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Functional Genomics and Tumor Microenvironment Analysis Reveal Prognostic Biological Subtypes in Mantle Cell Lymphoma [RNA-seq]

ABSTRACT: Functional Genomics and Tumor Microenvironment Analysis Reveal Prognostic Biological Subtypes in Mantle Cell Lymphoma [RNA-seq]

PROVIDER: PRJNA1132725 | ENA |

REPOSITORIES: ENA

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Functional genomics and tumor microenvironment analysis reveal prognostic biological subtypes in Mantle cell lymphoma

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Functional genomics and tumor microenvironment analysis reveal prognostic biological subtypes in Mantle cell lymphoma

Project description:Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We study two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone. TP53 alterations are consistently associated with poor prognosis, whereas ATM mutations correlate with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters are identified and refined into three prognostic groups: high-risk (TP53 mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk (ATM and epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lacking TP53 alterations, rare ATM mutations without 11q deletions, gains at 3q, deletions at 6q). Transcriptomic analysis reveals enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFNα, TNFα) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrates enrichment of CD4⁺ T cells with high expression of exhaustion markers and dominant population of myeloid cells skewed toward an M2-like phenotype. Spatially, TP53-perturbed MCLs are immune infiltrated but exhausted, while ATM-perturbed cases remain immune-cold with dense tumor. Functional analysis shows that p53 represses BCR signaling through PTPN6 activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-risk TP53-perturbed MCL.

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Prognostic analysis of mantle cell lymphoma genomes

Project description:Mantle cell lymphoma is characterized by a t(11;14) chromosomal translocation; however, it alone is insufficient to result in the disease. A number of secondary genetic alterations have been proposed as essential in MCL pathogenesis. Amongst these, numerous copy number altered regions remain ill-defined, both for location and prognostic significance. In this study we examined in detail the genomes of a panel of 52 MCL cases. Relating gene dosage alterations to disease outcome, we found seven loci that correlated with overall survival. A survival model was constructed based on four of these loci (P = 5.87 x 10-6). Using serial analysis of gene expression and quantitative PCR we investigated the expression of genes within these altered regions and determined that CCNI and CCNG2 may be important in MCL pathogenesis (P = 0.0201 and P = 0.0292, respectively). Our findings reinforce the hypothesis that cell cycle deregulation and apoptosis are key factors in MCL pathogenesis. Array CGH, Long-SAGE, and qPCR were utilized to determine regions of the genome that have prognostic significance when altered in copy number in MCL.

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Distinct Layer 6b transcriptomic subtypes parcellate the cortical mantle

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