Nagarajan Paramasivam
A5052465605- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- Genomics and Rare Diseases
- RNA modifications and cancer
- Lymphoma Diagnosis and Treatment
- Protein Degradation and Inhibitors
- Genetics and Neurodevelopmental Disorders
- Multiple Myeloma Research and Treatments
- Genomic variations and chromosomal abnormalities
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Genomics and Phylogenetic Studies
- CNS Lymphoma Diagnosis and Treatment
- Glioma Diagnosis and Treatment
- Cancer-related gene regulation
- Evolution and Genetic Dynamics
- Peptidase Inhibition and Analysis
- Chromosomal and Genetic Variations
- RNA Research and Splicing
- Thyroid Cancer Diagnosis and Treatment
- Cancer-related molecular mechanisms research
- Metabolism and Genetic Disorders
- DNA Repair Mechanisms
- BRCA gene mutations in cancer
- Myasthenia Gravis and Thymoma
German Cancer Research Center
2016-2025
University Hospital Heidelberg
2015-2025
Heidelberg University
2016-2025
National Center for Tumor Diseases
2020-2025
Heinrich Heine University Düsseldorf
2024
Düsseldorf University Hospital
2024
Integrated Oncology (United States)
2024
Metropolitan University
2023
DKFZ-ZMBH Alliance
2019
Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight need molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify full spectrum of driver genes molecular processes that operate in medulloblastoma subgroups. Here we analyse somatic landscape across 491 sequenced samples heterogeneity among 1,256 epigenetically analysed cases, subgroup-specific...
Abstract As whole-genome sequencing for cancer genome analysis becomes a clinical tool, full understanding of the variables affecting output is required. Here using tumour-normal sample pairs from two different types cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct benchmarking exercise within context International Cancer Genome Consortium. We compare methods, pipelines validation methods. show that PCR-free methods increasing depth to ∼100 × shows benefits, as long...
Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell (DLBCLs) confined to (CNS). Molecular drivers PCNSL have not been fully elucidated. Here, we profile and compare whole-genome transcriptome landscape 51 CNS (CNSL) 39 follicular lymphoma 36 DLBCL cases outside CNS. We find recurrent mutations in JAK-STAT, NFkB, receptor signaling pathways, including hallmark MYD88 L265P (67%) CD79B (63%), CDKN2A deletions (83%). PCNSLs exhibit significantly more focal...
Abstract Burkitt lymphoma (BL) is the most common B-cell in children. Within International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, unravel interaction structural, mutational, transcriptional changes, which contribute to MYC oncogene dysregulation together with pathognomonic IG- translocation. Moreover, by mapping IGH translocation breakpoints, provide evidence that precursor at least a subset BL poised express IGHA. We...
Incomplete understanding of the metastatic process hinders personalized therapy. Here we report most comprehensive whole-genome study colorectal metastases vs. matched primary tumors. 65% somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating higher mutation rate in metastases. Tumor- metastasis-specific harbor elevated levels BRCAness. We confirm multistage progression new components ARHGEF7/ARHGEF33. Recurrently mutated...
•14.3% of patients with rare cancers and/or younger age onset carried a PGV.•PGVs were highly enriched in certain cancer entities, i.e. wild-type GISTs and leiomyosarcomas.•High PGV yields ATM, BRCA2, or PALB2 entities indicated potentially novel genotype–phenotype associations.•75% PGVs predisposition genes newly diagnosed due to study participation (118/157).•45% all supported molecularly informed therapeutic recommendations benefit 40% patients. BackgroundGermline variant evaluation...
Abstract The benefit of molecularly-informed therapies in cancer unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and methylome analysis 70 CUP patients to reveal substantial mutational heterogeneity with TP53 , MUC16 KRAS LRP1B CSMD3 being the most frequently mutated known cancer-related genes. common fusion partner FGFR2 focal homozygous deletion affects CDKN2A . 56/70 (80%) receive genomics-based treatment...
The development of a fatal, clonal, autonomously proliferating CD4-CD8- chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) occurred 1 month after patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. PTCL had clonal rearrangement, which was already detectable in the apheresis product CAR manufacturing and 7 months earlier autologous transplantation. Somatic
Thymic epithelial tumors (TETs) are rare malignancies with limited treatment options and underexplored molecular features. We examined the genomic landscape therapeutic outcomes in 81 patients advanced TETs, including thymic carcinomas (TCs), thymomas, neuroendocrine neoplasms (TNENs), who were enrolled MASTER trial, a prospective observational precision oncology trial. Using whole-genome-sequencing whole-exome-sequencing analysis, transcriptome methylome we identified distinct features...
B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but mutational processes are poorly understood. By performing whole genome transcriptome sequencing 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct signatures linked SHM CSR. We show that not only SHM, presumably also...
Recently, de novo heterozygous variants in DDX3X have been reported about 1.5% of 2659 females with previously unexplained intellectual disability (ID). We report on the identification two unrelated girls clinical features Toriello–Carey Syndrome (T‐CS). In patient 1, recurrent variant c.1703C>T; p.(P568L) was identified when reconsidering X‐linked exome sequencing data. 2, c.1600C>G; p.(R534G) also detected by sequencing. Based these data, should be considered not only ID, but...
Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with genetic basis that has yet to be unequivocally established. In recent whole-genome sequencing study of five families occurrence NMTCs, we shortlisted promising variants the help bioinformatics tools. Here, report in silico analyses and vitro experiments on novel germline variant (p.V29L) highly conserved oligonucleotide/oligosaccharide binding domain Protection Telomeres 1 (POT1) gene one families. The results showed...
Abstract In contrast to adults, meningiomas are uncommon tumors in childhood and adolescence. Whether adult pediatric differ on a molecular level is unclear. Here we report detailed genomic analyses of 37 by sequencing DNA methylation profiling. Histologically, the series was dominated meningioma subtypes with aggressive behavior, 70% patients suffering from WHO grade II or III meningiomas. The most frequent cytogenetic aberrations were loss chromosomes 22 (23/37 [62%]), 1 (9/37 [24%]), 18...
Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole-genome sequencing in 15 Polish families of many affected individuals, without mutations CRC focused on loss-of-function variants and functionally characterized them. identified a frameshift variant the CYBA gene (c.246delC) one family splice site TRPM4 (c.25-1 G > T) another family. While both were absent or extremely rare databases, we four additional familial cases two...
The outcomes of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) remain poor. In this study, we performed whole genome transcriptome sequencing 39 heavily pretreated relapsed/refractory MM (RRMM) identify mechanisms resistance potential therapeutic targets. We observed a high mutational load indications increased genomic instability. Recurrently mutated genes in RRMM, which had not been previously reported or only at lower...
Abstract Ex vivo drug response profiling is a powerful tool to study genotype–drug associations and being explored as set for precision medicine in cancer. Here we conducted prospective non-interventional trial investigate feasibility of ex treatment guidance hematologic malignancies (SMARTrial, NCT03488641 ). The primary endpoint provide reports within 7 d was met 91% all participants ( N = 80). Secondary analysis revealed that resistance chemotherapeutic drugs predicted chemotherapy...
<title>Abstract</title> Desmoplastic small round cell tumor (DSRCT) is an ultra-rare sarcoma with limited treatment options. We performed whole-genome/exome, transcriptome, and DNA methylome analysis in 30 refractory DSRCT patients, complemented by (phospho)proteomic profiling nine, within a nationwide precision oncology program. In eight patients (27%), was diagnosed based on molecular profiling. Although all had “quiet” genomes, 28 (93%) received 107 molecular-based management...
Peritoneal, pericardial and pleural mesothelioma (PeM/PcM/PM) are rare aggressive diseases with limited survival. Molecularly guided therapy is currently not part of standard care. This study integrates molecular clinical data from 51 patients (among them 28 PM, one PcM, 21 PeM synchronous PeM/PM) enrolled in the National Center for Tumor Diseases German Cancer Consortium (NCT/DKTK) Aided Stratification Eradication Research (MASTER), a multicenter precision oncology registry trial addressing...
Thyroid cancer (TC) is the most common endocrine malignancy, with 90%-95% of cases representing non-medullary thyroid (NMTC). Familial account only for a few all and underlying genetic causes are still poorly understood. We whole-genome sequenced affected unaffected members an Italian NMTC family applied our in-house developed Cancer Variant Prioritization Pipeline (FCVPPv2) which prioritized 12 coding variants. refined this selection using VarSome American College Medical Genetics Genomics...
Abstract Molecularly-guided therapy can improve treatment outcomes in CUP, a heterogeneous group of cancers with very limited prognosis. Within DKFZ/NCT/DKTK MASTER, clinically embedded prospective precision oncology registry trial, patients receive molecularly-guided recommendations (TR) based on whole genome/exome sequencing (WGS/WES), transcriptome and methylome analysis from dedicated molecular tumor board (MTB). We retrospectively added phosphoproteomic (PPA) to assess its potential...
Whole-genome sequencing methods in familial cancer are useful to unravel rare clinically important predisposing variants. Here, we present improvements our pedigree-based variant prioritization pipeline referred as FCVPPv2, including 12 tools for evaluating deleteriousness and 5 intolerance scores missense This is also capable of assessing non-coding regions by combining FANTOM5 data with sets like Bedtools, ChromHMM, Miranda, SNPnexus Targetscan. We tested this a family history papillary...