Genomic landscape and molecular subtypes of primary central nervous system lymphoma

The genetic landscape and molecular subtypes of primary central nervous system lymphoma (PCNSL) remain inadequately characterized, presenting a major obstacle to the development of effective therapeutic strategies. We conducted a genomic study of 176 PCNSLs from five tertiary centers with long-term follow-up to expand the genomic landscape and identify new molecular subtypes. We first confirmed that the molecular subtyping of diffuse large B-cell lymphoma, as previously published, may not be fully applicable to Chinese PCNSL patients. We then identified (n = 58) and validated (n = 82) three prominent genetic subtypes related to different clinical and molecular features of PCNSL, and further confirmed by an independent external Chinese PCNSL cohort (n = 36). We called these BMIs (from the co-occurrence of mutations in two genes among BTG1, MYD88, and IRF4), which are associated with favorable outcomes; E3s (so-called EP300 mutations), which are associated with unfavorable outcomes; and UCs (unclassified, without characteristic mutations). Importantly, EP300 was mutated in more Asians (16.98%) than in Western PCNSLs (<4.53%), resulting in unfavorable outcomes independent of the specific mutation site. Our analysis comprehensively reveals the genomic landscape of Chinese PCNSL and emphasizes the clinical value of molecular classification for improving precision medicine strategies.