RESUMO
Non-clear cell renal cell carcinomas (non-ccRCCs) encompass diverse malignant and benign tumors. Refinement of differential diagnosis biomarkers, markers for early prognosis of aggressive disease, and therapeutic targets to complement immunotherapy are current clinical needs. Multi-omics analyses of 48 non-ccRCCs compared with 103 ccRCCs reveal proteogenomic, phosphorylation, glycosylation, and metabolic aberrations in RCC subtypes. RCCs with high genome instability display overexpression of IGF2BP3 and PYCR1. Integration of single-cell and bulk transcriptome data predicts diverse cell-of-origin and clarifies RCC subtype-specific proteogenomic signatures. Expression of biomarkers MAPRE3, ADGRF5, and GPNMB differentiates renal oncocytoma from chromophobe RCC, and PIGR and SOSTDC1 distinguish papillary RCC from MTSCC. This study expands our knowledge of proteogenomic signatures, biomarkers, and potential therapeutic targets in non-ccRCC.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Neoplasias Renais , Proteogenômica , Humanos , Proteogenômica/métodos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Transcriptoma/genética , Masculino , Feminino , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão GênicaRESUMO
Amyloidosis is a heterogeneous disorder characterized by abnormal protein aggregate deposition that often leads to kidney involvement and end-stage kidney disease. With advancements in diagnostic techniques and treatment options, the prevalence of patients with amyloidosis requiring chronic dialysis has increased. Kidney transplantation is a promising avenue for extending survival and enhancing quality of life in these patients. However, the complex and heterogeneous nature of amyloidosis presents challenges in determining optimal referral timing for transplantation and managing post-transplantation course. This review focuses on recent developments and outcomes of kidney transplantation for amyloidosis-related end-stage kidney disease. This review also aims to guide clinical decision-making and improve management of patients with amyloidosis-associated kidney disease, offering insights into optimizing patient selection and post-transplant care for favorable outcomes.
Assuntos
Amiloidose , Falência Renal Crônica , Transplante de Rim , Humanos , Falência Renal Crônica/cirurgia , Falência Renal Crônica/complicações , Amiloidose/terapia , Seleção de Pacientes , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Amiloidose de Cadeia Leve de Imunoglobulina/complicaçõesRESUMO
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.
Assuntos
Neoplasias , Proteogenômica , Humanos , Proteômica , Genômica , Neoplasias/genética , Perfilação da Expressão GênicaRESUMO
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.
Assuntos
Neoplasias , Proteogenômica , Humanos , Neoplasias/genética , Oncogenes , Transformação Celular Neoplásica/genética , Variações do Número de Cópias de DNARESUMO
Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.
Assuntos
Neoplasias , Processamento de Proteína Pós-Traducional , Proteômica , Humanos , Acetilação , Histonas/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Fosforilação , Proteômica/métodosRESUMO
Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and T cell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK)+ CD8+ effector memory T (TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility.
Assuntos
Mieloma Múltiplo , Mieloma Múltiplo Latente , Humanos , Biomarcadores , Progressão da Doença , Fatores Imunológicos , Imunoterapia , Lenalidomida/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo Latente/terapia , Ensaios Clínicos Fase II como AssuntoRESUMO
Multiple myeloma is a plasma cell malignancy almost always preceded by precursor conditions, but low tumor burden of these early stages has hindered the study of their molecular programs through bulk sequencing technologies. Here, we generate and analyze single cell RNA-sequencing of plasma cells from 26 patients at varying disease stages and 9 healthy donors. In silico dissection and comparison of normal and transformed plasma cells from the same bone marrow biopsy enables discovery of patient-specific transcriptional changes. Using Non-Negative Matrix Factorization, we discover 15 gene expression signatures which represent transcriptional modules relevant to myeloma biology, and identify a signature that is uniformly lost in abnormal cells across disease stages. Finally, we demonstrate that tumors contain heterogeneous subpopulations expressing distinct transcriptional patterns. Our findings characterize transcriptomic alterations present at the earliest stages of myeloma, providing insight into the molecular underpinnings of disease initiation.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Carcinogênese/genética , Carcinogênese/patologia , Transformação Celular Neoplásica/patologia , Plasmócitos/patologia , Medula Óssea/patologiaRESUMO
Lung adenocarcinoma (LUAD) is one of the most common cancer types and has various treatment options. Better biomarkers to predict therapeutic response are needed to guide choice of treatment modality and to improve precision medicine. Here, we used a consensus hierarchical clustering approach on 509 LUAD cases from The Cancer Genome Atlas to identify five robust LUAD expression subtypes. Genomic and proteomic data from patient samples and cell lines was then integrated to help define biomarkers of response to targeted therapies and immunotherapies. This approach defined subtypes with unique proteogenomic and dependency profiles. Subtype 4 (S4)-associated cell lines exhibited specific vulnerability to loss of CDK6 and CDK6-cyclin D3 complex gene (CCND3). Subtype 3 (S3) was characterized by dependency on CDK4, immune-related expression patterns, and altered MET signaling. Experimental validation showed that S3-associated cell lines responded to MET inhibitors, leading to increased expression of programmed death-ligand 1 (PD-L1). In an independent real-world patient dataset, patients with S3 tumors were enriched with responders to immune checkpoint blockade. Genomic features in S3 and S4 were further identified as biomarkers for enabling clinical diagnosis of these subtypes. Overall, our consensus hierarchical clustering approach identified robust tumor expression subtypes, and our subsequent integrative analysis of genomics, proteomics, and CRISPR screening data revealed subtype-specific biology and vulnerabilities. These LUAD expression subtypes and their biomarkers could help identify patients likely to respond to CDK4/6, MET, or PD-L1 inhibitors, potentially improving patient outcome. SIGNIFICANCE: Integrative analysis of multiomic and drug dependency data uncovers robust lung adenocarcinoma expression subtypes with unique therapeutic vulnerabilities and subtype-specific biomarkers of response.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Proteômica , Biomarcadores Tumorais/genética , Mutação , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/patologia , Prognóstico , Perfilação da Expressão GênicaRESUMO
Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.
Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Região Variável de Imunoglobulina/genética , Mutação , Prognóstico , GenômicaRESUMO
Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with significant heterogeneity in disease progression. Existing clinical models of progression risk do not fully capture this heterogeneity. Here we integrate 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clustering and identify six distinct genetic subtypes. These subtypes are differentially associated with established MM-related RNA signatures, oncogenic and immune transcriptional profiles, and evolving clinical biomarkers. Three genetic subtypes are associated with increased risk of progression to active MM in both the primary and validation cohorts, indicating they can be used to better predict high and low-risk patients within the currently used clinical risk stratification models.
Assuntos
Mieloma Múltiplo , Mieloma Múltiplo Latente , Progressão da Doença , Humanos , Mieloma Múltiplo/genética , Fenótipo , Risco , Fatores de Risco , Mieloma Múltiplo Latente/genéticaRESUMO
Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in myelodysplastic syndrome patients. Zbtb33 edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.
Assuntos
Hematopoiese Clonal , Síndromes Mielodisplásicas , Animais , Hematopoese/genética , Células-Tronco Hematopoéticas , Humanos , Camundongos , Síndromes Mielodisplásicas/genética , Splicing de RNA/genética , Fatores de Transcrição/genéticaRESUMO
Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Proteogenômica , Acetilação , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas de Neoplasias/metabolismo , Fosforilação , Ligação Proteica , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , UbiquitinaçãoRESUMO
PURPOSE: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.