflict of interest statement

Competing interests: K.C.H. has received research funding from NEC Corporation, Eli Lilly, and SEKISUI CHEMICAL. Y.K. has received honoraria from Kyowa Kirin, Nippon Shinyaku, Daiichi Sankyo, and Takeda Pharmaceutical. J.K. has received honoraria from TOMY DIGITAL BIOLOGY, Scrum, and Eisai. T.T. has received honoraria from Astellas Pharma, AstraZeneca, Kyowa-Kirin, SymBio Pharmaceuticals, Sumitomo Pharma, Nippon Shinyaku, Novartis, Janssen Pharmaceutical, and Bristol-Myers Squibb; has received research grants from Asahi Kasei Pharma, Eisai, Ono Pharmaceutical, Kyowa-Kirin, Shionogi, Sumitomo Pharma, Chugai Pharmaceutical, and Nippon Shinyaku; and has received research funding from Astellas Pharma, Otsuka Pharmaceutical, LUCA Science, and Priothera SAS. Y.H. has received honoraria from Eli Lilly, Daiichi Sankyo, AstraZeneca, Merck, Novartis, and Merck Sharp & Dohme; has received research funding from NEC Corporation, Eli Lilly, Shionogi, Daiichi Sankyo, and Sysmex; and has received consultancy fee from NEC Corporation. K.Kataoka has received honoraria from Ono Pharmaceutical, Eisai, Astellas Pharma, Novartis, Chugai Pharmaceutical, AstraZeneca, Sumitomo Pharma, Kyowa Kirin, Janssen Pharmaceutical, Takeda Pharmaceutical, Otsuka Pharmaceutical, SymBio Pharmaceuticals, Bristol Myers Squibb, Pfizer, Nippon Shinyaku, Daiichi Sankyo, Alexion Pharmaceuticals, AbbVie, Meiji Seika Pharma, Sanofi, Sysmex, Mundipharma, Incyte Corporation, and Kyorin Pharmaceutical; has received research funding from Asahi Kasei Pharma, Eisai, Otsuka Pharmaceutical, Ono Pharmaceutical, Kyowa Kirin, Shionogi, Takeda Pharmaceutical, Sumitomo Dainippon Pharma, Chugai Pharmaceutical, Teijin Pharma, Japan Blood Products Organization, Mochida Pharmaceutical, JCR Pharmaceuticals, Nippon Shinyaku, Chordia Therapeutics, and Meiji Seika Pharma; holds individual stocks in Asahi Genomics; and has a patent for Genetic alterations as a biomarker in T-cell lymphomas licensed to Kyoto University and PD-L1 abnormalities as a predictive biomarker for immune checkpoint blockade therapy licensed to Kyoto University. M.N. has received honoraria from Takeda Pharmaceutical, Meiji Seika Pharma, AstraZeneca, and Mundipharma; and has received research funding from Takeda Pharmaceutical and AbbVie. All remaining authors have declared no conflicts of interest.

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TP53 and CDKN2A alterations define a poor prognostic subgroup in patients with nodal T follicular helper cell lymphoma

Affiliations

TP53 and CDKN2A alterations define a poor prognostic subgroup in patients with nodal T follicular helper cell lymphoma

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous