Genomic characterization uncovers molecular subtypes in Mantle Cell Lymphoma

Abstract Introduction Mantle cell lymphoma (MCL) is a heterogeneous B-cell malignancy with variable prognosis, often driven by genetic alterations. Recent genomic and transcriptomic studies have identified prognostic clusters based on mutations, copy number variations (CNV), and pathway dysregulation. However, a clinically feasible mutation-based subtyping system to guide treatment and improve outcomes remains needed. This study aims to develop and validate a prognostic subtyping approach for MCL patients, emphasizing the role of high-risk mutations like TP53 and the therapeutic potential of BTK inhibitors. Methods We analyzed formalin-fixed, paraffin-embedded specimens from 104 newly diagnosed MCL patients using next-generation sequencing (NGS) with a 150-gene panel on the NovaSeq platform. DNA libraries were prepared, aligned to GRCh37, and variants called using BWA, Samtools, Picard, GATK, and ANNOVAR. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was performed on genes mutated >5%. Integrative clustering identified prognostic subtypes. Validation was conducted on two published datasets comprising 247 MCL patients. Survival analyses (Kaplan-Meier, log-rank test) and multivariate Cox regression (including MIPI/MIPI-C) assessed prognostic significance. Results We analyzed the mutation spectrum of mantle cell lymphoma (MCL) and classified 104 MCL patients into three subtypes based on their mutation profiles. Subtype C1, dominated by low-risk gene mutations (ATM, KMT2D, NOTCH1, SOCS1), exhibited the best prognosis. Subtype C3, enriched in high-risk gene mutations (TP53, CREBBP, CARD11), showed the worst prognosis. Subtype C2, comprising patients not classified into C1 or C3, had an intermediate prognosis. Additionally, treatment analysis revealed that ibrutinib significantly improved survival outcomes in the high-risk C3 subtype. Conclusion This mutation-based subtyping stratifies MCL into three prognostic groups, offering a practical tool for risk assessment and precision therapy. Targeting high-risk subtypes with BTK inhibitors may enhance outcomes, warranting prospective validation.