RESUMO
Tumor-infiltrating myeloid cells (TIMs) are key regulators in tumor progression, but the similarity and distinction of their fundamental properties across different tumors remain elusive. Here, by performing a pan-cancer analysis of single myeloid cells from 210 patients across 15 human cancer types, we identified distinct features of TIMs across cancer types. Mast cells in nasopharyngeal cancer were found to be associated with better prognosis and exhibited an anti-tumor phenotype with a high ratio of TNF+/VEGFA+ cells. Systematic comparison between cDC1- and cDC2-derived LAMP3+ cDCs revealed their differences in transcription factors and external stimulus. Additionally, pro-angiogenic tumor-associated macrophages (TAMs) were characterized with diverse markers across different cancer types, and the composition of TIMs appeared to be associated with certain features of somatic mutations and gene expressions. Our results provide a systematic view of the highly heterogeneous TIMs and suggest future avenues for rational, targeted immunotherapies.
Assuntos
Células Mieloides/patologia , Neoplasias/genética , Neoplasias/patologia , Análise de Célula Única , Transcrição Gênica , Linhagem Celular Tumoral , Linhagem da Célula , Células Dendríticas/metabolismo , Feminino , Humanos , Proteínas de Membrana Lisossomal/metabolismo , Macrófagos/metabolismo , Masculino , Mastócitos/patologia , Monócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Transcriptoma/genéticaRESUMO
Uncovering the immune response to an inactivated SARS-CoV-2 vaccine (In-Vac) and natural infection is crucial for comprehending COVID-19 immunology. Here we conducted an integrated analysis of single-cell RNA sequencing (scRNA-seq) data from serial peripheral blood mononuclear cell (PBMC) samples derived from 12 individuals receiving In-Vac compared with those from COVID-19 patients. Our study reveals that In-Vac induces subtle immunological changes in PBMC, including cell proportions and transcriptomes, compared with profound changes for natural infection. In-Vac modestly upregulates IFN-α but downregulates NF-κB pathways, while natural infection triggers hyperactive IFN-α and NF-κB pathways. Both In-Vac and natural infection alter T/B cell receptor repertoires, but COVID-19 has more significant change in preferential VJ gene, indicating a vigorous immune response. Our study reveals distinct patterns of cellular communications, including a selective activation of IL-15RA/IL-15 receptor pathway after In-Vac boost, suggesting its potential role in enhancing In-Vac-induced immunity. Collectively, our study illuminates multifaceted immune responses to In-Vac and natural infection, providing insights for optimizing SARS-CoV-2 vaccine efficacy.
Assuntos
COVID-19 , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Leucócitos Mononucleares , NF-kappa B , SARS-CoV-2 , Vacinas de Produtos Inativados , Imunidade , Análise de Sequência de RNA , Anticorpos AntiviraisRESUMO
SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.
Assuntos
Estudo de Associação Genômica Ampla , Glomerulonefrite por IGA , Humanos , Fator A de Crescimento do Endotélio Vascular/genética , Predisposição Genética para Doença , Glomerulonefrite por IGA/genética , Haptoglobinas/genética , Progressão da Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.
Assuntos
Terapia Neoadjuvante , Neoplasias Retais , Humanos , Terapia Neoadjuvante/métodos , Resultado do Tratamento , Capecitabina/uso terapêutico , Neoplasias Retais/patologia , Quimiorradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estadiamento de NeoplasiasRESUMO
Hepatocellular carcinoma (HCC) is frequently characterized by metabolic and immune remodeling in the tumor microenvironment. We previously discovered that liver-specific deletion of fructose-1, 6-bisphosphatase 1 (FBP1), a gluconeogenic enzyme ubiquitously suppressed in HCC tissues, promotes liver tumorigenesis and induces metabolic and immune perturbations closely resembling human HCC. However, the underlying mechanisms remain incompletely understood. Here, we reported that FBP1-deficient livers exhibit diminished amounts of natural killer (NK) cells and accelerated tumorigenesis. Using the diethylnitrosamine-induced HCC mouse model, we analyzed potential changes in the immune cell populations purified from control and FBP1-depleted livers and found that NK cells were strongly suppressed. Mechanistically, FBP1 attenuation in hepatocytes derepresses an zeste homolog 2 (EZH2)-dependent transcriptional program to inhibit PKLR expression. This leads to reduced levels of PKLR cargo proteins sorted into hepatocyte-derived extracellular vesicles (EVs), dampened activity of EV-targeted NK cells, and accelerated liver tumorigenesis. Our study demonstrated that hepatic FBP1 depletion promotes HCC-associated immune remodeling, partly through the transfer of hepatocyte-secreted, PKLR-attenuated EVs to NK cells.
Assuntos
Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Animais , Carcinogênese/genética , Carcinoma Hepatocelular/patologia , Comunicação , Vesículas Extracelulares/metabolismo , Hepatócitos/metabolismo , Células Matadoras Naturais/metabolismo , Neoplasias Hepáticas/metabolismo , Camundongos , Microambiente TumoralRESUMO
AIMS/HYPOTHESIS: The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes. METHODS: A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing. RESULTS: The susceptible DR3 (ß = -0.09, p = 0.0009) and DR4-DQ8 (ß = -0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (ß = 0.21, p = 0.0314) and DR12 (ß = 0.27, p < 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with DR-DQ haplotypes, A*11:01:01 was positively associated with onset age (ß = 0.06, p = 0.0370), while the susceptible C*15:02:01 was negatively associated with onset age (ß = -0.21, p = 0.0050). The unit for ß was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of DR4-DQ4, A*11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years. CONCLUSIONS/INTERPRETATION: In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies.
Assuntos
Diabetes Mellitus Tipo 1 , Idade de Início , Alelos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Genes MHC Classe I , Predisposição Genética para Doença/genética , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Haplótipos/genética , Humanos , Insulina/genéticaRESUMO
BACKGROUND: The aim of this study was to investigate differences in clinical features and HLA genotypes between adult-onset and childhood-onset patients with type 1 diabetes in a Chinese population. MATERIALS AND METHODS: This study enrolled 716 Han Chinese patients with type 1 diabetes from Guangdong (258 childhood-onset and 458 adult-onset) to compare their clinical features. Of them 214 patients with classical type 1 diabetes (100 childhood-onset and 114 adult-onset) were selected for HLA DR and DQ genotyping by next-generation sequencing. RESULTS: Adult-onset patients were characterized by longer duration of symptoms before diagnosis, lower frequency of DKA at disease onset, less frequent autoantibody positivity, higher serum C-peptide concentrations, and better glycemic control. These findings were replicated in the restricted cohort of 214 patients with classical type 1 diabetes. Compared with childhood-onset patients, adult-onset patients had a lower frequency of the DR9 haplotype, as well as lower frequency of high-risk DR3/DR4 and DR3/DR9 genotypes, but higher frequency of DR3/DR3 genotype and DR3/X, DR4/X or DR9/X (X, non-risk) genotypes. CONCLUSIONS: Adult-onset type 1 diabetic patients with susceptible haplotypes (DR3, DR4 or DR9) were more likely to carry protective DR-DQ haplotypes than childhood-onset patients, which suggested the association between less risk DR-DQ genotypes and the less severe clinical manifestation in adult-onset patients.
Assuntos
Diabetes Mellitus Tipo 1 , Antígenos HLA-DQ , Antígenos HLA-DR , Adulto , Idade de Início , Criança , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Genótipo , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Humanos , Gravidade do Paciente , Medição de RiscoRESUMO
Rates of gastroesophageal junction adenocarcinomas (GEJAs) have shown an alarming increase; however, the genetic background of GEJA and its Siewert classification have yet to be uncovered. Here, 60 paired tumor and normal DNA samples from GEJA patients were analyzed by whole-exome sequencing. Among them, 13 were Siewert type I, 14 were type II, and 33 were type III. A predominance of C/G>T/A substitutions was discovered in GEJA, followed by C/G>A/T substitutions. Notably, Siewert type I and type II/III display distinct sets of driver genes, mutational spectrum, and recurrently disrupted pathways. Siewert type I showed similarity to esophageal adenocarcinomas (EACs) and the chromosomal instability subtype of stomach adenocarcinomas, while Siewert type II/III showed similarity to the genomic stable subtype of stomach adenocarcinoma. We also found that mutation of FBXW7, a driver gene of GEJA, was enriched in Siewert type I. Our data identify differences between GEJA and stomach/EACs at the genomic level and provide evidence for differential treatment based on Siewert classification of GEJA. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/genética , Junção Esofagogástrica/patologia , Mutação , Neoplasias Gástricas/genética , Adenocarcinoma/classificação , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Variações do Número de Cópias de DNA , Diagnóstico Diferencial , Neoplasias Esofágicas/classificação , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/classificação , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Sequenciamento do ExomaRESUMO
BACKGROUND: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk. METHODS: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny. RESULTS: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119). CONCLUSIONS: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs. These variants may explain susceptibility differences between Chinese and European populations.
Assuntos
Povo Asiático/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Glomerulonefrite por IGA/genética , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética , Adulto , Estudos de Casos e Controles , China , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Pessoa de Meia-Idade , Proteína-Arginina Desiminase do Tipo 4/genética , Receptores Imunológicos/genéticaRESUMO
BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12â650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20â402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83â×â10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35â×â10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.
Assuntos
Biomarcadores Tumorais/genética , Proliferação de Células , Subunidade beta de Receptor de Interleucina-18/genética , Linfoma Extranodal de Células T-NK/genética , Células T Matadoras Naturais/patologia , Ásia , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Interleucina-18/metabolismo , Subunidade beta de Receptor de Interleucina-18/metabolismo , Desequilíbrio de Ligação , Linfoma Extranodal de Células T-NK/imunologia , Linfoma Extranodal de Células T-NK/metabolismo , Linfoma Extranodal de Células T-NK/patologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Fenótipo , Prognóstico , Locos de Características Quantitativas , Medição de Risco , Fatores de Risco , Transdução de Sinais , TranscriptomaRESUMO
Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of the JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 nonsynonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single-nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in STAT3 and TP53 (15%), followed by JAK3 and JAK1 (6%) and SOCS1 (4%). A high prevalence of STAT3 mutation (21%) was observed specifically in NKTL. Novel STAT3 mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokine, in which p.E616K induced programmed cell death-ligand 1 (PD-L1) expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot STAT3 mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the STAT3 wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in STAT3 mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL, and possibly PTCL.
Assuntos
Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica , Mutação de Sentido Incorreto , Proteínas de Neoplasias/biossíntese , Fator de Transcrição STAT3/biossíntese , Transdução de Sinais , Substituição de Aminoácidos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Humanos , Linfoma Extranodal de Células T-NK , Proteínas de Neoplasias/genética , Fator de Transcrição STAT3/genéticaRESUMO
Nasopharyngeal carcinoma (NPC) is prevalent among populations from southern China and is influenced by both genetic and environmental risk factors. The monocyte chemoattractant protein-1 (MCP-1), a member of cysteine-cysteine chemokine family, plays critical roles in cancers. A polymorphism within the MCP-1 promoter, rs1024611, has been shown to be significantly associated with the risk of several cancers. Our purpose was to assess the role of rs1024611 in NPC susceptibility. By polymerase chain reaction-restriction fragment length polymorphism method, we genotyped rs1024611 in 593 patients with NPC (cases) and 480 cancer-free subjects (controls) among Guangxi population from southern China. We observed that the G allele of rs1024611 was significantly associated with the increased risk of NPC in an additive model and dominant model, respectively (P = 0.018 and 0.010, odds ratio = 1.25 and 1.41, respectively). No appreciable variation of the effects was found across the subgroups stratified by age, sex, nationality, smoking and drinking status, and smoking level. In addition, significantly higher messenger RNA (mRNA) expression level of MCP-1 was observed in NPC tissues than that in normal nasopharyngeal tissues, and the G allele of rs1024611 was significantly associated with elevated mRNA expression level of MCP-1 in Epstein-Barr virus-transformed lymphocytes. In conclusion, our findings suggested that rs1024611 at the MCP-1 promoter may be a risk factor for NPC. Further studies with larger sample size are necessary to confirm these findings.
Assuntos
Quimiocina CCL2/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/patologia , PrognósticoRESUMO
The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Programas de Rastreamento/métodos , Proteína 1 Homóloga a MutL/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , China/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Variações do Número de Cópias de DNA/genética , Feminino , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
BACKGROUND: The goal of this study was to explore the value of adding neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy (ACT) to concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC) with different risks of treatment failure. PATIENTS AND METHODS: A total of 2,263 eligible patients with stage III-IVb NPC treated with CCRT ± NACT or ACT were included in this retrospective study. Distant metastasis-free survival (DMFS), overall survival, and progression-free survival were calculated using the Kaplan-Meier method and differences were compared using the log-rank test. RESULTS: Patients in the low-risk group (stage N0-1 disease and Epstein-Barr virus [EBV] DNA <4,000 copies/mL) who received NACT followed by CCRT achieved significantly better 5-year DMFS than those treated with CCRT alone (96.2% vs 91.3%; P= .008). Multivariate analyses also demonstrated that additional NACT was the only independent prognostic factor for DMFS (hazard ratio, 0.42; 95% CI, 0.22-0.80; P=.009). In both the intermediate-risk group (stage N0-1 disease and EBV DNA ≥4,000 copies/mL and stage N2-3 disease and EBV DNA <4,000 copies/mL) and the high-risk group (stage N2-3 disease and EBV DNA ≥4,000 copies/mL), comparison of NACT or ACT + CCRT versus CCRT alone indicated no significantly better survival for all end points. CONCLUSIONS: The addition of NACT to CCRT could reduce distant failure in patients with low risk of treatment failure.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4/isolamento & purificação , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Terapia Neoadjuvante/métodos , Adolescente , Adulto , Idoso , Quimiorradioterapia/métodos , DNA Viral/sangue , DNA Viral/isolamento & purificação , Intervalo Livre de Doença , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Adulto JovemRESUMO
To further identify novel susceptibility loci of nasopharyngeal carcinoma (NPC), we here extended our previous genome-wide association study (GWAS) by boosting statistical power with larger sample size and validating more SNPs in the ranking list based on the GWAS P-values. The discovery stage consisting of 463,250 SNPs in 1,583 cases and 2,979 controls of southern Chinese ancestry revealed 1,257 top SNPs to be associated with NPC, which were brought forward for validation in 1,925 cases and 1,947 controls of southern Chinese. Further, 11 SNPs were selected for another independent validation in 3,538 cases and 3,644 controls of southern Chinese. The joint analysis with 7,046 cases and 8,570 controls resulted in two associations surpassing genome-wide significance (P < 5 × 10-8), including TERT-CLPTM1L at chromosome 5p15 (rs401681; P = 2.65 × 10-14; odds ratio, OR = 0.82) and CIITA at chromosome 16p13 (rs6498114; P = 4.01 × 10-9; OR = 0.87). Conditional analysis revealed that rs401681 accounts for all the tested associations at TERT-CLPTM1L locus, which has been linked with multiple cancers' susceptibilities. Moreover, bioinformatics analyses showed that both SNPs are located in the regulatory regions and correlated with the expression of nearby genes (rs401681 for CLPTM1L and TERT, and rs6498114 for CIITA). CLPTM1L and TERT have been implicated in cancers, and CIITA is considered as the "master control factor" for the expression of NPC-associated MHC class II genes. These suggested that both SNPs might be functional. Altogether, our findings expand our understanding of the genetic contribution to NPC risk and provide novel biological insights into NPC pathogenesis.
Assuntos
Carcinoma/genética , Proteínas de Membrana/genética , Neoplasias Nasofaríngeas/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Telomerase/genética , Transativadores/genética , Povo Asiático , Carcinoma/patologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos/genética , Humanos , Desequilíbrio de Ligação , Masculino , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Purpose To evaluate the prognostic value of the restaging system after neoadjuvant chemotherapy (NACT) in patients with advanced-stage nasopharyngeal carcinoma (NPC). Materials and Methods This study was approved by the clinical research committee and a written informed consent was required before enrolling in the study. Prospectively enrolled were 412 consecutive patients with stage III-IVb NPC treated with NACT followed by concurrent chemotherapy and radiation therapy. Patients were staged before NACT and restaged after NACT. The progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated with the Kaplan-Meier method, and differences were compared by using the log-rank test. Results Post-NACT T classification (PFS, P = .001) and N classification (PFS, P < .001; DMFS, P = .001) resulted in better survival curve separations than pre-NACT T classification and N classification. Patients downstaged from N2-N3 to N0-N1 disease had a better prognosis than did patients who continued to have N2-N3 diseases (3-year PFS, 83.8% vs 66.6%, P = .001; 3-year DMFS, 88.0% vs 78.4%, P = .026). Multivariate analysis revealed that post-NACT T classification (hazard ratio [HR] = 1.67; 95% confidence interval [CI]: 1.18, 2.36; P = .003) and post-NACT N classification (HR = 1.54; 95% CI: 1.17, 2.03; P = .002) were independent prognostic factors for PFS; also, post-NACT N classification (HR = 1.48; 95% CI: 1.05, 2.07; P = .025) was an independent prognostic factor for DMFS. Multivariate analysis in patients with N2-N3 disease demonstrated that the N downstaging effects of NACT was the only independent prognostic factor for PFS (HR = 0.48; 95% CI: 0.29, 0.81; P = .006) and DMFS (HR = 0.52; 95% CI: 0.28, 0.97; P = .039). Conclusion The post-NACT stage is more representative of prognosis than the pre-NACT stage in advanced-stage NPC patients, which suggests that major clinical decisions should be based on the post-NACT stage. © RSNA, 2016 Online supplemental material is available for this article.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Carcinoma , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Docetaxel , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/radioterapia , Terapia Neoadjuvante , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Radioterapia de Intensidade Modulada , Taxa de Sobrevida , Taxoides , Resultado do TratamentoRESUMO
BACKGROUND: This study aimed to evaluate the long-term outcome and toxicities in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated by concurrent chemoradiotherapy (CCRT) with/without adding cetuximab. METHODS: A total of 62 patients treated with CCRT plus cetuximab were matched with 124 patients treated with CCRT alone by age, sex, pathological type, T category, N category, disease stage, radiotherapy (RT) technique, Epstein-Barr virus (EBV) DNA levels, and Eastern Cooperative Oncology Group (ECOG). Overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method and log-rank test. Treatment toxicities were clarified and compared between two groups. RESULTS: A total of 186 well-balanced stage II to IV NPC patients were retrospectively analyzed (median follow-up, 76 months). Compared to CCRT alone, adding cetuximab resulted in more grade 3 to 4 radiation mucositis (51.6% vs. 23.4%; P < 0.001). No differences were found between the CCRT + cetuximab group and the CCRT group in 5-year OS (89.7% vs. 90.7%, P = 0.386), 3-year PFS (83.9% vs. 88.7%, P = 0.115), the 3-year LRFS (95.0% vs. 96.7%, P = 0.695), and the 3-year DMFS (88.4% vs 91.9%, P = 0.068). Advanced disease stage was the independent prognostic factor predicting poorer OS and PFS. CONCLUSION: Adding cetuximab to CCRT did not significantly improve benefits in survival in stage II to IV NPC and exacerbated acute mucositis and acneiform rash. Further investigations are warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/terapia , Quimiorradioterapia , Neoplasias Nasofaríngeas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Carcinoma/diagnóstico , Carcinoma/mortalidade , Estudos de Casos e Controles , Cetuximab/administração & dosagem , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/mortalidade , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. METHODS: We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. FINDINGS: Associations exceeding the genome-wide significance threshold (p<5â×â10(-8)) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21â×â10(-19), odds ratio [OR] 1·84 [95% CI 1·61-2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32â×â10(-14)). This association is distinct from MHC associations with Epstein-Barr virus infection. INTERPRETATION: To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. FUNDING: Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).
Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Linfoma Extranodal de Células T-NK/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Estudos de Casos e Controles , China , Feminino , Seguimentos , Humanos , Linfoma Extranodal de Células T-NK/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Adulto JovemRESUMO
The X-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism (rs861539, C > T) has drawn wide attentions as its association with cancer risk and its involvement in DNA repair. Several studies have attempted to link rs861539 to nasopharyngeal cancer (NPC) risk; however, the sample sizes of these studies are small and the results are controversial. To investigate the relationship of rs861539 and NPC susceptibility, we conducted a large-scale case-control study involving 4001 NPC cases and 2967 controls of southern Chinese. Logistic regression analysis revealed significant association for rs861539 and NPC risk under the recessive model (TT vs. CT + CC) with adjustment of age and gender (odds ratio, OR = 2.72; 95 % CI 1.10-6.72; P = 0.03). Further, meta-analysis involving 4457 NPC cases and 4132 controls from four studies showed consistent association of TT carriers and NPC risk (OR = 3.12; 95 % CI 1.58-6.13; P = 0.001). Taken together, our findings based on large-scale sample size suggested rs861539 at XRCC3 to be associated with NPC risk through recessive model.
Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Neoplasias Nasofaríngeas/genética , Polimorfismo de Nucleotídeo Único/genética , Carcinoma , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/epidemiologia , Neoplasias Nasofaríngeas/patologia , Fatores de RiscoRESUMO
MOTIVATION: Next-generation genotyping microarrays have been designed with insights from 1000 Genomes Project and whole-exome sequencing studies. These arrays additionally include variants that are typically present at lower frequencies. Determining the genotypes of these variants from hybridization intensities is challenging because there is less support to locate the presence of the minor alleles when the allele counts are low. Existing algorithms are mainly designed for calling common variants and are notorious for failing to generate accurate calls for low-frequency and rare variants. Here, we introduce a new calling algorithm, iCall, to call genotypes for variants across the whole spectrum of allele frequencies. RESULTS: We benchmarked iCall against four of the most commonly used algorithms, GenCall, optiCall, illuminus and GenoSNP, as well as a post-processing caller zCall that adopted a two-stage calling design. Normalized hybridization intensities for 12 370 individuals genotyped on the Illumina HumanExome BeadChip were considered, of which 81 individuals were also whole-genome sequenced. The sequence calls were used to benchmark the accuracy of the genotype calling, and our comparisons indicated that iCall outperforms all four single-stage calling algorithms in terms of call rates and concordance, particularly in the calling accuracy of minor alleles, which is the principal concern for rare and low-frequency variants. The application of zCall to post-process the output from iCall also produced marginally improved performance to the combination of zCall and GenCall. AVAILABILITY AND IMPLEMENTATION: iCall is implemented in C++ for use on Linux operating systems and is available for download at http://www.statgen.nus.edu.sg/â¼software/icall.html.