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1.
Nature ; 2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35676472

RESUMO

Large-scale human genetic data1-3 have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL)4-6. VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2α (HIF2A) stabilization6,7. We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. 8). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants.

2.
JNCI Cancer Spectr ; 6(2)2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-35603848

RESUMO

BACKGROUND: Higher circulating vitamin D has been associated with improved overall cancer survival, but data for organ-specific cancers are mixed. METHODS: We examined the association between prediagnostic serum 25-hydroxyvitamin D [25(OH)D], the recognized biomarker of vitamin D status, and cancer survival in 4038 men and women diagnosed with 1 of 11 malignancies during 22 years of follow-up (median = 15.6 years) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Multivariable-adjusted proportional hazards regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between baseline 25(OH)D concentration and subsequent cancer survival; we also stratified on the common vitamin D binding protein isoforms (Gc1f, Gc1s, and Gc2) defined by two single-nucleotide polymorphisms (rs7041 and rs4588) in the vitamin D binding protein gene GC. All P values were 2-sided. RESULTS: Higher 25(OH)D concentrations were associated with greater overall cancer survival (HR for cancer mortality = 0.83, 95% CI = 0.70 to 0.98 for highest vs lowest quintile; Ptrend = .05) and lung cancer survival (HR = 0.63, 95% CI = 0.44 to 0.90; Ptrend = .03). These associations were limited to cases expressing the Gc2 isoform (HR = 0.38 for Gc2-2, 95% CI = 0.14 to 1.05 for highest vs lowest quintile; Ptrend = .02; and HR = 0.30 for Gc1-2/Gc2-2 combined, 95% CI = 0.16 to 0.56; Ptrend < .001 for overall and lung cancer, respectively). CONCLUSIONS: Higher circulating 25(OH)D was associated with improved overall and lung cancer survival. As this was especially evident among cases with the genetically determined Gc2 isoform of vitamin D binding protein, such individuals may gain a cancer survival advantage by maintaining higher 25(OH)D blood concentrations.


Assuntos
Neoplasias Pulmonares , Proteína de Ligação a Vitamina D , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/genética , Vitamina D , Proteína de Ligação a Vitamina D/genética
4.
J Natl Cancer Inst ; 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35438160

RESUMO

It is unclear if body weight in early life affects cancer risk independently of adult body weight. To investigate this question for six obesity-related cancers, we performed univariable and multivariable analyses using i) Mendelian randomization (MR) analysis and ii) longitudinal analyses in prospective cohorts. Both the MR and longitudinal analyses indicated that larger body size at age 10 was associated with higher risk of endometrial (ORMR=1.61, 95%CI = 1.23-2.11) and kidney cancer (ORMR=1.40, 95%CI = 1.09-1.80). These associations were attenuated after accounting for adult body size in both the MR and cohort analyses. Early life BMI was not consistently associated with the other investigated cancers. The lack of clear independent risk associations suggests that early life BMI influences endometrial and kidney cancer risk mainly through pathways that are common with adult BMI.

5.
Cancer Causes Control ; 33(1): 101-108, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34677742

RESUMO

PURPOSE: There is increasing evidence that coffee consumption is related to reduced risks for some cancers, but the evidence for renal cancer is inconclusive. Therefore, we conducted a meta-analysis to summarize the cohort evidence of this relationship. METHODS: A literature search was performed in PubMed and Embase through February 2021. Meta-analyses using a random effects model were conducted for reported relative risk estimates (RRs) relating coffee intake and renal cancer incidence or mortality. We also performed a two-stage random effects exposure-response meta-analysis. Between-study heterogeneity was assessed. RESULTS: In a meta-analysis of the ten identified cohort studies, we found a summary RR of 0.88 [95% confidence interval (CI) 0.78-0.99] relating the highest vs. the lowest category of coffee intake and renal cancer, with no significant between-study heterogeneity observed (I2 = 35%, p = 0.13). This inverse association remained among studies of incident cancers (RR 0.85, 95% CI 0.76-0.96) and studies adjusting for smoking and body mass index (RR 0.87, 95% CI 0.77-0.99). CONCLUSIONS: Our findings from this meta-analysis of the published cohort evidence are suggestive of an inverse association between coffee consumption and renal cancer risk.


Assuntos
Café , Neoplasias Renais , Café/efeitos adversos , Estudos de Coortes , Humanos , Incidência , Neoplasias Renais/epidemiologia , Neoplasias Renais/etiologia , Fatores de Risco
6.
Ann Epidemiol ; 68: 1-8, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34906633

RESUMO

BACKGROUND: Associations between benign gynecologic pathologies and circulating inflammatory markers are unknown. Our goal was to evaluate self-reported history of benign gynecologic pathology and subsequent alterations in systemic inflammation. METHODS: Using nested case-control studies from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, study-specific associations between self-reported history of benign ovarian cysts, uterine fibroids, and endometriosis with inflammatory marker concentrations were evaluated using logistic regression and combined using meta-analysis. Inflammatory markers associated with individual benign pathologies were mutually adjusted for one another to evaluate independent associations. RESULTS: Compared to women without a self-reported history of the pathology evaluated, benign ovarian cysts were associated with increased PAI-1 (OR [95% CI] 6.24 [2.53-15.39], P <.001) and TGF-ß1 (3.79 [1.62-8.86], P =.002) and decreased BCA-1 (0.38 [0.19-0.73], P =.004). Uterine fibroids were associated with decreased CXCL11 (0.37 [0.22-0.63], P <.001) and VEGFR3 (0.40 [0.24-0.65], P <.001). Endometriosis was associated with increased SIL-4R (4.75 [1.84-12.26], P =.001). CONCLUSIONS: Self-reported history of benign gynecologic pathologies were associated with alterations in inflammatory markers that have been previously linked to cancer risk. Understanding interactions between benign gynecologic pathologies and the systemic immune system may help inform disease risk later in life.


Assuntos
Neoplasias Colorretais , Neoplasias Ovarianas , Ensaios Clínicos como Assunto , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Detecção Precoce de Câncer , Feminino , Humanos , Modelos Logísticos , Pulmão , Masculino , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Próstata
7.
Am J Hum Genet ; 108(9): 1590-1610, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34390653

RESUMO

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.


Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos Par 14 , Proteínas de Ligação a DNA/genética , Loci Gênicos , Neoplasias Renais/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Linhagem Celular Tumoral , Cromatina/química , Cromatina/imunologia , Montagem e Desmontagem da Cromatina/imunologia , Citocinas/genética , Citocinas/imunologia , Proteínas de Ligação a DNA/imunologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT3/imunologia , Linfócitos T Citotóxicos , Fatores de Transcrição/imunologia
8.
Cancer Discov ; 11(12): 3106-3125, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34244212

RESUMO

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses based on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell-cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels, and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer. SIGNIFICANCE: We demonstrate that ccRCC cells are auxotrophic for exogenous cholesterol to maintain PI3K/AKT signaling pathway and ROS homeostasis. Blocking cholesterol import through the HDL transporter SCARB1 compromises ccRCC cell survival and tumor growth, suggesting a novel pharmacologic target for this disease. This article is highlighted in the In This Issue feature, p. 2945.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Colesterol/uso terapêutico , Humanos , Neoplasias Renais/patologia , Fosfatidilinositol 3-Quinases/metabolismo
9.
Int J Cancer ; 149(7): 1448-1454, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34058014

RESUMO

The ccA and ccB molecular subtypes of clear cell renal cell carcinoma (ccRCC) have well-characterized prognostic relevance. However, it is not known whether they possess distinct etiologies. We investigated the relationships between these subtypes and RCC risk factors within a case-control study conducted in Eastern Europe. We analyzed risk factor data for ccA (n = 144) and ccB (n = 106) cases and 1476 controls through case-only and case-control comparisons to assess risk factor differences across subtypes using logistic and polytomous regression models. We also performed a meta-analysis summarizing case-only results from our study and three patient cohorts. Patients with ccB tumors had poorer survival than those with ccA tumors and were more likely to be male (case-only odds ratio [OR] 2.68, 95% confidence interval [CI] 1.43-5.03). In case-control analyses, body mass index was significantly associated with ccA tumors (OR 2.45, 95% CI 1.18-5.10 for ≥35 vs <25 kg/m2 ) but not with ccB tumors (1.52, 0.56-4.12), while trichloroethylene was associated with ccB but not ccA (OR 3.09, 95% CI 1.11-8.65 and 1.25, 0.36-4.39 respectively for ≥1.58 ppm-years vs unexposed). A polygenic risk score of genetic variants identified from genome-wide association studies was associated with both ccA and, in particular, ccB (OR 1.82, 1.11-2.99 and 2.87, 95% CI 1.64-5.01 respectively for 90th vs 10th percentile). In a meta-analysis of case-only results including three patient cohorts, we still observed the ccB excess for male sex and the ccA excess for obesity. In conclusion, our findings suggest the existence of etiologic heterogeneity across ccRCC molecular subtypes for several risk factors.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Idoso , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/etiologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Neoplasias Renais/classificação , Neoplasias Renais/etiologia , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de Sobrevida
10.
Cancer ; 127(17): 3145-3155, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33974712

RESUMO

BACKGROUND: Studying the differential impact of aspirin and other nonsteroidal anti-inflammatory drugs across the stages of colorectal neoplasia from early adenoma to cancer is critical for understanding the benefits of these widely used drugs. METHODS: With 13 years of follow-up, the authors prospectively evaluated the association between aspirin and ibuprofen use and incident distal adenoma (1221 cases), recurrent adenoma (862 cases), and incident colorectal cancer (CRC; 2826 cases) among men and women in the population-based Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. With multivariable-adjusted models, odds ratio (ORs) and 95% confidence intervals (CIs) for adenoma incidence and recurrence and hazard ratios (HRs) and 95% CIs for incident CRC were determined. RESULTS: The authors observed a significantly reduced risk of incident adenoma with ibuprofen use (≥30 vs <4 pills per month: OR, 0.76 [95% CI, 0.60-0.95]; Ptrend = .04), particularly advanced adenoma (OR, 0.48 [95% CI, 0.28-0.83]; Ptrend = .005). Among those with a previous adenoma detected through screening, aspirin use was associated with a decreased risk of advanced recurrent adenoma (≥30 vs <4 pills per month: OR, 0.56 [95% CI, 0.36-0.87]; Ptrend = 0.006). Both aspirin (HR, 0.88 [95% CI, 0.81-0.96]; Ptrend <.0001) and ibuprofen use (HR, 0.81 [95% CI, 0.70-0.93); Ptrend = 0.003) ≥30 versus <4 pills per month were significantly associated with reduced CRC risk. CONCLUSIONS: In this large prospective study with long-term follow-up, a beneficial role for not only aspirin, but also ibuprofen, in preventing advanced adenoma and curbing progression to recurrence and cancer among older adults was observed.


Assuntos
Adenoma , Neoplasias Colorretais , Adenoma/diagnóstico , Adenoma/epidemiologia , Adenoma/prevenção & controle , Idoso , Aspirina/uso terapêutico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Detecção Precoce de Câncer , Feminino , Humanos , Ibuprofeno/uso terapêutico , Incidência , Masculino , Estudos Prospectivos
11.
Cancer Med ; 10(12): 4066-4074, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33963676

RESUMO

Previous analyses within the National Health and Nutrition Examination Survey (NHANES) II and III cycles suggested an association between blood lead levels (BLLs) and lung cancer mortality, although the evidence was limited by small case numbers. To clarify this relationship, we conducted updated analyses of 4,182 and 15,629 participants in NHANES II and III, respectively, (extending follow-up 20 and 8 years) aged ≥20 with BLL measurements and mortality follow-up through 2014. We fit multivariable Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) relating BLLs and lung cancer with adjustment for smoking and other factors. We did not observe an overall association between BLLs and lung cancer after adjustment for smoking (both surveys) and serum cotinine and environmental tobacco smoke exposure (NHANES III), although suggestive associations were observed among women (NHANES II: HR 2.7, 95% CI 0.7, 10.0 for ≥20.0 µg/dl vs. <10.0 µg/dl, Ptrend = 0.07; NHANES III: HR 11.2, 95% CI 2.1, 59.4 for ≥10.0 µg/dl vs. <2.5 µg/dl, Ptrend = 0.04). After stratifying on smoking status, an association with elevated BLLs was observed in NHANES II only among former smokers (HR 3.2, 95% CI 1.3, 8.0 for ≥15 vs. <15 µg/dl) and in NHANES III only among current smokers (HR 1.7, 95% CI 1.1, 2.8 for ≥5 vs. <5 µg/dl). In summary, we found elevated BLLs to be associated with lung cancer mortality among women in both NHANES II and III. Given the absence of an association among non-smokers, we cannot rule out residual confounding as an explanation for our findings.


Assuntos
Chumbo/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Adulto , Intervalos de Confiança , Cotinina/sangue , Ex-Fumantes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais/estatística & dados numéricos , Modelos de Riscos Proporcionais , Fatores Sexuais , Fumantes , Fumar/sangue , Poluição por Fumaça de Tabaco/efeitos adversos
12.
Int J Epidemiol ; 50(5): 1473-1481, 2021 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33624757

RESUMO

BACKGROUND: Coffee consumption has been associated with a reduced risk of some cancers, but the evidence for renal cell carcinoma (RCC) is inconclusive. We investigated the relationship between coffee and RCC within a large cohort. METHODS: Coffee intake was assessed at baseline in the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Among 420 118 participants eligible for analysis, 2674 incident cases were identified. We fitted Cox-regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for coffee consumption vs non-drinkers. RESULTS: We observed HRs of 0.94 (95% CI 0.81, 1.09), 0.94 (0.81, 1.09), 0.80 (0.70, 0.92) and 0.77 (0.66, 0.90) for usual coffee intake of <1, 1, 2-3 and ≥4 cups/day, respectively (Ptrend = 0.00003). This relationship was observed among never-smokers (≥4 cups/day: HR 0.62, 95% CI 0.46, 0.83; Ptrend = 0.000003) but not ever-smokers (HR 0.85, 95% CI 0.70, 1.05; Ptrend = 0.35; Pinteraction = 0.0009) and remained in analyses restricted to cases diagnosed >10 years after baseline (HR 0.65, 95% CI 0.51, 0.82; Ptrend = 0.0005). Associations were similar between subgroups who drank predominately caffeinated or decaffeinated coffee (Pinteraction = 0.74). CONCLUSION: In this investigation of coffee and RCC, to our knowledge the largest to date, we observed a 20% reduced risk for intake of ≥2 cups/day vs not drinking. Our findings add RCC to the growing list of cancers for which coffee consumption may be protective.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Cafeína , Carcinoma de Células Renais/epidemiologia , Café , Dieta , Humanos , Neoplasias Renais/epidemiologia , National Institutes of Health (U.S.) , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia
13.
J Natl Cancer Inst ; 113(5): 580-587, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32944748

RESUMO

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of over 98% of the US population. Studies among highly exposed individuals suggest an association with perfluorooctanoic acid (PFOA) exposure and kidney cancer. It remains unclear whether PFOA or other PFAS are renal carcinogens or if they influence risk of renal cell carcinoma (RCC) at concentrations observed in the general population. METHODS: We measured prediagnostic serum concentrations of PFOA and 7 additional PFAS in 324 RCC cases and 324 individually matched controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) relating serum PFAS concentrations and RCC risk. Individual PFAS were modeled continuously (log2-transformed) and categorically, with adjustment for kidney function and additional potential confounders. All statistical tests were 2-sided. RESULTS: We observed a positive association with RCC risk for PFOA (doubling in serum concentration, ORcontinuous = 1.71, 95% CI = 1.23 to 2.37, P = .002) and a greater than twofold increased risk among those in the highest quartile vs the lowest (OR = 2.63, 95% CI = 1.33 to 5.20, Ptrend = .007). The association with PFOA was similar after adjustment for other PFAS (ORcontinuous = 1.68, 95% CI = 1.07 to 2.63, P = .02) and remained apparent in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed 8 or more years after phlebotomy. CONCLUSIONS: Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical.


Assuntos
Carcinoma de Células Renais , Fluorcarbonetos , Neoplasias Renais , Carcinoma de Células Renais/induzido quimicamente , Carcinoma de Células Renais/epidemiologia , Fluorcarbonetos/efeitos adversos , Fluorcarbonetos/sangue , Humanos , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/epidemiologia , Masculino , Risco
14.
Brief Bioinform ; 22(3)2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32789507

RESUMO

The NanoString RNA counting assay for formalin-fixed paraffin embedded samples is unique in its sensitivity, technical reproducibility and robustness for analysis of clinical and archival samples. While commercial normalization methods are provided by NanoString, they are not optimal for all settings, particularly when samples exhibit strong technical or biological variation or where housekeeping genes have variable performance across the cohort. Here, we develop and evaluate a more comprehensive normalization procedure for NanoString data with steps for quality control, selection of housekeeping targets, normalization and iterative data visualization and biological validation. The approach was evaluated using a large cohort ($N=\kern0.5em 1649$) from the Carolina Breast Cancer Study, two cohorts of moderate sample size ($N=359$ and$130$) and a small published dataset ($N=12$). The iterative process developed here eliminates technical variation (e.g. from different study phases or sites) more reliably than the three other methods, including NanoString's commercial package, without diminishing biological variation, especially in long-term longitudinal multiphase or multisite cohorts. We also find that probe sets validated for nCounter, such as the PAM50 gene signature, are impervious to batch issues. This work emphasizes that systematic quality control, normalization and visualization of NanoString nCounter data are an imperative component of study design that influences results in downstream analyses.


Assuntos
Neoplasias da Mama , Bases de Dados de Ácidos Nucleicos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , RNA Neoplásico , RNA , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , RNA/biossíntese , RNA/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
15.
JNCI Cancer Spectr ; 4(2): pkz104, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33336146

RESUMO

BACKGROUND: Experimental and clinical studies have implicated certain chemokines and angiogenic cytokines in multiple myeloma (MM) pathogenesis. To investigate whether systemic concentrations of these markers are associated with future MM risk and progression from its precursor, monoclonal gammopathy of undetermined significance (MGUS), we conducted a prospective study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. METHODS: We measured concentrations of 45 immunologic and pro-angiogenic markers in sera from 241 MM case patients, 441 participants with nonprogressing MGUS, and 258 MGUS-free control participants using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. We also evaluated absolute risk of progression using weighted Kaplan-Meier estimates. All statistical tests were two-sided. RESULTS: Prediagnostic levels of six markers were statistically significantly elevated among MM case patients compared with MGUS-free control participants using a false discovery rate of 10% (EGF, HGF, Ang-2, CXCL12, CCL8, and BMP-9). Of these, three angiogenesis markers were associated with future progression from MGUS to MM: EGF (fourth vs first quartile: OR = 3.01, 95% CI = 1.61 to 5.63, P trend = .00028), HGF (OR = 2.59, 95% CI = 1.33 to 5.03, P trend = .015), and Ang-2 (OR = 2.14, 95% CI = 1.15 to 3.98, P trend = .07). A composite angiogenesis biomarker score substantially stratified risk of MGUS progression to MM beyond established risk factors for progression, particularly during the first 5 years of follow-up (areas under the curve of 0.71 and 0.64 with and without the angiogenesis marker score, respectively). CONCLUSIONS: Our prospective findings provide new insights into mechanisms involved in MM development and suggest that systemic angiogenesis markers could potentially improve risk stratification models for MGUS patients.

16.
Cancer Epidemiol Biomarkers Prev ; 29(10): 2065-2069, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32732251

RESUMO

BACKGROUND: Much of the heritable risk of renal cell carcinoma (RCC) associated with common genetic variation is unexplained. New analytic approaches have been developed to increase the discovery of risk variants in genome-wide association studies (GWAS), including multi-locus testing through pathway analysis. METHODS: We conducted a pathway analysis using GWAS summary data from six previous scans (10,784 cases and 20,406 controls) and evaluated 3,678 pathways and gene sets drawn from the Molecular Signatures Database. To replicate findings, we analyzed GWAS summary data from the UK Biobank (903 cases and 451,361 controls) and the Genetic Epidemiology Research on Adult Health and Aging cohort (317 cases and 50,511 controls). RESULTS: We identified 14 pathways/gene sets associated with RCC in both the discovery (P < 1.36 × 10-5, the Bonferroni correction threshold) and replication (P < 0.05) sets, 10 of which include components of the PI3K/AKT pathway. In tests across 2,035 genes in these pathways, associations (Bonferroni corrected P < 2.46 × 10-5 in discovery and replication sets combined) were observed for CASP9, TIPIN, and CDKN2C. The strongest SNP signal was for rs12124078 (P Discovery = 2.6 × 10-5; P Replication = 1.5 × 10-4; P Combined = 6.9 × 10-8), a CASP9 expression quantitative trait locus. CONCLUSIONS: Our pathway analysis implicates genetic variation within the PI3K/AKT pathway as a source of RCC heritability and identifies several promising novel susceptibility genes, including CASP9, which warrant further investigation. IMPACT: Our findings illustrate the value of pathway analysis as a complementary approach to analyzing GWAS data.


Assuntos
Carcinoma de Células Renais/genética , Estudo de Associação Genômica Ampla/métodos , Carcinoma de Células Renais/patologia , Humanos
17.
Br J Cancer ; 123(2): 316-324, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376888

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -ß, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. METHODS: We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). RESULTS: Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. CONCLUSIONS: This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.


Assuntos
Colangiocarcinoma/epidemiologia , Anticoncepcionais Orais Hormonais/efeitos adversos , Hormônios/efeitos adversos , Neoplasias Hepáticas/epidemiologia , Idoso , Ductos Biliares , Ductos Biliares Intra-Hepáticos , Bancos de Espécimes Biológicos , Colangiocarcinoma/induzido quimicamente , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Estudos de Coortes , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hormônios/uso terapêutico , Humanos , Histerectomia/efeitos adversos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Menopausa/efeitos dos fármacos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Reino Unido/epidemiologia
18.
J Hepatol ; 73(4): 863-872, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32437829

RESUMO

BACKGROUND & AIMS: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear. METHODS: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study. RESULTS: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only. CONCLUSION: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography. LAY SUMMARY: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.


Assuntos
Neoplasias do Sistema Biliar/epidemiologia , Sistema de Registros , Reprodução/fisiologia , Medição de Risco/métodos , Adulto , Idoso , Neoplasias do Sistema Biliar/etiologia , Feminino , Seguimentos , Saúde Global , Humanos , Incidência , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Taxa de Sobrevida/tendências , Fatores de Tempo , Adulto Jovem
19.
Cancer Epidemiol Biomarkers Prev ; 29(5): 1074-1078, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32108027

RESUMO

BACKGROUND: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis. METHODS: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated (P < 5 × 10-8) with high-density lipoprotein (HDL, n = 164), low-density lipoprotein (LDL, n = 137), total cholesterol (TC, n = 161), and triglycerides (TG, n = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance-weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI). RESULTS: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00-1.30) and MZL (OR = 1.09; 95% CI, 1.01-1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83-0.99), all at nominal significance (P < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99-1.19; P = 0.087). No associations were noteworthy after adjusting for multiple testing. CONCLUSIONS: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. IMPACT: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.


Assuntos
Leucemia Linfocítica Crônica de Células B/epidemiologia , Metabolismo dos Lipídeos/genética , Linfoma de Zona Marginal Tipo Células B/epidemiologia , Linfoma Folicular/epidemiologia , Linfoma Difuso de Grandes Células B/epidemiologia , Causalidade , Colesterol/sangue , Colesterol/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Lipoproteínas HDL/sangue , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/sangue , Lipoproteínas LDL/metabolismo , Linfoma de Zona Marginal Tipo Células B/sangue , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma Folicular/sangue , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Análise da Randomização Mendeliana , Razão de Chances , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco , Triglicerídeos/sangue , Triglicerídeos/metabolismo
20.
Hepatology ; 72(2): 535-547, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31808181

RESUMO

BACKGROUND AND AIMS: In almost all countries, incidence rates of liver cancer (LC) are 100%-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of LC cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with LC risk, overall and by histology, by leveraging resources from five prospective cohorts. APPROACH AND RESULTS: Seven sex steroid hormones and SHBG were quantitated using gas chromatography/tandem mass spectrometry and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 postmenopausal female LC cases (HCC, n = 83; ICC, n = 56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log2 hormone value (approximate doubling of circulating concentration) and LC were calculated using multivariable-adjusted conditional logistic regression. A doubling in the concentration of 4-androstenedione (4-dione) was associated with a 50% decreased LC risk (OR = 0.50; 95% CI = 0.30-0.82), whereas SHBG was associated with a 31% increased risk (OR = 1.31; 95% CI = 1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR = 1.40; 95% CI = 1.05-1.89), but not HCC (OR = 1.12; 95% CI = 0.81-1.54). CONCLUSIONS: This study provides evidence that higher levels of 4-dione may be associated with lower, and SHBG with higher, LC risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease LC risk. Indeed, estradiol may be associated with an increased ICC risk.


Assuntos
Carcinoma Hepatocelular/sangue , Hormônios Esteroides Gonadais/sangue , Neoplasias Hepáticas/sangue , Pós-Menopausa/sangue , Globulina de Ligação a Hormônio Sexual/análise , Idoso , Carcinoma Hepatocelular/epidemiologia , Feminino , Humanos , Neoplasias Hepáticas/epidemiologia , Pessoa de Meia-Idade , Medição de Risco , Fatores Sexuais
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