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Cell Aug 2023Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our...
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 their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.
Topics: Humans; Proteogenomics; Neoplasms; Oncogenes; Cell Transformation, Neoplastic; DNA Copy Number Variations
PubMed: 37582357
DOI: 10.1016/j.cell.2023.07.014 -
Nature Reviews. Cancer May 2022Genomic analyses in cancer have been enormously impactful, leading to the identification of driver mutations and development of targeted therapies. But the functions of... (Review)
Review
Genomic analyses in cancer have been enormously impactful, leading to the identification of driver mutations and development of targeted therapies. But the functions of the vast majority of somatic mutations and copy number variants in tumours remain unknown, and the causes of resistance to targeted therapies and methods to overcome them are poorly defined. Recent improvements in mass spectrometry-based proteomics now enable direct examination of the consequences of genomic aberrations, providing deep and quantitative characterization of tumour tissues. Integration of proteins and their post-translational modifications with genomic, epigenomic and transcriptomic data constitutes the new field of proteogenomics, and is already leading to new biological and diagnostic knowledge with the potential to improve our understanding of malignant transformation and therapeutic outcomes. In this Review we describe recent developments in proteogenomics and key findings from the proteogenomic analysis of a wide range of cancers. Considerations relevant to the selection and use of samples for proteogenomics and the current technologies used to generate, analyse and integrate proteomic with genomic data are described. Applications of proteogenomics in translational studies and immuno-oncology are rapidly emerging, and the prospect for their full integration into therapeutic trials and clinical care seems bright.
Topics: DNA Copy Number Variations; Genomics; Humans; Neoplasms; Proteogenomics; Proteomics
PubMed: 35236940
DOI: 10.1038/s41568-022-00446-5 -
Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages.Nature Communications May 2022Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated HCCs. Here we present an integrated proteogenomic analysis of HCCs... (Review)
Review
Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated HCCs. Here we present an integrated proteogenomic analysis of HCCs across clinical stages and etiologies. Pathways related to cell cycle, transcriptional and translational control, signaling transduction, and metabolism are dysregulated and differentially regulated on the genomic, transcriptomic, proteomic and phosphoproteomic levels. We describe candidate copy number-driven driver genes involved in epithelial-to-mesenchymal transition, the Wnt-β-catenin, AKT/mTOR and Notch pathways, cell cycle and DNA damage regulation. The targetable aurora kinase A and CDKs are upregulated. CTNNB1 and TP53 mutations are associated with altered protein phosphorylation related to actin filament organization and lipid metabolism, respectively. Integrative proteogenomic clusters show that HCC constitutes heterogeneous subgroups with distinct regulation of biological processes, metabolic reprogramming and kinase activation. Our study provides a comprehensive overview of the proteomic and phophoproteomic landscapes of HCCs, revealing the major pathways altered in the (phospho)proteome.
Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Mutation; Proteogenomics; Proteomics; beta Catenin
PubMed: 35508466
DOI: 10.1038/s41467-022-29960-8 -
Cell Aug 2023To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and...
To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.
Topics: Female; Humans; Cystadenocarcinoma, Serous; Ovarian Neoplasms; Proteogenomics
PubMed: 37541199
DOI: 10.1016/j.cell.2023.07.004 -
Cell Feb 2020We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This...
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 of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.
Topics: Acetylation; Animals; Antigens, Neoplasm; Carcinoma; Endometrial Neoplasms; Epithelial-Mesenchymal Transition; Feedback, Physiological; Female; Gene Expression Regulation, Neoplastic; Genomic Instability; Humans; Mice; MicroRNAs; Microsatellite Repeats; Phosphorylation; Protein Processing, Post-Translational; Proteome; Signal Transduction; Transcriptome
PubMed: 32059776
DOI: 10.1016/j.cell.2020.01.026 -
Cancer Cell Aug 2023The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics... (Review)
Review
The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics datasets connecting genomic aberrations to cancer phenotypes. To facilitate pan-cancer investigations, we have generated harmonized genomic, transcriptomic, proteomic, and clinical data for >1000 tumors in 10 cohorts to create a cohesive and powerful dataset for scientific discovery. We outline efforts by the CPTAC pan-cancer working group in data harmonization, data dissemination, and computational resources for aiding biological discoveries. We also discuss challenges for multi-omics data integration and analysis, specifically the unique challenges of working with both nucleotide sequencing and mass spectrometry proteomics data.
Topics: Humans; Proteogenomics; Proteomics; Genomics; Neoplasms; Gene Expression Profiling
PubMed: 37582339
DOI: 10.1016/j.ccell.2023.06.009 -
Cancer Cell Mar 2022Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis. We report a comprehensive proteogenomic analysis of bone marrow biopsies from 252...
Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis. We report a comprehensive proteogenomic analysis of bone marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative proteomics, our analysis includes cytogenetic profiling and DNA/RNA sequencing. We identify five proteomic AML subtypes, each reflecting specific biological features spanning genomic boundaries. Two of these proteomic subtypes correlate with patient outcome, but none is exclusively associated with specific genomic aberrations. Remarkably, one subtype (Mito-AML), which is captured only in the proteome, is characterized by high expression of mitochondrial proteins and confers poor outcome, with reduced remission rate and shorter overall survival on treatment with intensive induction chemotherapy. Functional analyses reveal that Mito-AML is metabolically wired toward stronger complex I-dependent respiration and is more responsive to treatment with the BCL2 inhibitor venetoclax.
Topics: Humans; Leukemia, Myeloid, Acute; Proteogenomics; Proteomics
PubMed: 35245447
DOI: 10.1016/j.ccell.2022.02.006 -
Cancer Cell Mar 2024The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative...
The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention.
Topics: Animals; Humans; Glioblastoma; Proteogenomics; Proto-Oncogene Proteins B-raf; Proteomics; Cell Line, Tumor; Neoplasm Recurrence, Local; Disease Models, Animal; Brain Neoplasms; Drug Resistance, Neoplasm; Xenograft Model Antitumor Assays
PubMed: 38215747
DOI: 10.1016/j.ccell.2023.12.015 -
Cell Feb 2024Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%-20% cancer cases have demonstrated durable responses from immune...
Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%-20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data, we studied kinase activities in different immune subtypes, which revealed potential subtype-specific therapeutic targets. Insights from this work will facilitate the development of future immunotherapy strategies and enhance precision targeting with existing agents.
Topics: Humans; Combined Modality Therapy; Genomics; Neoplasms; Proteogenomics; Proteomics; Tumor Escape
PubMed: 38359819
DOI: 10.1016/j.cell.2024.01.027 -
Cancer Cell Sep 2023We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted...
We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.
Topics: Female; Humans; Proto-Oncogene Proteins c-akt; Prospective Studies; Proteogenomics; Endometrial Neoplasms; beta Catenin; Metformin
PubMed: 37567170
DOI: 10.1016/j.ccell.2023.07.007