May 26, 2025
Hokkaido University Hospital
National Cancer Center Japan
Keio University
[Key Points]
Conducted a genetic analysis on 173 cases of nodal T-follicular helper cell lymphoma (nTFHL), the largest cohort to date, revealing the overall landscape of genetic abnormalities in nTFHL.
Identified four molecular subtypes of nTFHL—TR-I(+), TR-I(-), AC53, and NSD—with distinct clinical features and prognoses, based on abnormalities in the TET2, RHOA, IDH2, TP53, and CDKN2A genes.
Developed the mTFHL-PI, a model incorporating information on genetic abnormalities and clinical factors, and demonstrated its ability to stratify the prognosis of nTFHL.
A research group led by former physician Joji Shimono (at the time) and Lecturer Masao Nakagawa of Hokkaido University Hospital, in collaboration with Yuta Ito (voluntary trainee) from the Division of Molecular Oncology, National Cancer Center Research Institute; Professor Keisuke Kataoka of the Division of Hematology, Department of Internal Medicine, Keio University School of Medicine (who also serves as Chief of the Division of Molecular Oncology, National Cancer Center Research Institute); and Keisuke Kawamoto, Professor Hiroaki Miyoshi, and Professor Koichi Ohshima of the Department of Pathology, Kurume University School of Medicine, has clarified the overall landscape of genetic abnormalities in nodal T-follicular helper cell lymphoma (nTFHL), a type of malignant lymphoma with a poor prognosis, and the clinical utility of a molecular classification based on these findings.
Malignant lymphoma is a type of blood cancer originating from lymphocytes, which are components of the blood. nTFHL, the subject of this study, is classified as a peripheral T-cell lymphoma derived from T-cells. Pathologically, it is characterized by the expression of T-follicular helper (TFH)-related markers such as PD1 and ICOS, and genetically, by mutations in genes that activate T-cell receptor signaling pathways and in epigenetic modifiers such as RHOA G17V, TET2, and IDH2. While nTFHL generally has a poor prognosis, it is a clinically heterogeneous disease, with some cases progressing slowly. This necessitates the search for more sensitive prognostic factors and the selection of appropriate treatments based on them.
In this study, we analyzed mutations and copy number abnormalities in 173 cases—the largest cohort in any genetic analysis study of nTFHL reported to date—using targeted sequencing of 242 driver genes in T/NK-cell neoplasms. As a result, we identified 36 driver genes, including four novel ones (TET3, HLA-C, KLF2, and NRAS), suggesting that the diversity of these genetic abnormalities is associated with the clinical heterogeneity of nTFHL.
Based on these analysis results, we created a molecular classification consisting of four molecular subtypes with different clinical features and prognoses, focusing on abnormalities in TET2, RHOA, IDH2, TP53, and CDKN2A. In particular, the subtype with TP53 and CDKN2A abnormalities (AC53) had an extremely poor prognosis, whereas the subtype with none of these abnormalities (NSD) had a favorable prognosis. Based on these results, we developed a clinicogenomic prognostic model, the "mTFHL-PI," composed of three factors: (1) TP53 or CDKN2A abnormalities, (2) any driver abnormality, and (3) high risk according to the clinical factor International Prognostic Index (IPI). We demonstrated that this model can stratify the prognosis of nTFHL.
The results of this study have revealed the overall landscape of genetic abnormalities in nTFHL and demonstrated the utility of this information for prognostic stratification. These findings are expected to provide a foundation for future personalized medicine and the development of new therapies.
This research was published online in the British scientific journal "Leukemia" on May 2, 2025.
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