Genomic Landscape and Molecular Subtypes of Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive brain tumor with a poor prognosis and almost exclusively comprises diffuse large B-cell lymphoma (DLBCL). Its genetic characteristics and molecular subtypes in Chinese patients remain poorly understood, which in turn makes developing effective new therapies challenging. In our study, 140 Chinese patients with PCNSL that was newly diagnosed at one of three tertiary care centers and who underwent extensive follow-up were included. With this sample, we performed a genomic study aimed at expanding the genomic landscape and identifying new molecular subtypes. We first confirmed that the molecular subtype categories of DLBCL, as previously published, are not applicable to PCNSLs in Chinese 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 them in 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 PCNSLs from Asian patients (16.88%) than from Western patients (< 5.26%), resulting in unfavorable outcomes independent of the specific mutation site. Our analysis comprehensively reveals the genomic landscape of PCNSL in Chinese patients and emphasizes the clinical value of molecular classification for improving precision medicine strategies.

Abstract Figure

Highlights

In this study, the genomic landscape of 140 Chinese patients with primary central nervous system lymphomas (PCNSLs) was evaluated.

Chinese PCNSL patients have a defining genetic signature that differs from that of both PCNSL patients in other racial groups and DLBCL patients.

Three robust molecular subtypes of PCNSL related to clinical and molecular features were identified and validated.

The rate of EP300 mutation in PCNSLs was approximately three times higher among Asians than among Western patients, resulting in unfavorable outcomes independent of the specific mutation site.