Biology subjects

Pararajalingam, P.

Publications and source records attributed to Pararajalingam, P..

4 recordsLinked to original sources

bioRxiv2025

LCR-modules: a collection of workflows for cancer genome analysis

The surge of genomic data from advanced sequencing technologies is outpacing current analytical pipelines. We introduce LCR-modules, an open-source suite of bioinformatics tools designed for flexible and automated cancer genome data analysis. LCR-modules enables reproducible analysis of diverse cancer genomics data at scale. The suite comprises 49 Snakemake-based workflows organized into three levels, facilitating tasks from low-level quality control to complex cohort-level analyses. LCR-modules supports various sequencing types and integrates pipelines such as mutation calling, expression quantification, and cohort-level aggregation, ensuring flexibility and reproducibility. LCR-modules represents a significant advancement in genomic data analysis, reducing barriers in reproducibility and scalability and has already been applied to a combination of exomes and genomes from over 10,800 samples.

bioinformatics↗

bioRxiv2025

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

Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We studied two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone. TP53 alterations were consistently associated with poor prognosis, whereas ATM mutations correlated with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters were 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 revealed enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFN, TNF) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrated enrichment of CD8 T cells with high expression of exhaustion markers and dominant population of myeloid cells skewed toward an M2-like phenotype. Compared to ATM-perturbed tumors, TP53-perturbed tumors exhibited enriched SOX11 tumor cells and enhanced tumor-immune cell interactions. Functional analysis revealed 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-altered MCL.

cancer biology↗

bioRxiv2019

Coding and regulatory drivers of mantle cell lymphoma identified through exome and genome sequencing

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 212 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations and further nominate two additional genes, EWSR1 and MEF2B, whose mutation respectively associated with poor and good outcome. Our sequencing revealed novel recurrent mutations including a unique missense hot spot in MEF2B and a pattern of non-coding mutations surrounding a single exon of the HNRNPH1 gene. We sequenced the whole genomes of 34 MCLs to confirm the focal nature of HNRNPH1 mutations. Using RNA-seq data from 110 of these cases, we identified a functional role for recurrent non-coding HNRNPH1 mutations in disrupting an auto-regulatory feedback mechanism. Overall, we identified three novel MCL-related genes with roles in RNA trafficking or splicing, namely DAZAP1, EWSR1, and HNRNPH1. Taken together, these data strongly implicate a role for aberrant regulation of splicing in MCL pathobiology.\n\nKey pointsO_LIRNA-binding proteins with roles in regulating alternative splicing, DAZAP1, EWSR1, HNRNPH1, are frequently mutated in MCL\nC_LIO_LIThe majority of recurrent somatic HNRNPH1 mutations are intronic and HNRNPH1 exhibits self-regulation through alternative splicing\nC_LI

genomics↗

bioRxiv2017

Genome-wide discovery of somatic coding and regulatory variants in Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Many known driver mutations are over-represented in one of its two molecular subgroups, knowledge of which has aided in the development of therapeutics that target these features. The heterogeneity of DLBCL determined through prior genomic analysis suggests an incomplete understanding of its molecular aetiology, with a limited diversity of genetic events having thus far been attributed to the activated B-cell (ABC) subgroup. Through an integrative genomic analysis we uncovered genes and non-coding loci that are commonly mutated in DLBCL including putative regulatory sequences. We implicate recurrent mutations in the 3UTR of NFKBIZ as a novel mechanism of oncogene deregulation and found small amplifications associated with over-expression of FC-{gamma} receptor genes. These results inform on mechanisms of NF-{kappa}B pathway activation in ABC DLBCL and may reveal a high-risk population of patients that might not benefit from standard therapeutics.

genomics↗