Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 36
Filtrar
1.
Cancer Discov ; 10(4): 568-587, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32086311

RESUMO

Disease recurrence causes significant mortality in B-progenitor acute lymphoblastic leukemia (B-ALL). Genomic analysis of matched diagnosis and relapse samples shows relapse often arising from minor diagnosis subclones. However, why therapy eradicates some subclones while others survive and progress to relapse remains obscure. Elucidation of mechanisms underlying these differing fates requires functional analysis of isolated subclones. Here, large-scale limiting dilution xenografting of diagnosis and relapse samples, combined with targeted sequencing, identified and isolated minor diagnosis subclones that initiate an evolutionary trajectory toward relapse [termed diagnosis Relapse Initiating clones (dRI)]. Compared with other diagnosis subclones, dRIs were drug-tolerant with distinct engraftment and metabolic properties. Transcriptionally, dRIs displayed enrichment for chromatin remodeling, mitochondrial metabolism, proteostasis programs, and an increase in stemness pathways. The isolation and characterization of dRI subclones reveals new avenues for eradicating dRI cells by targeting their distinct metabolic and transcriptional pathways before further evolution renders them fully therapy-resistant. SIGNIFICANCE: Isolation and characterization of subclones from diagnosis samples of patients with B-ALL who relapsed showed that relapse-fated subclones had increased drug tolerance and distinct metabolic and survival transcriptional programs compared with other diagnosis subclones. This study provides strategies to identify and target clinically relevant subclones before further evolution toward relapse.

2.
Clin Cancer Res ; 25(14): 4493-4503, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31015346

RESUMO

PURPOSE: OBI-3424 is a highly selective prodrug that is converted by aldo-keto reductase family 1 member C3 (AKR1C3) to a potent DNA-alkylating agent. OBI-3424 has entered clinical testing for hepatocellular carcinoma and castrate-resistant prostate cancer, and it represents a potentially novel treatment for acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: We assessed AKR1C3 expression by RNA-Seq and immunoblotting, and evaluated the in vitro cytotoxicity of OBI-3424. We investigated the pharmacokinetics of OBI-3424 in mice and nonhuman primates, and assessed the in vivo efficacy of OBI-3424 against a large panel of patient-derived xenografts (PDX). RESULTS: AKR1C3 mRNA expression was significantly higher in primary T-lineage ALL (T-ALL; n = 264) than B-lineage ALL (B-ALL; n = 1,740; P < 0.0001), and OBI-3424 exerted potent cytotoxicity against T-ALL cell lines and PDXs. In vivo, OBI-3424 significantly prolonged the event-free survival (EFS) of nine of nine ALL PDXs by 17.1-77.8 days (treated/control values 2.5-14.0), and disease regression was observed in eight of nine PDXs. A significant reduction (P < 0.0001) in bone marrow infiltration at day 28 was observed in four of six evaluable T-ALL PDXs. The importance of AKR1C3 in the in vivo response to OBI-3424 was verified using a B-ALL PDX that had been lentivirally transduced to stably overexpress AKR1C3. OBI-3424 combined with nelarabine resulted in prolongation of mouse EFS compared with each single agent alone in two T-ALL PDXs. CONCLUSIONS: OBI-3424 exerted profound in vivo efficacy against T-ALL PDXs derived predominantly from aggressive and fatal disease, and therefore may represent a novel treatment for aggressive and chemoresistant T-ALL in an AKR1C3 biomarker-driven clinical trial.

3.
Nat Genet ; 51(2): 296-307, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643249

RESUMO

Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations); a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.


Assuntos
Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Doença Aguda , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Cromossomos/genética , Feminino , Rearranjo Gênico/genética , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação/genética , Transcriptoma/genética , Adulto Jovem
4.
Bioinformatics ; 35(1): 126-129, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561549

RESUMO

Motivation: Single nucleotide polymorphism (SNP) array is the most widely used platform to assess somatic copy number variations (CNVs) in cancer studies. Many SNP data-based CNV callers are available, however, the false positive rates from automated calling are commonly high, and reported breakpoints can be inaccurate. Manual review for each reported CNV by visualizing the SNP data is important, but is challenging for users lacking computational experience. To address this, we present a Shiny/R application ShinyCNV, an interactive graphical user interface to view and annotate CNVs. Results: With this application, normalized SNP data, which includes log R ratio (LRR) and B allele frequency, can be plotted against the reported CNVs, and users can visually check the reliability of CNVs per se or adjust the incorrectly assigned breakpoints. Further, the interactive LRR spectrum panel within ShinyCNV can facilitate the process to identify commonly affected CNV regions from a group of samples, and to visually check if important focal gains/losses are missing from reported CNVs. ShinyCNV is designed to be intuitive for cancer researchers and can be easily installed for either personal use or deployed on servers to provide online service. Availability and implementation: ShinyCNV and the tutorial are freely available from https://github.com/gzhmat/ShinyCNV. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Variações do Número de Cópias de DNA , Anotação de Sequência Molecular/métodos , Neoplasias/genética , Software , Algoritmos , Biologia Computacional , Humanos , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes
5.
Nature ; 562(7727): 373-379, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30209392

RESUMO

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.


Assuntos
Leucemia Aguda Bifenotípica/genética , Leucemia Aguda Bifenotípica/patologia , Linhagem da Célula/genética , Análise Mutacional de DNA , Feminino , Variação Genética/genética , Genoma Humano/genética , Genômica , Humanos , Imunofenotipagem , Leucemia Aguda Bifenotípica/classificação , Masculino , Modelos Genéticos , Mutação/genética , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Transativadores/genética
6.
Blood ; 132(8): 815-824, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-29997224

RESUMO

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; BCR-ABL1-like ALL) in children with National Cancer Institute (NCI) intermediate- or high-risk (HR) ALL is associated with poor outcome. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor and kinase signaling and may be amenable to treatment with tyrosine kinase inhibitors. The prevalence, outcome, and potential for targeted therapy of Ph-like ALL in standard-risk (SR) ALL is less clear. We retrospectively analyzed a cohort of 1023 SR childhood B-ALL consecutively enrolled in the Children's Oncology Group AALL0331 clinical trial. The Ph-like ALL gene expression profile was identified in 206 patients, and 67 patients with either BCR-ABL1 (n = 6) or ETV6-RUNX1 (n = 61) were excluded from downstream analysis, leaving 139 of 1023 (13.6%) as Ph-like. Targeted reverse transcription polymerase chain reaction assays and RNA-sequencing identified kinase-activating alterations in 38.8% of SR Ph-like cases, including CRLF2 rearrangements (29.5% of Ph-like), ABL-class fusions (1.4%), JAK2 fusions (1.4%), an NTRK3 fusion (0.7%), and other sequence mutations (IL7R, KRAS, NRAS; 5.6%). Patients with Ph-like ALL had inferior 7-year event-free survival compared with non-Ph-like ALL (82.4 ± 3.6% vs 90.7 ± 1.0%, P = .0022), with no difference in overall survival (93.2 ± 2.4% vs 95.8 ± 0.7%, P = .14). These findings illustrate the significant differences in the spectrum of kinase alterations and clinical outcome of Ph-like ALL based on presenting clinical features and establish that genomic alterations potentially targetable with approved kinase inhibitors are less frequent in SR than in HR ALL.


Assuntos
Proteínas de Neoplasias/genética , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , National Cancer Institute (U.S.) , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Estados Unidos
7.
Haematologica ; 103(9): e427-e431, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29773603
8.
Cancer Cell ; 33(5): 937-948.e8, 2018 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-29681510

RESUMO

Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL.


Assuntos
Mutação em Linhagem Germinativa , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Animais , Criança , Feminino , Mutação da Fase de Leitura , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Linhagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Análise de Sequência de DNA
9.
Blood ; 129(25): 3352-3361, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28408464

RESUMO

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of BCR-ABL1 (n = 46) or ETV6-RUNX1 (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of CRLF2 (IGH-CRLF2 or P2RY8-CRLF2) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (JAK1, JAK2, IL7R) identified in 63 patients (50.8% of those with CRLF2 rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (ABL1, ABL2, CSF1R, and PDGFRB) in 14.1%, EPOR rearrangements or JAK2 fusions in 8.8%, alterations activating other JAK-STAT signaling genes (IL7R, SH2B3, JAK1) in 6.3% or other kinases (FLT3, NTRK3, LYN) in 4.6%, and mutations involving the Ras pathway (KRAS, NRAS, NF1, PTPN11) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL trials.


Assuntos
Fusão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Quinases/genética , Criança , Feminino , Proteínas de Fusão bcr-abl/genética , Regulação Leucêmica da Expressão Gênica , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Janus Quinase 2/genética , Masculino , Mutação , Cromossomo Filadélfia , Receptores de Citocinas/genética , Estudos Retrospectivos , Transcriptoma
10.
Int J Cancer ; 140(1): 103-108, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27646734

RESUMO

Intratumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The recognition of ITH helps identify high-risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12-paired normal-tumor tissues were subjected to whole-genome/whole-exome sequencing. From these, 367 non-silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non-mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. In addition, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Mutação , Análise de Sequência de DNA/métodos , Proteína Supressora de Tumor p53/genética , Progressão da Doença , Evolução Molecular , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Perda de Heterozigosidade , Filogenia
11.
J Clin Oncol ; 35(4): 394-401, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27870571

RESUMO

Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Prognóstico , Resultado do Tratamento , Adulto Jovem
12.
Blood Adv ; 1(20): 1657-1671, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-29296813

RESUMO

New therapies for Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) patients are urgently needed. The genetic landscape of Ph-like ALL is characterized by a diverse array of kinase-activating alterations (including rearrangements, sequence mutations, and copy number alterations), suggesting that patients with Ph-like ALL are candidates for targeted therapy, similar to BCR-ABL1 ALL. We sought to investigate the functional role and targetability of the spectrum of kinase-activating alterations identified in Ph-like ALL. We demonstrate cytokine-independent growth and activation of JAK-STAT signaling pathways in Ba/F3 cells by all alterations tested. The development of murine Arf-/- pre-B ALL expressing RCSD1-ABL2 or SSBP2-CSF1R was accelerated with the presence of IK6, a dominant negative isoform of Ikaros common in Ph-like ALL, providing evidence that these fusions are leukemogenic. In vitro screening using a panel of tyrosine kinase inhibitors against 14 different kinase alterations identified the ABL1-inhibitor, dasatinib, as a potent inhibitor of ABL-class fusions (ABL1, ABL2, CSF1R, PDGFRB), whereas the JAK1/JAK2 inhibitor ruxolitinib, was most effective against JAK-STAT-activating alterations (JAK1, JAK2, JAK3, IL7R, IL2RB), but not TYK2. Evaluation of dasatinib or ruxolitinib against patient-derived xenograft models demonstrated superior antileukemic efficacy when combined with dexamethasone compared with either agent alone. These data provide the foundation for rationally designed clinical trials that assess the efficacy of targeted therapy in patients with Ph-like ALL.

13.
Nat Commun ; 7: 13331, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27824051

RESUMO

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.


Assuntos
Genômica/métodos , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Sequência de Bases , Regulação Leucêmica da Expressão Gênica , Rearranjo Gênico/genética , Inibidores de Histona Desacetilases/farmacologia , Humanos , Luciferases/metabolismo , Fatores de Transcrição MEF2/genética , Camundongos , Células NIH 3T3 , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Análise de Sequência de RNA , Transcriptoma , Resultado do Tratamento
14.
Cancer Cell ; 29(2): 186-200, 2016 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-26859458

RESUMO

Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues. This resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation. Expression of truncated EPOR in mouse B cell progenitors induced ALL in vivo. Human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition, suggesting a therapeutic option in high-risk ALL.


Assuntos
Ordem dos Genes , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores da Eritropoetina/genética , Sequência de Aminoácidos , Antineoplásicos/uso terapêutico , Sequência de Bases , Humanos , Dados de Sequência Molecular , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
15.
EBioMedicine ; 2(6): 563-71, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26285909

RESUMO

BACKGROUND: Acute promyelocytic leukemia (APL) is a model for synergistic target cancer therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which yields a very high 5-year overall survival (OS) rate of 85 to 90%. Nevertheless, about 15% of APL patients still get early death or relapse. We performed this study to address the possible impact of additional gene mutations on the outcome of APL. METHODS: We included a consecutive series of 266 cases as training group, and then validated the results in a testing group of 269 patients to investigate the potential prognostic gene mutations, including FLT3-ITD or -TKD, N-RAS, C-KIT, NPM1, CEPBA, WT1, ASXL1, DNMT3A, MLL (fusions and PTD), IDH1, IDH2 and TET2. RESULTS: More high-risk patients (50.4%) carried additional mutations, as compared with intermediate- and low-risk ones. The mutations of epigenetic modifier genes were associated with poor prognosis in terms of disease-free survival in both training (HR = 6.761, 95% CI 2.179-20.984; P = 0.001) and validation (HR = 4.026, 95% CI 1.089-14.878; P = 0.037) groups. Sanz risk stratification was associated with CR induction and OS. CONCLUSION: In an era of ATRA/ATO treatment, both molecular markers and clinical parameter based stratification systems should be used as prognostic factors for APL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arsenicais/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Óxidos/uso terapêutico , Tretinoína/uso terapêutico , Adolescente , Adulto , Idoso , Trióxido de Arsênio , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Intervalo Livre de Doença , Epigênese Genética/genética , Feminino , Genes Modificadores/genética , Humanos , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Resultado do Tratamento , Adulto Jovem
16.
EBioMedicine ; 2(6): 583-90, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26288819

RESUMO

Air pollution has been classified as Group 1 carcinogenic to humans, but the underlying tumorigenesis remains unclear. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China attributed to severe air pollution generated by combustion of smoky coal, providing a unique opportunity to dissect lung carcinogenesis of air pollution. Here we analyzed the somatic mutations of 164 non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used. Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the frequent C:G â†’ A:T nucleotide substitutions in Xuanwei NSCLCs. Exome sequencing of 2010 genes showed that Xuanwei and CR NSCLCs had a mean of 68 and 22 mutated genes per tumor, respectively (p < 0.0001). We found 167 genes (including TP53, RYR2, KRAS, CACNA1E) which had significantly higher mutation frequencies in Xuanwei than CR patients, and mutations in most genes in Xuanwei NSCLCs differed from those in CR cases. The mutation rates of 70 genes (e.g., RYR2, MYH3, GPR144, CACNA1E) were associated with patients' lifetime benzo(a)pyrene exposure. This study uncovers the mutation spectrum of air pollution-related lung cancers, and provides evidence for pollution exposure-genomic mutation relationship at a large scale.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Benzo(a)pireno/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Idoso , Sequência de Bases , Carcinoma Pulmonar de Células não Pequenas/induzido quimicamente , Transformação Celular Neoplásica , Carvão Mineral/efeitos adversos , Exposição Ambiental/efeitos adversos , Feminino , Frequência do Gene/genética , Genoma/genética , Humanos , Neoplasias Pulmonares/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Mutação/genética , Taxa de Mutação , Análise de Sequência de DNA , Fumaça/efeitos adversos
17.
Nat Genet ; 47(9): 1061-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26192917

RESUMO

Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56(+) and cytoCD3(+) lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.


Assuntos
RNA Helicases DEAD-box/genética , Exoma , Linfoma de Células T/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Ciclo Celular , Análise Mutacional de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células T/mortalidade , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Prognóstico , Transdução de Sinais , Dissomia Uniparental/genética , Adulto Jovem
18.
Neural Regen Res ; 9(14): 1402-8, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25221599

RESUMO

Although cholecystokinin octapeptide-8 is important for neurological function, its neuroprotective properties remain unclear. We speculated that cholecystokinin octapeptide-8 can protect human retinal pigment epithelial cells against oxidative injury. In this study, retinal pigment epithelial cells were treated with peroxynitrite to induce oxidative stress. Peroxynitrite triggered apoptosis in these cells, and increased the expression of Fas-associated death domain, Bax, caspa-se-8 and Bcl-2. These changes were suppressed by treatment with cholecystokinin octapeptide-8. These results suggest that cholecystokinin octapeptide-8 can protect human retinal pigment epithelial cells against apoptosis induced by peroxynitrite.

19.
Proc Natl Acad Sci U S A ; 111(23): 8589-94, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24850867

RESUMO

Myelodysplastic syndrome (MDS) includes a group of diseases characterized by dysplasia of bone marrow myeloid lineages with ineffective hematopoiesis and frequent evolution to acute myeloid leukemia (AML). Whole-genome sequencing was performed in CD34(+) hematopoietic stem/progenitor cells (HSPCs) from eight cases of refractory anemia with excess blasts (RAEB), the high-risk subtype of MDS. The nucleotide substitution patterns were found similar to those reported in AML, and mutations of 96 protein-coding genes were identified. Clonal architecture analysis revealed the presence of subclones in six of eight cases, whereas mutation detection of CD34(+) versus CD34(-) cells revealed heterogeneity of HSPC expansion status. With 39 marker genes belonging to eight functional categories, mutations were analyzed in 196 MDS cases including mostly RAEB (n = 89) and refractory cytopenia with multilineage dysplasia (RCMD) (n = 95). At least one gene mutation was detected in 91.0% of RAEB, contrary to that in RCMD (55.8%), suggesting a higher mutational burden in the former group. Gene abnormality patterns differed between MDS and AML, with mutations of activated signaling molecules and NPM1 being rare, whereas those of spliceosome more common, in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression free survival.


Assuntos
Genoma Humano/genética , Genômica/métodos , Células-Tronco Hematopoéticas/metabolismo , Mutação , Síndromes Mielodisplásicas/genética , Antígenos CD34/metabolismo , Biomarcadores Tumorais/genética , Diferenciação Celular/genética , Proliferação de Células , Evolução Clonal , Feminino , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/diagnóstico , Prognóstico , Análise de Sequência de DNA/métodos
20.
Hum Mol Genet ; 23(20): 5505-17, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24852370

RESUMO

Thyroid-stimulating hormone (TSH) is a sensitive indicator of thyroid function. High and low TSH levels reflect hypothyroidism and hyperthyroidism, respectively. Even within the normal range, small differences in TSH levels, on the order of 0.5-1.0 mU/l, are associated with significant differences in blood pressure, BMI, dyslipidemia, risk of atrial fibrillation and atherosclerosis. Most of the variance in TSH levels is thought to be genetically influenced. We conducted a genome-wide association study of TSH levels in 1346 Chinese Han individuals. In the replication study, we genotyped four candidate SNPs with the top association signals in an independent isolated Chinese She cohort (n = 3235). We identified a novel serum TSH susceptibility locus within XKR4 at 8q12.1 (rs2622590, Pcombined = 2.21 × 10(-10)), and we confirmed two previously reported TSH susceptibility loci near FOXE1 at 9q22.33 and near CAPZB at 1p36.13, respectively. The rs2622590_T allele at XKR4 and the rs925489_C allele near FOXE1 were correlated with low TSH levels and were found to be nominally associated to patients with papillary thyroid carcinoma (PTC) (OR = 1.41, P= 0.014 for rs2622590_T, and OR = 1.61, P= 0.030 for rs925489_C). The rs2622590 and rs925489 genotypes were also correlated with the expression levels of FOXE1 and XKR4, respectively, in PTC tissues (P = 2.41 × 10(-4) and P= 0.02). Our findings suggest that the SNPs in XKR4 and near FOXE1 are involved in the regulation of TSH levels.


Assuntos
Carcinoma/genética , Fatores de Transcrição Forkhead/genética , Hipotireoidismo/genética , Proteínas de Membrana Transportadoras/genética , Neoplasias da Glândula Tireoide/genética , Tireotropina/sangue , Grupo com Ancestrais do Continente Asiático/genética , Proteína de Capeamento de Actina CapZ/genética , Carcinoma Papilar , China , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 9/genética , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Câncer Papilífero da Tireoide , Tireotropina/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA