Genomic Landscape and Molecular Subtypes of Primary Central Nervous System Lymphoma

Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was funded by the National Natural Science Foundation of China (82302582), the Shanghai Municipal Health Commission Project (20224Y0317), the Shanghai Science and Technology Commission (17430750200), the Join Breakthrough Project for New Frontier Technologies of Shanghai Hospital Development Center (SHDC12016120), and the Youth Medical Talents Clinical Laboratory Practitioner Program (202265).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was conducted with the approval of the Institutional Review Boards at Huashan Hospital of Fudan University, Shanghai Cancer Center of Fudan University, and Renji Hospital of Shanghai Jiao Tong University.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors.

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