RESUMO
Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene1,2. However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together oncogenic MMs are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations.
Assuntos
Carcinogênese/genética , Mutação/genética , Neoplasias/genética , Oncogenes/genética , Animais , Viés , Linhagem da Célula , Classe I de Fosfatidilinositol 3-Quinases/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Feminino , Humanos , Camundongos , Neoplasias/patologia , Seleção GenéticaRESUMO
We present our novel software, nanomonsv, for detecting somatic structural variations (SVs) using tumor and matched control long-read sequencing data with a single-base resolution. The current version of nanomonsv includes two detection modules, Canonical SV module, and Single breakend SV module. Using tumor/control paired long-read sequencing data from three cancer and their matched lymphoblastoid lines, we demonstrate that Canonical SV module can identify somatic SVs that can be captured by short-read technologies with higher precision and recall than existing methods. In addition, we have developed a workflow to classify mobile element insertions while elucidating their in-depth properties, such as 5' truncations, internal inversions, as well as source sites for 3' transductions. Furthermore, Single breakend SV module enables the detection of complex SVs that can only be identified by long-reads, such as SVs involving highly-repetitive centromeric sequences, and LINE1- and virus-mediated rearrangements. In summary, our approaches applied to cancer long-read sequencing data can reveal various features of somatic SVs and will lead to a better understanding of mutational processes and functional consequences of somatic SVs.
Assuntos
Variação Estrutural do Genoma , Neoplasias , Software , Humanos , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Neoplasias/genética , Análise de Sequência de DNA/métodosRESUMO
Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform-specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3'-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell-like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.
Assuntos
Ataxina-1/genética , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Leucemia-Linfoma de Células T do Adulto/patologia , Mutação , Proteínas Proto-Oncogênicas c-rel/genética , Proteínas Repressoras/genética , Animais , Variações do Número de Cópias de DNA , Feminino , Genoma Humano , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Camundongos , Camundongos Endogâmicos C57BL , Prognóstico , Taxa de Sobrevida , Sequenciamento do ExomaRESUMO
Neutrophils play an essential role in innate immune responses to bacterial and fungal infections, and loss of neutrophil function can increase the risk of acquiring lethal infections in clinical settings. Here, we show that engineered neutrophil-primed progenitors derived from human induced pluripotent stem cells can produce functional neutrophil-like cells at a clinically applicable scale that can act rapidly in vivo against lethal bacterial infections. Using 5 different mouse models, we systematically demonstrated that these neutrophil-like cells migrate to sites of inflammation and infection and increase survival against bacterial infection. In addition, we found that these human neutrophil-like cells can recruit murine immune cells. This system potentially provides a straight-forward solution for patients with neutrophil deficiency: an off-the-shelf neutrophil transfusion. This platform should facilitate the administration of human neutrophils for a broad spectrum of physiological and pathological conditions.
Assuntos
Infecções Bacterianas/terapia , Células-Tronco Pluripotentes Induzidas/citologia , Neutrófilos/transplante , Animais , Infecções Bacterianas/imunologia , Técnicas de Cultura de Células , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Humanos , Imunidade Inata , Células-Tronco Pluripotentes Induzidas/imunologia , Inflamação/imunologia , Inflamação/terapia , Camundongos Endogâmicos BALB C , Neutrófilos/citologia , Neutrófilos/imunologiaRESUMO
The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and highrisk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (-4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (-2), and GATA3 (-3).
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma de Células T do Adulto , Linfoma , Adulto , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/terapia , Prognóstico , Receptores CCR7 , Estudos RetrospectivosRESUMO
Identification of genetic alterations through next-generation sequencing (NGS) can guide treatment decision-making by providing information on diagnosis, therapy selection, and prognostic stratification in patients with hematological malignancies. Although the utility of NGS-based genomic profiling assays was investigated in hematological malignancies, no assays sufficiently cover driver mutations, including recently discovered ones, as well as fusions and/or pathogenic germline variants. To address these issues, here we have devised an integrated DNA/RNA profiling assay to detect various types of somatic alterations and germline variants at once. Particularly, our assay can successfully identify copy number alterations and structural variations, including immunoglobulin heavy chain translocations, IKZF1 intragenic deletions, and rare fusions. Using this assay, we conducted a prospective study to investigate the feasibility and clinical usefulness of comprehensive genomic profiling for 452 recurrently altered genes in hematological malignancies. In total, 176 patients (with 188 specimens) were analyzed, in which at least one alteration was detected in 171 (97%) patients, with a median number of total alterations of 7 (0-55). Among them, 145 (82%), 86 (49%), and 102 (58%) patients harbored at least one clinically relevant alteration for diagnosis, treatment, and prognosis, respectively. The proportion of patients with clinically relevant alterations was the highest in acute myeloid leukemia, whereas this assay was less informative in T/natural killer-cell lymphoma. These results suggest the clinical utility of NGS-based genomic profiling, particularly for their diagnosis and prognostic prediction, thereby highlighting the promise of precision medicine in hematological malignancies.
Assuntos
Neoplasias Hematológicas , Sequenciamento de Nucleotídeos em Larga Escala , Estudos de Viabilidade , Genômica/métodos , Neoplasias Hematológicas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Estudos ProspectivosRESUMO
Recent studies of the cancer genome have identified numerous patients harboring multiple mutations (MM) within individual oncogenes. These MM (de novo MM) in cis synergistically activate the mutated oncogene and promote tumorigenesis, indicating a positive epistatic interaction between mutations. The relatively frequent de novo MM suggest that intramolecular positive epistasis is widespread in oncogenes. Studies also suggest that negative and higher-order epistasis affects de novo MM. Comparison of de novo MM and MM associated with drug-resistant secondary mutations (secondary MM) revealed several similarities with respect to allelic configuration, mutational selection and functionality of individual mutations. Conversely, they have several differences, most notably the difference in drug sensitivities. Secondary MM usually confer resistance to molecularly targeted therapies, whereas several de novo MM are associated with increased sensitivity, implying that both can be useful as therapeutic biomarkers. Unlike secondary MM in which specific secondary resistant mutations are selected, minor (infrequent) functionally weak mutations are convergently selected in de novo MM, which may provide an explanation as to why such mutations accumulate in cancer. The third type of MM is MM from different subclones. This type of MM is associated with parallel evolution, which may contribute to relapse and treatment failure. Collectively, MM within individual oncogenes are diverse, but all types of MM are associated with cancer evolution and therapeutic response. Further evaluation of oncogenic MM is warranted to gain a deeper understanding of cancer genetics and evolution.
Assuntos
Neoplasias/genética , Oncogenes/genética , Carcinogênese/genética , Humanos , MutaçãoRESUMO
Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a novel therapeutic target of Evi1 by analyzing transcriptomic, epigenetic, and metabolomic profiling of mouse high Evi1 leukemia cells. We revealed that Evi1 overexpression and Evi1-driven leukemic transformation upregulate transcription of gluconeogenesis enzyme Fbp1 and other pentose phosphate enzymes with interaction between Evi1 and the enhancer region of these genes. Metabolome analysis using Evi1-overexpressing leukemia cells uncovered pentose phosphate pathway upregulation by Evi1 overexpression. Suppression of Fbp1 as well as pentose phosphate pathway enzymes by shRNA-mediated knockdown selectively decreased Evi1-driven leukemogenesis in vitro. Moreover, pharmacological or shRNA-mediated Fbp1 inhibition in secondarily transplanted Evi1-overexpressing leukemia mouse significantly decreased leukemia cell burden. Collectively, targeting FBP1 is a promising therapeutic strategy of high Evi1 AML.
Assuntos
Frutose-Bifosfatase/metabolismo , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Via de Pentose Fosfato , Animais , Modelos Animais de Doenças , Progressão da Doença , Elementos Facilitadores Genéticos , Epigênese Genética , Frutose-Bifosfatase/antagonistas & inibidores , Frutose-Bifosfatase/genética , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/patologia , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Via de Pentose Fosfato/genética , RNA Interferente Pequeno , Ensaio Tumoral de Célula-Tronco , Regulação para CimaRESUMO
BACKGROUND: The occurrence of a mediastinal germ cell tumor (GCT) and hematological malignancy in the same patient is very rare. Due to its rarity, there have been only two reports of the concurrent cases undergoing detailed genetic analysis with whole-exome sequencing (WES), and the possible clonal relationship between the both tumors remained not fully elucidated. METHODS: We performed whole-exome sequencing analysis of mediastinal GCT and acute myeloid leukemia (AML) samples obtained from one young Japanese male adult patient with concurrent both tumors, and investigated the possible clonal relationship between them. RESULTS: Sixteen somatic mutations were detected in the mediastinal GCT sample and 18 somatic mutations in the AML sample. Mutations in nine genes, including TP53 and PTEN both known as tumor suppressor genes, were shared in both tumors. CONCLUSIONS: All in our case and in the previous two cases with concurrent mediastinal GCT and AML undergoing with whole-exome sequencing analysis, TP53 and PTEN mutations were commonly shared in both tumors. These data not only suggest that these tumors share a common founding clone, but also indicate that associated mediastinal GCT and AML harboring TP53 and PTEN mutations represent a unique biological entity.
Assuntos
Leucemia Megacarioblástica Aguda/genética , Neoplasias Embrionárias de Células Germinativas/genética , PTEN Fosfo-Hidrolase/genética , Proteína Supressora de Tumor p53/genética , Adulto , Biópsia , Medula Óssea/patologia , Evolução Clonal/genética , Análise Citogenética , Humanos , Hibridização in Situ Fluorescente , Japão , Leucemia Megacarioblástica Aguda/diagnóstico , Masculino , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Radiografia Torácica , Tomografia Computadorizada por Raios X , Sequenciamento do ExomaRESUMO
Despite advances in the treatment of acute myeloid leukemia (AML), relapse and drug resistance frequently occur. Therefore, detailed mechanisms of refractoriness, including leukemia-initiating cell (LIC) biology, should be elucidated to treat AML. The self-degradative property of cytosolic macromolecules is central to autophagy and can contribute to homeostasis and stress response. Recent reports suggest the importance of autophagy in hematopoietic stem cells and various tumors. Thus, this study investigated the functional role of autophagy in AML maintenance and drug resistance using tamoxifen-inducible conditional knockout mice of Atg5 or Atg7, which are essential genes for autophagy, combined with an mixed lineage leukemia-eleven nineteen leukemia-induced murine AML model. Inactivation of autophagy by deletion of Atg5 or Atg7 prolonged survival in leukemic mice and reduced functional LICs. Atg7-deficient LICs displayed enhanced mitochondrial activity and reactive oxygen species production together with increased cell death. In addition, Atg7 deletion markedly decreased peripheral blood leukemia cells, concurrent with increased apoptosis, suggesting a higher dependency on autophagy compared with bone marrow leukemia cells. Finally, cytarabine (AraC) treatment activated autophagy in LICs, and Atg7 deletion potentiated the therapeutic effects of AraC, which included decreased LICs and prolonged survival, suggesting that autophagy contributes to AraC resistance. Our results highlight the intratumoral heterogeneity related to autophagy in AML and the unique role of autophagy in leukemia development and drug resistance.
Assuntos
Autofagia/efeitos dos fármacos , Citarabina/farmacologia , Leucemia Experimental/patologia , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/patologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/fisiologia , Leucemia Experimental/tratamento farmacológico , Leucemia Experimental/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Atypical Myeloproliferative Neoplasms (aMPN) share characteristics of MPN and Myelodysplastic Syndromes. Although abnormalities in cytokine signaling are common in MPN, the pathophysiology of atypical MPN still remains elusive. Since deregulation of microRNAs is involved in the biology of various cancers, we studied the miRNome of aMPN patients. METHODS: MiRNome and mutations in epigenetic regulator genes ASXL1, TET2, DNMT3A, EZH2 and IDH1/2 were explored in aMPN patients. Epigenetic regulation of miR-10a and HOXB4 expression was investigated by treating hematopoietic cell lines with 5-aza-2'deoxycytidine, valproic acid and retinoic acid. Functional effects of miR-10a overexpression on cell proliferation, differentiation and self-renewal were studied by transducing CD34+ cells with lentiviral vectors encoding the pri-miR-10a precursor. RESULTS: MiR-10a was identified as the most significantly up-regulated microRNA in aMPN. MiR-10a expression correlated with that of HOXB4, sitting in the same genomic locus. The transcription of these two genes was increased by DNA demethylation and histone acetylation, both necessary for optimal expression induction by retinoic acid. Moreover, miR-10a and HOXB4 overexpression seemed associated with DNMT3A mutation in hematological malignancies. However, overexpression of miR-10a had no effect on proliferation, differentiation or self-renewal of normal hematopoietic progenitors. CONCLUSIONS: MiR-10a and HOXB4 are overexpressed in aMPN. This overexpression seems to be the result of abnormalities in epigenetic regulation mechanisms. Our data suggest that miR-10a could represent a simple marker of transcription at this genomic locus including HOXB4, widely recognized as involved in stem cell expansion.
Assuntos
Expressão Gênica , Proteínas de Homeodomínio/genética , MicroRNAs/genética , Transtornos Mieloproliferativos/genética , Fatores de Transcrição/genética , Animais , Biomarcadores , Estudos de Casos e Controles , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Genótipo , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Reação Leucemoide/genética , Camundongos , Mutação , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Fatores de Transcrição/metabolismoRESUMO
Bloodstream infection with non-Candida albicans Candida species is one of the serious complications among patients with hematological malignancies who receive long-term prophylactic antifungal agents. Here we describe three cases of Candida fermentati (C. fermentati) candidemia after allogeneic stem cell transplantation for hematological malignancies. Case 1 is fluconazole-breakthrough C. fermentati fungemia, which was well controlled with liposomal amphotericin B. Case 2 and 3 were caspofungin-breakthrough C. fermentati fungemia. In case 2, blood culture turned negative for Candida responding to liposomal amphotericin B. Although in vitro susceptibility data for the isolated pathogen suggested the efficacy of both caspofungin and liposomal amphotericin B in all three cases, clinically liposomal amphotericin B seemed to have been more effective for eradication of the pathogen from blood stream. C. fermentati needs to be considered as a possible cause for breakthrough candidemia among post-transplant patients with prolonged antifungal prophylaxis. Discrepancy between in vitro and in vivo susceptibility to antifungals, especially to echinocandins, might provide a clue for the optimal choice of antifungals for C. fermentati infections.
Assuntos
Candida/isolamento & purificação , Candidemia/microbiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transtornos Linfoproliferativos/cirurgia , Idoso , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Candida/classificação , Candida/genética , Candidemia/sangue , Candidemia/tratamento farmacológico , Caspofungina , DNA Ribossômico/genética , Equinocandinas/uso terapêutico , Evolução Fatal , Feminino , Fluconazol/uso terapêutico , Humanos , Lipopeptídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNARESUMO
A current broad spectrum of genomic studies on acute myeloid leukemia (AML) has demonstrated that a gene encoding for DNA methyltransferase, specifically DNA methyltransferase 3 alpha (DNMT3A) is frequently mutated. However, DNMT3A variants are present in elderly healthy individuals and patients with AML in complete remission, which suggests that DNMT3A mutations may contribute to pre-leukemic clonal hematopoiesis. Although DNMT3A mutation has been thought to play a pivotal role in AML pathogenesis through the loss of DNA methylation functionality, other potential disease-related mechanisms are poorly understood. We identified that DNMT3A Arg882 mutation has two distinct mechanisms for developing clonal hematopoiesis and leukemia: (1) DNA methylation-dependent effect, which caused up-regulation of the anterior Hoxb cluster and many hematopoietic stem cell (HSC) -related genes, with hypo-methylation of the promoter-associated CpG island; and (2) DNA methylation-independent effect with enhanced recruitment of polycomb repressive complex 1 (PRC1) that subsequently suppressed the expression of an array of differentiation-associated genes. Through these mechanisms, DNMT3A mutations were shown to inhibit the differentiation of HSCs and leukemic cells. These results identified PRC1 as a promising candidate for the development of therapeutic strategies in mutant DNMT3A-associated AML. Here, we review recent studies on AML with a focus on the clinical features and functional roles of DNMT3A mutations, and discuss future challenges to effectively cure DNMT3A mutation-associated hematopoietic disorders.
Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda , Metilação de DNA , DNA Metiltransferase 3A , Hematopoese , Humanos , Leucemia Mieloide Aguda/genética , MutaçãoRESUMO
Antibiotic-resistant infections remain to be a major issue for all over the world. Although appropriate diagnosis and rapid treatment initiation are crucially important particularly in immunocompromised patients, selection of antibiotics without identification of causative bacteria is often challenging. A 44-year-old woman with acute myeloid leukemia (AML) under myelosuppression suffered from teicoplanin-resistant gram-positive cocci bacteremia. Taking severe neutropenia due to chemotherapy and glycopeptide-resistance into account, teicoplanin was empirically substituted with daptomycin, which led to prompt defervescence. This microorganism later turned out to be Leuconostoc lactis (L. Lactis), and daptmycin was continued to use based on antimicrobial susceptibility tests. As a result, empiric use of daptomycin successfully controlled glycopeptide-resistant gram-positive cocci bacteremia under neutropenia. This is the first report of daptomycin treatment for L. lactis bacteremia in a patient with AML under neutropenia. Our findings suggest that daptomycin would be a suitable treatment option for glycopeptide-resistant gram-positive cocci bloodstream infections, especially in myelosuppressive patients.
Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Enterococcus/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Imunossupressores/efeitos adversos , Leuconostoc/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Antibacterianos/farmacologia , Bacteriemia/sangue , Bacteriemia/microbiologia , Neutropenia Febril Induzida por Quimioterapia/sangue , Neutropenia Febril Induzida por Quimioterapia/microbiologia , Daptomicina/farmacologia , Daptomicina/uso terapêutico , Farmacorresistência Bacteriana , Enterococcus/isolamento & purificação , Enterococcus/patogenicidade , Enterococcus/fisiologia , Feminino , Infecções por Bactérias Gram-Positivas/sangue , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Hospedeiro Imunocomprometido , Leuconostoc/isolamento & purificação , Leuconostoc/patogenicidade , Leuconostoc/fisiologia , Testes de Sensibilidade Microbiana , Teicoplanina/farmacologia , Teicoplanina/uso terapêutico , Vancomicina/uso terapêuticoRESUMO
Using 48,627 samples from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), we present a pan-cancer landscape of driver alterations and their clinical actionability in Japanese patients. Comparison with White patients in Genomics Evidence Neoplasia Information Exchange (GENIE) demonstrates high TP53 mutation frequencies in Asian patients across multiple cancer types. Integration of C-CAT, GENIE, and The Cancer Genome Atlas data reveals many cooccurring and mutually exclusive relationships between driver mutations. At pathway level, mutations in epigenetic regulators frequently cooccur with PI3K pathway molecules. Furthermore, we found significant cooccurring mutations within the epigenetic pathway. Accumulation of mutations in epigenetic regulators causes increased proliferation-related transcriptomic signatures. Loss-of-function of many epigenetic drivers inhibits cell proliferation in their wild-type cell lines, but this effect is attenuated in those harboring mutations of not only the same but also different epigenetic drivers. Our analyses dissect various genetic properties and provide valuable resources for precision medicine in cancer. SIGNIFICANCE: We present a genetic landscape of 26 principal cancer types/subtypes, including Asian-prevalent ones, in Japanese patients. Multicohort data integration unveils numerous cooccurring and exclusive relationships between driver mutations, identifying cooccurrence of multiple mutations in epigenetic regulators, which coordinately cause transcriptional and phenotypic changes. These findings provide insights into epigenetic regulator-driven oncogenesis. This article is featured in Selected Articles from This Issue, p. 695.
Assuntos
Bases de Dados Genéticas , Genômica , Mutação , Neoplasias , Humanos , Neoplasias/genética , Genômica/métodos , Japão , Epigênese Genética , Povo Asiático/genética , População do Leste AsiáticoRESUMO
Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1. Among them, CD274 (24%) was the most frequently altered, followed by TP53 (20%), CDKN2A (19%), ARID1A (15%), HLA-A (15%), BCOR (14%), and MSN (14%). Chromosome X losses were the most common arm-level CNAs in females (â¼40%), and alterations of four X-linked driver genes (MSN, BCOR, DDX3X, and KDM6A) were more frequent in males and females harboring chromosome X losses. Among X-linked drivers, MSN was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines showed that MSN disruption promoted cell proliferation and NF-κB activation. Moreover, MSN inactivation increased sensitivity to NF-κB inhibition in vitro and in vivo. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, nonnegative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognoses irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL. Significance: Integrative genetic analyses and functional studies in extranodal NK/T-cell lymphoma identify frequent disruptions of X-linked drivers, reveal prognostic molecular subgroups, and uncover recurrent MSN alterations that confer sensitivity to NF-κB inhibition.
Assuntos
Cromossomos Humanos X , Linfoma Extranodal de Células T-NK , Humanos , Masculino , Feminino , Cromossomos Humanos X/genética , Linfoma Extranodal de Células T-NK/genética , Linfoma Extranodal de Células T-NK/virologia , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/metabolismo , Variações do Número de Cópias de DNA , Mutação , Pessoa de Meia-Idade , Animais , Adulto , Camundongos , Prognóstico , Idoso , Perfilação da Expressão Gênica , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Adulto Jovem , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicaçõesAssuntos
Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Promielocítica Aguda , Segunda Neoplasia Primária , Humanos , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Cromossomo FiladélfiaAssuntos
Medula Óssea/patologia , Evolução Clonal , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Plasmocitária/patologia , Linfocitose/patologia , Idoso de 80 Anos ou mais , Anemia Hemolítica Autoimune/complicações , Anemia Hemolítica Autoimune/tratamento farmacológico , Antígenos CD/análise , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Células Clonais/química , Células Clonais/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Progressão da Doença , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfocitose/complicações , Melfalan/administração & dosagem , Prednisolona/efeitos adversos , Prednisolona/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/uso terapêuticoRESUMO
Patients with von Hippel-Lindau disease (vHL) are at risk of developing spatially and temporally multiple clear cell renal cell carcinomas (ccRCCs), which offers a valuable opportunity to analyze inter- and intra-tumor heterogeneity of genetic and immune profiles within the same patient. Here, we perform whole-exome and RNA sequencing, digital gene expression, and immunohistochemical analyses for 81 samples from 51 ccRCCs of 10 patients with vHL. Inherited ccRCCs are clonally independent and have less genomic alterations than sporadic ccRCCs. Hierarchical clustering of transcriptome profiles shows two clusters with distinct immune signatures: immune hot and cold clusters. Interestingly, not only samples from the same tumors but also different tumors from the same patients tend to show a similar immune signature, whereas samples from different patients frequently exhibit different signatures. Our findings reveal the genetic and immune landscape of inherited ccRCCs, demonstrating the relevance of host factors in shaping anti-tumor immunity.