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<jats:p>Peripheral T-cell lymphoma (PTCL) exhibits a diverse clinical spectrum, necessitating methods to categorize patients based on genomic abnormalities or tumor microenvironment (TME) profiles. We conducted an integrative multiomics study in 129 PTCL patients, performing whole-exome sequencing and identifying three genetic subtypes: C1, C2, and C3. C2 was characterized by loss of tumor suppressor genes and chromosomal instability, while C1 and C3 shared T follicular helper (TFH)-related genomic alterations, with C3 also showing a high incidence of <jats:italic>IDH2<\/jats:italic> mutations and chromosome 5 gain. Compared to C1, survival was significantly worse in C2 (HR 2.52; 95% CI, 1.37\u20134.63) and C3 (HR 2.14; 95% CI, 1.17\u20133.89). We also estimated the proportions of immune cell fractions from the bulk RNA sequencing data using CIBERSORTx and classified TME signatures into the following hierarchical clusters: TME1 (characterized by increased B and TFH cells), TME2 (macrophages), and TME3 (activated mast cells). TME2 was associated with shorter survival (HR 3.4; 95% CI, 1.6\u20137.5) and was more frequent in C2 (64.3%) than in C1 (7.7%), whereas C1 had more TME3 signatures (80.8% vs. 28.6%). These findings highlight a significant relationship between genetic subtypes and TME signatures in PTCL, with important implications for clinical prognosis.<\/jats:p>","DOI":"10.1038\/s41375-025-02563-0","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T05:35:30Z","timestamp":1743399330000},"page":"1184-1195","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Discrete genetic subtypes and tumor microenvironment signatures correlate with peripheral T-cell lymphoma outcomes"],"prefix":"10.1038","volume":"39","author":[{"given":"Yasuhito","family":"Suehara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kana","family":"Sakamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1122-6549","authenticated-orcid":false,"given":"Manabu","family":"Fujisawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Fukumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1021-7911","authenticated-orcid":false,"given":"Yoshiaki","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5808-816X","authenticated-orcid":false,"given":"Kenichi","family":"Makishima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakurako","family":"Suma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6852-0721","authenticated-orcid":false,"given":"Tatsuhiro","family":"Sakamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichiro","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Sugio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7763-5723","authenticated-orcid":false,"given":"Koichi","family":"Akashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosei","family":"Matsue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Narita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6129-8299","authenticated-orcid":false,"given":"Joaquim","family":"Carreras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoya","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Chiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Shiraishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1753-6616","authenticated-orcid":false,"given":"Satoru","family":"Miyano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seishi","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Chiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7310-8045","authenticated-orcid":false,"given":"Mamiko","family":"Sakata-Yanagimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"2563_CR1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ccr.2011.06.003","volume":"20","author":"C Quivoron","year":"2011","unstructured":"Quivoron C, Couronn\u00e9 L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, et al. 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