Matthew A. Wyczalkowski
A5024153866- Cancer Genomics and Diagnostics
- Multiple Myeloma Research and Treatments
- Renal cell carcinoma treatment
- Protein Degradation and Inhibitors
- Ferroptosis and cancer prognosis
- Bioinformatics and Genomic Networks
- RNA modifications and cancer
- Single-cell and spatial transcriptomics
- Ubiquitin and proteasome pathways
- Advanced Proteomics Techniques and Applications
- Genetics, Bioinformatics, and Biomedical Research
- Computational Drug Discovery Methods
- Epigenetics and DNA Methylation
- CAR-T cell therapy research
- Cellular Mechanics and Interactions
- Monoclonal and Polyclonal Antibodies Research
- Ultrasound and Hyperthermia Applications
- RNA Research and Splicing
- Genomics and Rare Diseases
- Genomics and Phylogenetic Studies
- Cancer-related Molecular Pathways
- Ultrasound and Cavitation Phenomena
- Lung Cancer Treatments and Mutations
- Renal and related cancers
- Pancreatic and Hepatic Oncology Research
Washington University in St. Louis
2015-2025
James S. McDonnell Foundation
2015-2024
Pacific Northwest National Laboratory
2020
Saint Louis University
2010-2018
Research Network (United States)
2017
University of Notre Dame
2010
University of California, Berkeley
1999-2003
The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data analytical results for point mutations small insertions/deletions from 3,281 tumours 12 tumour types as part TCGA Pan-Cancer effort. We illustrate distributions mutation frequencies, contexts types, establish their links tissues origin, environmental/carcinogen influences, DNA repair defects. Using integrated sets, identified 127...
Highlights•871 predisposition variants/CNVs discovered in 8% of 10,389 cases 33 cancers•Pan-cancer approach identified shared variants and genes across cancers•33 affecting activating domains oncogenes showed high expression•47 VUSs prioritized using cancer enrichment, LOH, expression other evidenceSummaryWe conducted the largest investigation to date, discovering 853 pathogenic or likely from types. Twenty-one single cross-cancer associations, including novel associations SDHA melanoma...
To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization 110 tumors 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, gender. Proteomic phosphoproteomic data illuminated downstream copy number aberrations, somatic...
To elucidate the deregulated functional modules that drive clear cell renal carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration proteogenomic measurements uniquely protein dysregulation cellular mechanisms impacted by alterations, including...
Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated 9,624 tumors across 33 cancer types using multiple fusion calling tools. identified a total 25,664 fusions, with 63% validation rate. Integration gene expression, copy number, and annotation data revealed that involving oncogenes tend to exhibit increased whereas tumor suppressors have the opposite effect. For kinases, we found 1,275 intact kinase domain, proportion which varied...
Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification metabolomic data on 99 treatment-naive GBMs provides insights GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 PLCG1) as potential switches mediating oncogenic pathway activation, well targets for EGFR-, TP53-, RB1-altered tumors. Immune...
The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued preserve post-translational modifications, including protein phosphorylation acetylation. Proteogenomics challenged standard cancer diagnoses, provided detailed analysis the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint...
We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences perturbations to the p53 Wnt/β-catenin pathways, identified potential role for circRNAs in epithelial-mesenchymal transition, provided information about proteomic markers clinical genomic tumor subgroups, including relationships known druggable pathways. An extensive genome-wide...
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 tissues. Proteomic, phosphoproteomic, glycoproteomic analyses were used to characterize proteins their modifications. In addition, whole-genome sequencing, whole-exome methylation, RNA sequencing...
Highlights•An overview of PanCancer Atlas analyses on oncogenic molecular processes•Germline genome affects somatic genomic landscape in a pathway-dependent fashion•Genome mutations impact expression, signaling, and multi-omic profiles•Mutation burdens drivers influence immune-cell composition microenvironmentSummaryThe Cancer Genome (TCGA) has catalyzed systematic characterization diverse alterations underlying human cancers. At this historic junction marking the completion over 11,000...
Abstract Large-scale cancer sequencing data enable discovery of rare germline susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas representing 12 types. We find that the frequency truncations in 114 cancer-susceptibility-associated genes varies widely, 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high 11% stomach cancer. Burden testing identifies 13 significant enrichment truncations, some associated specific cancers...
We present a proteogenomic study of 108 human papilloma virus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). Proteomic analysis systematically catalogs HNSCC-associated proteins phosphosites, prioritizes copy number drivers, highlights an oncogenic role for RNA processing genes. investigation mutual exclusivity between FAT1 truncating mutations 11q13.3 amplifications reveals dysregulated actin dynamics as common functional consequence. Phosphoproteomics characterizes two...
Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape LSCC, providing deeper exposition LSCC biology potential implications. identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 overexpressing target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such LSD1 EZH2 to SOX2-overexpressing tumors. Our data support...
For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for large-scale discovery of splice-site-creating (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated clear evidence creating alternative splice junctions. TP53 and GATA3 26 18 SCMs, respectively, ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including...
Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, transcriptomics cellular imaging. Subpopulations of tumor cells exhibited signatures proliferation, KRAS signaling, cell stress epithelial-to-mesenchymal transition. Mapping mutations copy number events distinguished populations normal transitional...
Clear cell renal carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- intratumoral heterogeneity (ITH) results in varying prognosis treatment outcomes. To obtain the comprehensive profile ccRCC, we perform integrative histopathologic, proteogenomic, metabolomic analyses on 305 ccRCC tumor segments 166 paired adjacent normal tissues from 213 cases. Combining histologic molecular profiles reveals ITH 90% ccRCCs, with 50% demonstrating immune...
Chromatin accessibility is essential in regulating gene expression and cellular identity, alterations have been implicated driving cancer initiation, progression metastasis
Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying significant cis-effects and distal trans-effects quantified at RNA, protein, phosphoprotein levels. Salient observations include association point mutations copy-number alterations with rewiring protein interaction networks,...
Despite remarkable advances in the genomic characterization of adult melanoma, molecular pathogenesis pediatric melanoma remains largely unknown. We analyzed 15 conventional melanomas (CMs), 3 arising congenital nevi (CNMs), and 5 spitzoid (SMs), using various platforms, including whole genome or exome sequencing, inversion probe assay, and/or targeted sequencing. CMs demonstrated a high burden somatic single-nucleotide variations (SNVs), with each case containing TERT promoter (TERT-p)...
Abstract Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast patient-derived xenograft (PDX) models. Integrated proteogenomic shows positive correlation between measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal markers. Proteogenomic also validates a number...
We present a systematic analysis of the effects synchronizing large-scale, deeply characterized, multi-omic dataset to current human reference genome, using updated software, pipelines, and annotations. For each 5 molecular data platforms in The Cancer Genome Atlas (TCGA)—mRNA miRNA expression, single nucleotide variants, DNA methylation copy number alterations—comprehensive sample, gene, probe-level studies were performed, towards quantifying degree similarity between 'legacy' GRCh37 (hg19)...
Abstract Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it still incurable as disease progression not fully understood. To investigate MM and its immune environment, we apply single cell RNA linked-read whole genome sequencing to profile 29 longitudinal samples at different stages from 14 patients. Here, collect 17,267 cells 57,719 cells, discovering patient-specific profiles expression changes. Patients with same...