Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical indications are not fully understood. Here, we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA-Seq data from 48 samples. We classified MCL into 4 robust clusters (C1–C4). C1 featured mutated immunoglobulin heavy variable (IGHV), CCND1 mutation, amp(11q13), and active B cell receptor (BCR) signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-κB and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1, and NSD2, with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q), and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these 4 clusters had distinct outcomes (5-year overall survival [OS] rates for C1–C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival, while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes.

Raman spectroscopy (RS) can provide fingerprint-type information on biochemical molecules. RS-based blood plasma analysis of solid tumors has been reported in recent years; however, there are no studies on the use of this analysis for detecting blood diseases. We studied the features of blood plasma in patients with diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) by RS with the aim of developing a simple blood test for noninvasive DLBCL and CLL detection. We analyzed blood plasma from 33 DLBCL patients, 39 CLL patients and 30 healthy volunteers. Orthogonal partial least squares discriminant analysis (OPLS-DA) could build two clusters with almost no overlap between DLBCL/CLL and the controls. We used the prediction set to test the model built by OPLS-DA. For the CLL model, the sensitivity was 92.86%, and the specificity was 100%, whereas for the DLBCL model, the sensitivity was 80% and the specificity was 92.31%. We found Raman bands specific to both DLBCL and CLL patients in comparison with the healthy volunteers. Most importantly, we found that the combination of the 1445 cm^-1 and 1655 cm^-1 Raman shifts could discriminate DLBCL from CLL and even the other solid tumors reported to date. Further analysis of the assignments of 1655 cm^-1 also gave us a clue to find potential important variables hemoglobin and serum albumin related with the CLL prognosis. Our exploratory study primarily demonstrated the great potential of developing RS blood plasma analysis as a novel clinical tool for the noninvasive detection of DLBCL and CLL.

Objective: To evaluate the prognostic value of TP53 mutations in patients with diffuse large B-cell lymphoma (DLBCL). Methods: We retrospectively analyzed the clinical data and gene sequencing results of 253 newly diagnosed DLBCL. Survival and correlation analyses were performed. Results: We further revealed significant prognostic heterogeneity among different TP53 hotspot mutations, with mutations at codons G245, R175, R273, and R282 indicating a poorer prognosis. Within the DBD, mutations in exons 5, 7, and 8 were associated with poorer PFS, while mutations in exons 5, 6, and 8 were linked to poorer OS. Additionally, mutations in the Loop-L2, Loop-L3, and LSH motifs within the DBD were all significantly associated with unfavorable PFS and OS. Notably, in the cohort treated with R-CHOP plus novel agents (R-CHOP+X), there were no significant differences in response rates or survival between TP53-mut and TP53-wt patients, suggesting this combination may overcome the adverse prognosis associated with TP53 mutations. Conclusion: TP53 mutation is a crucial adverse prognostic factor in DLBCL. Given the significant prognostic heterogeneity among different TP53 hotspot mutations, a more refined risk stratification based on the TP53 mutational profile is warranted in clinical practice. For patients with high-risk mutations, combining R-CHOP with targeted therapies and exploring novel combination strategies targeting specific pathways are recommended. In contrast, standard R-CHOP may remain an appropriate option for patients with low-risk mutations. Future prospective trials are needed to validate the efficacy of R-CHOP combined with targeted agents in TP53-mutated DLBCL to optimize treatment strategies and improve patient outcomes.