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1.
Cell ; 182(2): 317-328.e10, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32526205

RESUMO

Hepatocellular carcinoma (HCC) is an aggressive malignancy with its global incidence and mortality rate continuing to rise, although early detection and surveillance are suboptimal. We performed serological profiling of the viral infection history in 899 individuals from an NCI-UMD case-control study using a synthetic human virome, VirScan. We developed a viral exposure signature and validated the results in a longitudinal cohort with 173 at-risk patients who had long-term follow-up for HCC development. Our viral exposure signature significantly associated with HCC status among at-risk individuals in the validation cohort (area under the curve: 0.91 [95% CI 0.87-0.96] at baseline and 0.98 [95% CI 0.97-1] at diagnosis). The signature identified cancer patients prior to a clinical diagnosis and was superior to alpha-fetoprotein. In summary, we established a viral exposure signature that can predict HCC among at-risk patients prior to a clinical diagnosis, which may be useful in HCC surveillance.

4.
Nat Commun ; 10(1): 5735, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844068

RESUMO

Reducing or eliminating persistent disparities in lung cancer incidence and survival has been challenging because our current understanding of lung cancer biology is derived primarily from populations of European descent. Here we show results from a targeted sequencing panel using NCI-MD Case Control Study patient samples and reveal a significantly higher prevalence of PTPRT and JAK2 mutations in lung adenocarcinomas among African Americans compared with European Americans. This increase in mutation frequency was validated with independent WES data from the NCI-MD Case Control Study and TCGA. We find that patients carrying these mutations have a concomitant increase in IL-6/STAT3 signaling and miR-21 expression. Together, these findings suggest the identification of these potentially actionable mutations could have clinical significance for targeted therapy and the enrollment of minority populations in clinical trials.


Assuntos
Adenocarcinoma de Pulmão/genética , Afro-Americanos/genética , Janus Quinase 2/genética , Neoplasias Pulmonares/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Idoso , Estudos de Casos e Controles , Análise Mutacional de DNA , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Disparidades nos Níveis de Saúde , Humanos , Interleucina-6/metabolismo , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Mutação , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética
5.
Cancer Causes Control ; 30(11): 1259-1268, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31468279

RESUMO

PURPOSE: African Americans, especially men, have a higher incidence of lung cancer compared with all other racial and ethnic groups in the US. Self-reported race is frequently used in genomic research studies to capture an individual's race or ethnicity. However, it is clear from studies of genetic admixture that human genetic variation does not segregate into the same biologically discrete categories as socially defined categories of race. Previous studies have suggested that the degree of West African ancestry among African Americans can contribute to cancer risk in this population, though few studies have addressed this question in lung cancer. METHODS: Using a genetic ancestry panel of 100 SNPs, we estimated West African, European, and Native American ancestry in 1,407 self-described African Americans and 2,413 European Americans. RESULTS: We found that increasing West African ancestry was associated with increased risk of lung cancer among African American men (ORQ5 vs Q1 = 2.55 (1.45-4.48), p = 0.001), while no association was observed in African American women (ORQ5 vs Q1 = 0.90 (0.51-1.59), p = 0.56). This relationship diminished following adjustment for income and education. CONCLUSIONS: Genetic ancestry is not a major contributor to lung cancer risk or survival disparities.


Assuntos
Grupo com Ancestrais do Continente Africano , Neoplasias Pulmonares , África Ocidental , Grupo com Ancestrais do Continente Africano/etnologia , Grupo com Ancestrais do Continente Africano/genética , Idoso , Feminino , Humanos , Incidência , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco
6.
Cancer Epidemiol Biomarkers Prev ; 28(10): 1704-1711, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31358519

RESUMO

BACKGROUND: Liver cancer is the second leading cause of cancer-related deaths worldwide. With a predicted 2.4-fold rise in liver cancer incidence by 2020, there is an urgent need for early, inexpensive diagnostic biomarkers to deploy in the clinic. METHODS: We employed ultraperformance liquid chromatography tandem mass-spectrometry (UPLC/MS-MS) for the quantitation of four metabolites, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate, and a lipid molecule designated as 561+, in urine samples from the NCI-MD cohort comprising 98 hepatocellular carcinoma (HCC) cases, 101 high-risk subjects, and 95 controls. Validation was carried out in the TIGER-LC cohort [n = 370 HCC and intrahepatic cholangiocarcinoma (ICC) cases, 471 high-risk subjects, 251 controls], where ICC, the second most common primary hepatic malignancy, is highly prevalent. Metabolite quantitation was also conducted in TIGER-LC tissue samples (n = 48 ICC; n = 51 HCC). RESULTS: All profiled metabolites were significantly increased in liver cancer when compared with high-risk subjects and controls in the NCI-MD study. In the TIGER-LC cohort, the four-metabolite profile was superior at classifying ICC than a clinically utilized marker, CA19-9, and their combination led to a significantly improved model (AUC = 0.88, P = 4E-8). Metabolites CR and NANA were significantly elevated in ICC when compared with HCC cases in both urine and tissue samples. High levels of CR were associated with poorer prognosis in ICC. CONCLUSIONS: Four metabolites are significantly increased in HCC and ICC and are robust at classifying ICC in combination with the clinically utilized marker CA19-9. IMPACT: Noninvasive urinary metabolite biomarkers hold promise for diagnostic and prognostic evaluation of ICC.


Assuntos
Neoplasias dos Ductos Biliares/urina , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Biomarcadores Tumorais/urina , Colangiocarcinoma/urina , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Estudos de Casos e Controles , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC
7.
J Thorac Oncol ; 14(7): 1192-1203, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30953795

RESUMO

INTRODUCTION: Lung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States. We and others have previously shown a relationship between immune and inflammation proteins with lung cancer in EAs. Our aim was to investigate the etiologic relationship between inflammation and lung cancer in AAs. METHODS: We adopted a two-stage, independent study design (discovery cases, n = 316; control cases, n = 509) (validation cases, n = 399; control cases, n = 400 controls) and measured 30 inflammation proteins in blood using Meso Scale Discovery V- PLEX multiplex assays. RESULTS: We identified and validated 10 proteins associated with lung cancer in AAS, some that were common between EAs and AAs (C-reactive proteins [OR: 2.90; 95% confidence interval (CI): 1.99-4.22], interferon γ [OR: 1.55; 95% CI: 1.10-2.19], interleukin 6 [OR: 6.28; 95% CI: 4.10-9.63], interleukin 8 [OR: 2.76; 95% CI: 1.92-3.98]) and some that are only observed among AAs (interleukin 10 [OR: 1.69; 95% CI: 1.20-2.38], interleukin 15 [OR: 2.83; 95% CI: 1.96-4.07], interferon gamma-induced protein 10 [OR: 1.54; 95% CI: 1.09-2.18], monocyte chemotactic protein-4 [OR: 0.54; 95% CI: 0.38-0.76], macrophage inflammatory protein-1 alpha [OR: 1.57; 95% CI: 1.12-2.21], and tumor necrosis factor ß [OR: 0.52; 95% CI: 0.37-0.74]). We did not find evidence that either menthol cigarette smoking or global genetic ancestry drove these population differences. CONCLUSIONS: Our results highlight a distinct inflammation profile associated with lung cancer in AAs compared with EAs. These data provide new insight into the etiology of lung cancer in AAs. Further work is needed to understand what drives this relationship with lung cancer and whether these proteins have utility in the setting of early diagnosis.


Assuntos
Afro-Americanos/estatística & dados numéricos , Biomarcadores/sangue , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Mediadores da Inflamação/sangue , Inflamação/complicações , Neoplasias Pulmonares/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto Jovem
8.
J Thorac Oncol ; 14(8): 1360-1369, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31009812

RESUMO

INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.


Assuntos
Cromossomos Humanos Par 5 , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Telomerase/genética , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
9.
Cancer Epidemiol Biomarkers Prev ; 27(12): 1518-1526, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30171037

RESUMO

BACKGROUND: African Americans (AA) experience higher incidence and mortality of lung cancer as compared with European Americans (EA). Inflammation is associated with lung cancer, many aspects of which differ between AA and EA. We investigated whether use, frequency, and duration of the anti-inflammatory drug aspirin were associated with lung cancer risk and survival, separately among AA and EA populations. METHODS: Using data from the Maryland Non-Small Cell Lung Cancer (NSCLC) Case-Control Study (1,220 cases [404 AA and 816 EA] and 1,634 controls [1,004 EA and 630 AA]), we estimated the adjusted odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) of the associations between aspirin use and NSCLC risk and survival, respectively. RESULTS: Any aspirin use (OR: 0.66; 95% CI, 0.49-0.89), daily use of ≥ 1 tablet (OR: 0.68; 95% CI, 0.50-0.90), and use for ≥ 3 years (OR: 0.61; 95% CI, 0.44-0.85) was associated with lower NSCLC risk only among men, even after adjustment for covariates including body mass index and global genetic ancestry. These variables were also associated with improved survival, but only among AA (HR: 0.64; 95% CI, 0.46-0.91; HR: 0.61; 95% CI, 0.42-0.90; and HR: 0.60; 95% CI, 0.39-0.92, respectively). Tylenol and other NSAIDs were either associated with elevated or no NSCLC risk. CONCLUSIONS: Aspirin use is associated with lower risk of NSCLC among men and improved survival among AA. IMPACT: Preventive regular aspirin use could be considered among men and AA.


Assuntos
Aspirina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Casos e Controles , Grupos de Populações Continentais , Grupos Étnicos , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
10.
Genome Biol ; 19(1): 123, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143034

RESUMO

BACKGROUND: Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort. RESULTS: Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which Acidovorax is enriched in smokers. Acidovorax temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas. CONCLUSIONS: The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/microbiologia , Microbiota/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Biodiversidade , Comamonadaceae/classificação , Comamonadaceae/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neoplasias de Células Escamosas/genética , Neoplasias de Células Escamosas/microbiologia , Proteobactérias/metabolismo , Reprodutibilidade dos Testes , Fumantes , Proteína Supressora de Tumor p53/metabolismo
11.
Lung Cancer ; 122: 151-159, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30032824

RESUMO

OBJECTIVES: Surgery with curative intent is the standard treatment for stage I lung adenocarcinoma. However, disease recurrence occurs in a third of patients. Prognostic biomarkers are needed to improve postoperative management. Here, we evaluate the utility of Homeobox A9 (HOXA9) promoter methylation, alone or in combination with Blood Vessel Invasion (BVI) assessment, for prognostic stratification of stage I lung adenocarcinoma patients. MATERIALS AND METHODS: We developed a Droplet Digital PCR (ddPCR) assay to measure HOXA9 promoter methylation in formalin-fixed paraffin-embedded (FFPE) biospecimens generated during routine pathology. The prognostic value of HOXA9 promoter methylation and BVI, alone and in combination, was evaluated by Kaplan-Meier survival and Cox regression analyses in a cohort of 177 stage I lung adenocarcinoma patients from the NCI-MD study. RESULTS: The ddPCR assay showed linearity, sensitivity and specificity for measuring HOXA9 promoter methylation down to 0.1% methylated DNA input. The HOXA9 promoter was methylated de novo in FFPE tumors (P < 0.0001). High methylation was independently associated with worse cancer-specific survival (Hazard Ratio [HR], 3.37; P = 0.0002) and identified high-risk stage IA and IB patients. Addition of this molecular marker improved a risk model comprised of clinical and pathologic parameters (age, gender, race, stage, and smoking history; nested likelihood ratio test; P = 0.0004) and increased the C-index from 0.60 (95% CI 0.51-0.69) to 0.68 (0.60-0.76). High methylation tumors displayed high frequency of TP53 mutations and other molecular characteristics associated with aggressiveness. BVI was independently associated with poor outcome (HR, 2.62; P = 0.054). A score that combined BVI with HOXA9 promoter methylation further stratified high-risk patients (trend P = 0.0001 comparing 0, 1 or 2 positive markers). CONCLUSIONS: ddPCR can be used to quantify HOXA9 promoter methylation in FFPE samples. Alone or combined with BVI in a prognostic classifier, HOXA9 promoter methylation could potentially inform the clinical management of patients with early-stage lung adenocarcinoma.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/metabolismo , Vasos Sanguíneos/patologia , Proteínas de Homeodomínio/genética , Neoplasias Pulmonares/genética , Regiões Promotoras Genéticas/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Metilação de DNA , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
12.
Cancer Med ; 7(6): 2764-2775, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29726119

RESUMO

Vitamin D is an essential micronutrient required for normal physiological function and recognized for its role regulating calcium metabolism. Recent work is beginning to emerge demonstrating a role for vitamin D in chronic illnesses, such as cancer. Circulating serum levels of 25(OH)D2/3 were quantitatively measured using sensitive ultraperformance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) in 406 lung cancer cases and 437 population controls, while 1,25(OH)2 D2/3 levels were measured in a subset of 90 cases and 104 controls using the same method, from the NCI-MD case-control cohort. 25(OH)D3 levels were inversely associated with lung cancer status across quartiles (Q2 vs. Q1: ORadjusted  = 0.5, 95% CI = 0.3-0.8; Q3 vs. Q1: ORadjusted  = 0.5, 95% CI = 0.3-0.8; Q4 vs. Q1: ORadjusted  = 0.5, 95% CI = 0.2-0.9; Ptrend  = 0.004). Levels of 1,25(OH)2 D3 were also inversely associated with lung cancer status (Q2 vs. Q1: ORadjusted  = 0.2, 95% CI = 0.03-0.7; Q3 vs. Q1: ORadjusted  = 0.1, 95% CI = 0.01-0.4; Q4 vs. Q1: ORadjusted  = 0.04, 95% CI = 0.01-0.3; Ptrend <0.0001). Although the observed trends were similar for the 25(OH)D2 (Ptrend  = 0.08), no significant associations were seen between vitamin D2 and lung cancer status. Additionally, genotyping of 296 SNPs in the same subjects resulted in findings that 27 SNPs, predominantly in CYP24A1 and VDR genes, were significantly associated with lung cancer status, affected mRNA expression, and modulated vitamin D levels. These findings suggest a protective role for vitamin D3 in lung cancer, with similar trends but insignificant findings for D2 . Vitamin D3 levels appeared to be modulated by genetic variation in CYP24A1 and VDR genes. Additional research to illuminate the mechanism(s) through which vitamin D exacerbates effects against lung carcinogenesis is warranted.


Assuntos
Colecalciferol/metabolismo , Variação Genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Idoso , Estudos de Casos e Controles , Colecalciferol/sangue , Cromatografia Líquida , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/sangue , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Espectrometria de Massas em Tandem , Vitamina D3 24-Hidroxilase/genética
13.
Cancer Treat Res Commun ; 10: 33-39, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28944316

RESUMO

OBJECTIVES: In recent years, the anti-cancer properties of several commonly used drugs have been explored, with drugs such as aspirin and beta-blockers associated with improved cancer outcomes. Previous preclinical work demonstrated that tricyclic anti-depressants have antitumor efficacy in lung cancer. Our goal was to examine the association between anti-depressant use and survival in lung cancer. MATERIALS AND METHODS: We examined the association between use of common anti-depressants and survival in 1,097 lung cancer patients from the NCI-Maryland lung cancer study. The types of anti-depressants included in the study were norepinephrine and dopamine reuptake inhibitors, serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, and tricyclic anti-depressants. Anti-depressant use was extracted from the medical history section of a detailed interviewer-administered questionnaire. Specific use in the three months before a lung cancer diagnosis was determined. Cox portioned hazards modeling was used to estimate the association between anti-depressant use with lung cancer-specific death with adjustment for potential confounding co-factors. RESULTS: Anti-depressant use was associated with extended lung cancer-specific survival. In an analysis of specific classes of anti-depressant use, NDRIs and TCAs were associated with improved survival. Importantly, the extended survival associated with anti-depressants was maintained after adjustment for the clinical indications for these drugs, suggestive of a direct effect on lung cancer biology. CONCLUSIONS: Considering the manageable and largely tolerable side effects of anti-depressants, and the low cost of these drugs, these results indicate that evaluation of anti-depressants as adjunct therapeutics with chemotherapy may have a translational effect for lung cancer patients.

14.
J Thorac Oncol ; 12(1): 65-76, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27613525

RESUMO

INTRODUCTION: There are no validated molecular methods that prospectively identify patients with surgically resected lung squamous cell carcinoma (SCC) at high risk for recurrence. By focusing on the expression of genes with known functions in development of lung SCC and prognosis, we sought to develop a robust prognostic classifier of early-stage lung SCC. METHODS: The expression of 253 genes selected by literature search was evaluated in microarrays from 107 stage I/II tumors. Associations with survival were evaluated by Cox regression and Kaplan-Meier survival analyses in two independent cohorts of 121 and 91 patients with SCC, respectively. A classifier score based on multivariable Cox regression was derived and examined in six additional publicly available data sets of stage I/II lung SCC expression profiles (n = 358). The prognostic value of this classifier was evaluated in meta-analysis of patients with stage I/II (n = 479) and stage I (n = 326) lung SCC. RESULTS: Dual specificity phosphatase 6 gene (DUSP6) and actinin alpha 4 gene (ACTN4) were associated with prognostic outcome in two independent patient cohorts. Their expression values were utilized to develop a classifier that identified patients with stage I/II lung SCC at high risk for recurrence (hazard ratio [HR] = 4.7, p = 0.018) or cancer-specific mortality (HR = 3.5, p = 0.016). This classifier also identified patients at high risk for recurrence (HR = 2.7, p = 0.008) or death (HR = 2.2, p = 0.001) in publicly available data sets of stage I/II and in meta-analysis of stage I patients. CONCLUSIONS: We have established and validated a prognostic classifier to inform clinical management of patients with lung SCC after surgical resection.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Estudos de Coortes , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida
15.
Lung Cancer ; 98: 33-42, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27393504

RESUMO

OBJECTIVES: Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping. MATERIALS AND METHODS: We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2. RESULTS AND CONCLUSION: In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.


Assuntos
Afro-Americanos/genética , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 5 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Locos de Características Quantitativas , Estudos de Casos e Controles , Humanos , Polimorfismo de Nucleotídeo Único , Vigilância da População
16.
Cancer Epidemiol Biomarkers Prev ; 25(6): 978-86, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27013655

RESUMO

BACKGROUND: Lung cancer is a major health burden causing 160,000 and 1.6 million deaths annually in the United States and worldwide, respectively. METHODS: While seeking to identify stable and reproducible biomarkers in noninvasively collected biofluids, we assessed whether previously identified metabolite urinary lung cancer biomarkers, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate, and indeterminate metabolite 561+, were elevated in the urines of subjects prior to lung cancer diagnosis in a well-characterized prospective Southern Community Cohort Study (SCCS). Urine was examined from 178 patients and 351 nondiseased controls, confirming that one of four metabolites was associated with lung cancer risk in the overall case-control set, whereas two metabolites were associated with lung cancer risk in European-Americans. RESULTS: OR of lung cancer associated with elevated CR levels, and adjusted for smoking and other potential confounders, was 2.0 [95% confidence interval (CI), 1.2-3.4; P= 0.01]. In European-Americans, both CR and NANA were significantly associated with lung cancer risk (OR = 5.3; 95% CI, 1.6-17.6; P= 0.006 and OR=3.5; 95% CI, 1.5-8.4; P= 0.004, respectively). However, race itself did not significantly modify the associations. ROC analysis showed that adding CR and NANA to a model containing previously established lung cancer risk factors led to a significantly improved classifier (P= 0.01). Increasing urinary levels of CR and NANA displayed a positive association with increasing tumor size, strengthening a previously established link to altered tumor metabolism. CONCLUSION AND IMPACT: These replicated results provide evidence that identified urinary metabolite biomarkers have a potential utility as noninvasive, clinical screening tools for early diagnosis of lung cancer. Cancer Epidemiol Biomarkers Prev; 25(6); 978-86. ©2016 AACR.


Assuntos
Biomarcadores Tumorais/urina , Neoplasias Pulmonares/urina , Modelos Biológicos , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Fatores de Risco
17.
Cancer Epidemiol Biomarkers Prev ; 25(3): 488-97, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26711330

RESUMO

BACKGROUND: African Americans have a higher risk of developing lung cancer than European Americans. Previous studies suggested that certain circulating cytokines were associated with lung cancer. We hypothesized that variations in serum cytokine levels exist between African Americans and European Americans, and increased circulating cytokine levels contribute to lung cancer differently in the two races. METHODS: Differences in 10 serum cytokine levels, IL1ß, IL4, IL5, IL6, IL8, IL10, IL12, granulocyte macrophage colony-stimulating factor, IFNγ, and TNFα, between 170 African-American and 296 European-American controls from the National Cancer Institute-Maryland (NCI-MD) case-control study were assessed. Associations of the serum cytokine levels with lung cancer were analyzed. Statistically significant results were replicated in the prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the Wayne State University Karmanos Cancer Institute case-control study. RESULTS: Six cytokines, IL4, IL5, IL8, IL10, IFNγ, and TNFα, were significantly higher among European-American as compared with African-American controls. Elevated IL6 and IL8 levels were associated with lung cancer among both races in all three studies. Elevated IL1ß, IL10, and TNFα levels were associated with lung cancer only among African Americans. The association between elevated TNFα levels and lung cancer among European Americans was significant after adjustment for additional factors. CONCLUSIONS: Serum cytokine levels vary by race and might contribute to lung cancer differently between African Americans and European Americans. IMPACT: Future work examining risk prediction models of lung cancer can measure circulating cytokines to accurately characterize risk within racial groups.


Assuntos
Citocinas/efeitos adversos , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/etiologia , Afro-Americanos , Idoso , Citocinas/sangue , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
18.
J Thorac Oncol ; 10(7): 1037-48, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26134223

RESUMO

INTRODUCTION: Up to 30% stage I lung cancer patients suffer recurrence within 5 years of curative surgery. We sought to improve existing protein-coding gene and microRNA expression prognostic classifiers by incorporating epigenetic biomarkers. METHODS: Genome-wide screening of DNA methylation and pyrosequencing analysis of HOXA9 promoter methylation were performed in two independently collected cohorts of stage I lung adenocarcinoma. The prognostic value of HOXA9 promoter methylation alone and in combination with mRNA and miRNA biomarkers was assessed by Cox regression and Kaplan-Meier survival analysis in both cohorts. RESULTS: Promoters of genes marked by polycomb in embryonic stem cells were methylated de novo in tumors and identified patients with poor prognosis. The HOXA9 locus was methylated de novo in stage I tumors (p < 0.0005). High HOXA9 promoter methylation was associated with worse cancer-specific survival (hazard ratio [HR], 2.6; p = 0.02) and recurrence-free survival (HR, 3.0; p = 0.01), and identified high-risk patients in stratified analysis of stages IA and IB. Four protein-coding gene (XPO1, BRCA1, HIF1α, and DLC1), miR-21 expression, and HOXA9 promoter methylation were each independently associated with outcome (HR, 2.8; p = 0.002; HR, 2.3; p = 0.01; and HR, 2.4; p = 0.005, respectively), and when combined, identified high-risk, therapy naive, stage I patients (HR, 10.2; p = 3 × 10). All associations were confirmed in two independently collected cohorts. CONCLUSION: A prognostic classifier comprising three types of genomic and epigenomic data may help guide the postoperative management of stage I lung cancer patients at high risk of recurrence.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Metilação de DNA , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Adenocarcinoma de Pulmão , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Coortes , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Medicina de Precisão , Prognóstico , RNA Mensageiro/genética , Estudos Retrospectivos
19.
PLoS One ; 10(4): e0124899, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25894979

RESUMO

The microRNA-34 family (miR-34a, -34b and -34c) have been reported to be tumor suppressor microRNAs (miRNAs) that are regulated by the TP53 and DNA hypermethylation. However, the expression, regulation, and prognostic value of the miR-34 family have not been systematically studied in colon cancer. To elucidate the roles of miR-34 family in colon carcinogenesis, miR-34a/b/c were measured in tumors and adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients using quantitative RT-PCR, and we examined associations between miR-34a/b/c expression with TNM staging, cancer-specific mortality, TP53 mutation status and Affymetrix microarray data. All miR-34 family members were significantly increased in colon tumors, counter to the proposed tumor suppressor role for these miRNAs. Increased miR-34b/c were observed in more advanced tumors in two independent cohorts and increased expression of miR-34b/c was associated with poor cancer-specific mortality. While the expression of miR-34 family was not associated with TP53 mutation status, TP53 transcriptional activity was associated with miR-34a/b/c expression that is consistent with the proposed regulation of miR-34a/b/c by TP53. To examine where the miR-34 family is expressed, the expression of miR-34 family was compared between epitheliums and stromal tissues using laser microdissection technique. The expression of miR-34b/c was increased significantly in stromal tissues, especially in cancer stroma, compared with epithelial tissue. In conclusion, increased miR-34b/c predominantly expressed in stromal tissues is associated with poor prognosis in colon cancer. MiR-34 may contribute to cancer-stromal interaction associated with colon cancer progression.


Assuntos
Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/patologia , Feminino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Células Estromais/metabolismo , Proteína Supressora de Tumor p53/genética , Regulação para Cima
20.
Cancer Res ; 75(3): 566-75, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25480945

RESUMO

Global changes in gene expression accompany the development of cancer. Thus, inherited variants in miRNA-binding sites are likely candidates for conferring inherited susceptibility. Using an in silico approach, we compiled a comprehensive list of SNPs predicted to modulate miRNA binding in genes from several key lung cancer pathways. We then investigated whether these SNPs were associated with lung cancer risk in two independent populations. In general, SNPs in miRNA-binding sites are rare. However, some allelic variation was observed. We found that rs1126579 in CXCR2 was associated with a reduced risk of lung cancer in both European American [ORTT vs. CC 0.56 (0.37-0.88); P = 0.008] and Japanese [ORTT vs. CC 0.62 (0.38-1.00); P = 0.049] populations. Furthermore, we found that the SNP disrupted a novel binding site for miR-516a-3p, led to a moderate increase in CXCR2 mRNA and protein expression, and increased MAPK signaling. Moreover, analysis of rs1126579 with serum levels of IL8, its endogenous ligand, supported an interaction whereby rs1126579-T and high serum IL8 conferred synergistic protection from lung cancer. Our findings demonstrate a function for a 3'UTR SNP in modulating CXCR2 expression, signaling, and susceptibility to lung cancer.


Assuntos
Regiões 3' não Traduzidas , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-8B/genética , Idoso , Alelos , Sítios de Ligação , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Variação Genética , Genótipo , Humanos , Interleucina-8/metabolismo , Japão , Ligantes , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Fatores de Risco , Transdução de Sinais
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