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2.
Chest ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32798520

RESUMO

BACKGROUND: The Centers for Medicare and Medicaid Services stipulate shared decision-making (SDM) counseling as a prerequisite to lung cancer screening (LCS) reimbursement, despite well-known challenges implementing SDM in practice. RESEARCH QUESTION: How have health-care organizations implemented SDM for LCS? STUDY DESIGN AND METHODS: For this qualitative study, we used data from in-depth, semistructured interviews with key informants directly involved in implementing SDM for LCS, managing SDM for LCS, or both. We identified respondents using a snowball sampling technique and used template analysis to identify and analyze responses thematically. RESULTS: We interviewed 30 informants representing 23 health-care organizations located in 12 states and 4 Census regions. Respondents described two types of SDM for LCS programs: centralized models (n = 7), in which front-end practitioners (eg, primary care providers) referred patients to an LCS clinic where trained staff (eg, advanced practice nurses) delivered SDM at the time of screening, or decentralized models (n = 10), in which front-end practitioners delivered SDM before referring patients for screening. Some organizations used both models simultaneously (n = 6). Respondents discussed tradeoffs between SDM quality and access. They perceived centralized models as enhancing SDM quality, but limiting patient access to care, and vice versa. Respondents reported ongoing challenges with limited resources and budgetary constraints, ambiguity regarding what constitutes SDM, and an absence of benchmarks for evaluating SDM for LCS quality. INTERPRETATION: Those responsible for developing and managing SDM for LCS programs voiced concerns regarding both patient access and SDM quality, regardless of organizational context, or the SDM for LCS model implemented. The challenge facing these organizations, and those wanting to help patients and clinicians balance the tradeoffs inherent with LCS, is how to move beyond a check-box documentation requirement to a process that enables LCS to be offered to all high-risk patients, but used only by those who are informed and for whom screening represents a value-concordant service.

3.
Eur Urol ; 78(3): 316-320, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32409115

RESUMO

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

4.
Breast Cancer Res Treat ; 180(1): 219-226, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31975315

RESUMO

PURPOSE: Reports suggest that up to 50% of women with hormone receptor-positive (HR+) breast cancer (BC) do not complete the recommended 5 years of adjuvant endocrine therapy (AET). We examined the impact of an outreach program at Kaiser Permanente Northern California (KPNC) on adherence and discontinuation of AET among patients who initiated AET. METHODS: We assembled a retrospective cohort of all KPNC patients diagnosed with HR+, stage I-III BC initiating AET before (n = 4287) and after (n = 3580) implementation of the outreach program. We compared adherence proportions and discontinuation rates before and after program implementation, both crude and adjusted for age, race/ethnicity, education, income, and stage. We conducted a pooled analysis of data from six Cancer Research Network (CRN) sites that had not implemented programs for improving AET adherence, using identical methods and time periods, to assess possible secular trends. RESULTS: In the pre-outreach period, estimated adherence in years 1, 2, and 3 following AET initiation was 75.2%, 71.0%, and 67.3%; following the outreach program, the estimates were 79.4%, 75.6%, and 72.2% (p-values < .0001 for pairwise comparisons). Results were comparable after adjusting for clinical and demographic factors. The estimated cumulative incidence of discontinuation was 0.22 (0.21-0.24) and 0.18 (0.17-0.19) at 3 years for pre- and post-outreach groups (p-value < .0001). We found no evidence of an increase in adherence between the study periods at the CRN sites with no AET adherence program. CONCLUSION: Adherence and discontinuation after AET initiation improved modestly following implementation of the outreach program.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , California/epidemiologia , Quimioterapia Adjuvante , Terapia Combinada , Feminino , Implementação de Plano de Saúde , Humanos , Adesão à Medicação , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Melhoria de Qualidade , Programas Médicos Regionais , Sistema de Registros , Estudos Retrospectivos , Fatores Socioeconômicos
5.
Int J Cancer ; 147(3): 747-756, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31709530

RESUMO

Genome-wide association studies (GWAS) have identified several loci contributing to lung cancer and COPD risk independently; however, inflammation-related pathways likely harbor additional lung cancer risk-associated variants in biologically relevant immune genes that differ dependent on COPD. We selected single nucleotide polymorphisms (SNPs) proximal to 2,069 genes within 48 immune pathways. We modeled the contribution of these variants to lung cancer risk in a discovery sample of 1,932 lung cancer cases and controls stratified by COPD status and validation sample of 953 cases and controls also stratified by COPD. There were 43 validated SNPs in those with COPD and 60 SNPs in those without COPD associated with lung cancer risk. Furthermore, 29 of 43 and 28 of 60 SNPs demonstrated a statistically significant interaction with COPD in the pooled sample. These variants demonstrated tissue-dependent effects on proximal gene expression, enhanced network connectivity and resided together in specific immune pathways. These results reveal that key inflammatory related genes and pathways, not found in prior GWAS, impact lung cancer risk in a COPD-dependent manner. Genetic variation identified in our study supplements prior lung cancer GWAS and serves as a foundation to further interrogate risk relationships in smoking and COPD populations.

6.
Cancer Prev Res (Phila) ; 13(2): 129-136, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31871221

RESUMO

Numerous organizations, including the United States Preventive Services Task Force, recommend annual lung cancer screening (LCS) with low-dose CT for high risk adults who meet specific criteria. Despite recommendations and national coverage for screening eligible adults through the Centers for Medicare and Medicaid Services, LCS uptake in the United States remains low (<4%). In recognition of the need to improve and understand LCS across the population, as part of the larger Population-based Research to Optimize the Screening PRocess (PROSPR) consortium, the NCI (Bethesda, MD) funded the Lung PROSPR Research Consortium consisting of five diverse healthcare systems in Colorado, Hawaii, Michigan, Pennsylvania, and Wisconsin. Using various methods and data sources, the center aims to examine utilization and outcomes of LCS across diverse populations, and assess how variations in the implementation of LCS programs shape outcomes across the screening process. This commentary presents the PROSPR LCS process model, which outlines the interrelated steps needed to complete the screening process from risk assessment to treatment. In addition to guiding planned projects within the Lung PROSPR Research Consortium, this model provides insights on the complex steps needed to implement, evaluate, and improve LCS outcomes in community practice.

7.
JCO Clin Cancer Inform ; 3: 1-10, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31487201

RESUMO

PURPOSE: To evaluate health care systems for the availability of population-level data on the frequency of use and results of clinical molecular marker tests to inform precision cancer care. METHODS: We assessed cancer-related molecular marker test data availability across 12 US health care systems in the Cancer Research Network. Overall, these systems provide care to a diverse population of more than 12 million people in the United States. We performed qualitative analyses of test data availability for five blood-based protein, nine germline, and 14 tissue-based tumor marker tests in each health care system's electronic health record and tumor registry using key informants, test code lists, and manual review of data types and output. We then performed quantitative analyses to estimate the proportion of patients with cancer with test utilization data and results for specific molecular marker tests. RESULTS: Health systems were able to systematically capture population-level data on all five blood protein markers, six of 14 tissue-based tumor markers, and none of the nine germline markers. Successful, systematic data capture was achievable for tests with electronic data feeds for test results (blood protein markers) or through prior manual abstraction by tumor registrars (select tumor-based markers). For test results stored in scanned image files (particularly germline and tumor marker tests), information on which test was performed and test results was not readily accessible in an electronic format. CONCLUSION: Even in health care systems with sophisticated electronic health records, there were few codified data elements available for evaluating precision cancer medicine test use and results at the population level. Health care organizations should establish standards for electronic reporting of precision medicine tests to expedite cancer research and facilitate the implementation of precision medicine approaches.


Assuntos
Registros Eletrônicos de Saúde , Neoplasias/epidemiologia , Biomarcadores Tumorais , Coleta de Dados , Assistência à Saúde , Gerenciamento Clínico , Humanos , Biópsia Líquida , Técnicas de Diagnóstico Molecular , Neoplasias/diagnóstico , Neoplasias/etiologia , Neoplasias/terapia , Medicina de Precisão , Vigilância em Saúde Pública , Pesquisa , Estados Unidos/epidemiologia
8.
Med Phys ; 46(7): 3207-3216, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087332

RESUMO

PURPOSE: Computed tomography (CT) is an effective method for detecting and characterizing lung nodules in vivo. With the growing use of chest CT, the detection frequency of lung nodules is increasing. Noninvasive methods to distinguish malignant from benign nodules have the potential to decrease the clinical burden, risk, and cost involved in follow-up procedures on the large number of false-positive lesions detected. This study examined the benefit of including perinodular parenchymal features in machine learning (ML) tools for pulmonary nodule assessment. METHODS: Lung nodule cases with pathology confirmed diagnosis (74 malignant, 289 benign) were used to extract quantitative imaging characteristics from computed tomography scans of the nodule and perinodular parenchyma tissue. A ML tool development pipeline was employed using k-medoids clustering and information theory to determine efficient predictor sets for different amounts of parenchyma inclusion and build an artificial neural network classifier. The resulting ML tool was validated using an independent cohort (50 malignant, 50 benign). RESULTS: The inclusion of parenchymal imaging features improved the performance of the ML tool over exclusively nodular features (P < 0.01). The best performing ML tool included features derived from nodule diameter-based surrounding parenchyma tissue quartile bands. We demonstrate similar high-performance values on the independent validation cohort (AUC-ROC = 0.965). A comparison using the independent validation cohort with the Fleischner pulmonary nodule follow-up guidelines demonstrated a theoretical reduction in recommended follow-up imaging and procedures. CONCLUSIONS: Radiomic features extracted from the parenchyma surrounding lung nodules contain valid signals with spatial relevance for the task of lung cancer risk classification. Through standardization of feature extraction regions from the parenchyma, ML tool validation performance of 100% sensitivity and 96% specificity was achieved.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Processamento de Imagem Assistida por Computador/provisão & distribução , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Aprendizado de Máquina , Tomografia Computadorizada por Raios X , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Referência
9.
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
10.
Cancer Epidemiol Biomarkers Prev ; 28(4): 724-730, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30642838

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition with respect to onset, progression, and response to therapy. Incorporating clinical- and imaging-based features to refine COPD phenotypes provides valuable information beyond that obtained from traditional clinical evaluations. We characterized the spectrum of COPD-related phenotypes in a sample of former and current smokers and evaluated how these subgroups differ with respect to sociodemographic characteristics, COPD-related comorbidities, and subsequent risk of lung cancer. METHODS: White (N = 659) and African American (N = 520) male and female participants without lung cancer (controls) in the INHALE study who completed a chest CT scan, interview, and spirometry test were used to define distinct COPD-related subgroups based on hierarchical clustering. Seven variables were used to define clusters: pack years, quit years, FEV1/FVC, % predicted FEV1, and from quantitative CT (qCT) imaging, % emphysema, % air trapping, and mean lung density ratio. Cluster definitions were then applied to INHALE lung cancer cases (N = 576) to evaluate lung cancer risk. RESULTS: Five clusters were identified that differed significantly with respect to sociodemographic (e.g., race, age) and clinical (e.g., BMI, limitations due to breathing difficulties) characteristics. Increased risk of lung cancer was associated with increasingly detrimental lung function clusters (when ordered from most detrimental to least detrimental). CONCLUSIONS: Measures of lung function vary considerably among smokers and are not fully explained by smoking intensity. IMPACT: Combining clinical (spirometry) and radiologic (qCT) measures of COPD defines a spectrum of lung disease that predicts lung cancer risk differentially among patient clusters.


Assuntos
Diagnóstico por Imagem/métodos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Fumar/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fatores de Risco
11.
J Drugs Dermatol ; 17(10): 1032-1036, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30365582

RESUMO

BACKGROUND: Epidemiologic studies of patients who present to dermatology clinics are necessary to identify the needs of patients. OBJECTIVE: To quantify and compare diagnoses according to race, ethnicity, and socioeconomic status (SES) at 6 general dermatology clinics from January 2013 to December 2016. METHODS: A retrospective cohort of new patients was established using an electronic medical record database. Primary diagnoses and diagnostic codes were recorded. Geocoding was utilized to obtain SES. RESULTS: There were 65969 new patient visits. Racial and ethnic demographics were obtained with the overall top 3 conditions being eczema or dermatitis, benign skin neoplasm, and adnexal disease. In blacks, however, follicular disorders were the third most common condition seen. The most frequently encountered diagnoses at the clinics with the highest and lowest SES were benign skin neoplasm and eczema or dermatitis, respectively. LIMITATIONS: Only primary diagnoses were included in analysis. Determining one's race is increasingly difficult. CONCLUSION: Follicular disorders occurred with an increased frequency in blacks. When examining SES, eczema or dermatitis was the most frequently encountered primary diagnosis at the clinic with the lowest SES, with benign skin neoplasm seen with the highest frequency at the clinic with the highest SES. J Drugs Dermatol. 2018;17(10):1032-1036.


Assuntos
Dermatopatias/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Eczema/epidemiologia , Eczema/etnologia , Eczema/etiologia , Grupos Étnicos , Feminino , Humanos , Lactente , Masculino , Registros Médicos , Michigan/epidemiologia , Pessoa de Meia-Idade , Visita a Consultório Médico/estatística & dados numéricos , Estudos Retrospectivos , Dermatopatias/etnologia , Dermatopatias/etiologia , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/etnologia , Neoplasias Cutâneas/etiologia , Fatores Socioeconômicos , Adulto Jovem
12.
Carcinogenesis ; 39(12): 1447-1454, 2018 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-30202894

RESUMO

Immunotherapy is a promising advancement in the treatment of non-small-cell lung carcinoma (NSCLC), although much of how lung tumors interact with the immune system in the natural course of disease remains unknown. We investigated the impact of the expression of immune-centric genes and pathways in tumors on patient survival to reveal novel candidates for immunotherapeutic research. Tumor transcriptomes and detailed clinical characteristics were obtained from patients with NSCLC who were participants of either the Inflammation, Health and Lung Epidemiology (INHALE) (discovery, N = 280) or The Cancer Genome Atlas (TCGA) Lung (replication, N = 1026) studies. Expressions of 2253 genes derived from 48 major immune pathways were assessed for association with patient prognosis using a multivariable Cox model and pathway effects were assessed with an in-house implementation of the Gene Set Enrichment Analysis (GSEA) algorithm. Prognosis-guided gene and pathway analysis of immune-centric expression in tumors revealed significant survival enrichments across both cohorts. The 'Interleukin Signaling' pathway, containing 430 genes, was found to be statistically and significantly enriched with prognostic signal in both the INHALE (P = 0.008) and TCGA (P = 0.039) datasets. Subsequent leading-edge analysis identified a subset of genes (N = 23) shared between both cohorts, driving the pathway enrichment. Cumulative expression of this leading-edge gene signature was a strong predictor of patient survival [discovery: hazard ratio (HR) = 1.59, P = 3.0 × 10-8; replication: HR = 1.29, P = 7.4 × 10-7]. These data demonstrate the impact of immune-centric expression on patient outcomes in NSCLC. Furthermore, prognostic gene effects were localized to discrete immune pathways, of which Interleukin Signaling had the greatest impact on overall survival and the subset of genes driving these effects have promise for future therapeutic intervention.


Assuntos
Interleucinas/genética , Transdução de Sinais/genética , Transcriptoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Prognóstico , Adulto Jovem
13.
Future Med Chem ; 10(17): 2087-2108, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30066579

RESUMO

The ubiquitin proteasome system has been validated as a target of cancer therapies evident by the US FDA approval of anticancer 20S proteasome inhibitors. Deubiquitinating enzymes (DUBs), an essential component of the ubiquitin proteasome system, regulate cellular processes through the removal of ubiquitin from ubiquitinated-tagged proteins. The deubiquitination process has been linked with cancer and other pathologies. As such, the study of proteasomal DUBs and their inhibitors has garnered interest as a novel strategy to improve current cancer therapies, especially for cancers resistant to 20S proteasome inhibitors. This article reviews proteasomal DUB inhibitors in the context of: discovery through rational design approach, discovery from searching natural products and discovery from repurposing old drugs, and offers a future perspective.


Assuntos
Antineoplásicos/farmacologia , Enzimas Desubiquitinantes/antagonistas & inibidores , Desenho de Fármacos , Reposicionamento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Enzimas Desubiquitinantes/metabolismo , Descoberta de Drogas/métodos , Humanos , Neoplasias/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Inibidores de Proteassoma/uso terapêutico , Ubiquitina/metabolismo , Ubiquitinação/efeitos dos fármacos
14.
J Thorac Oncol ; 13(10): 1483-1495, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29981437

RESUMO

BACKGROUND: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. METHODS: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. RESULTS: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility. CONCLUSION: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.


Assuntos
Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
15.
J Trace Elem Med Biol ; 48: 233-238, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29773186

RESUMO

Cadmium is a known carcinogen that has been implicated in prostate cancer, but how it affects prostate carcinogenesis in humans remains unclear. Evidence from basic science suggests that cadmium can bind to the androgen receptor causing endocrine disruption. The androgen receptor is required for normal prostate development and is the key driver of prostate cancer progression. In this study, we examined the association between cadmium content and androgen receptor protein expression in prostate cancer tissue of African American (N = 22) and European American (N = 30) men. Although neither overall tumor cadmium content (log transformed) nor androgen receptor protein expression level differed by race, we observed a race-cadmium interaction with regard to androgen receptor expression (P = 0.003) even after accounting for age at prostatectomy, smoking history, and Gleason score. African American men had a significant positive correlation between tumor tissue cadmium content and androgen receptor expression (Pearson correlation = 0.52, P = 0.013), while European Americans showed a non-significant negative correlation between the two (Pearson correlation = -0.19, P = 0.31). These results were unchanged after further accounting for tissue zinc content or dietary zinc or selenium intake. African American cases with high-cadmium content (>median) in tumor tissue had more than double the androgen receptor expression (0.021 vs. 0.008, P = 0.014) of African American men with low-cadmium level. No difference in androgen receptor expression was observed in European Americans by cadmium level (high 0.015 vs. low 0.011, P = 0.30). Larger studies are needed to confirm these results and if upheld, determine the biologic mechanism by which cadmium increases androgen receptor protein expression in a race-dependent manner. Our results suggest that cadmium may play a role in race disparities observed in prostate cancer.


Assuntos
Cádmio/análise , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/biossíntese , Afro-Americanos , Grupo com Ancestrais do Continente Europeu , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos
16.
J Natl Cancer Inst ; 109(8)2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29117387

RESUMO

Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Loci Gênicos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2/genética , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 22 , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Masculino
17.
Ann Am Thorac Soc ; 14(12): 1827-1835, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28683215

RESUMO

RATIONALE: Lung cancer screening registries can monitor screening outcomes and improve quality of care. OBJECTIVES: To describe nascent lung cancer screening programs and share efficient data collection approaches for mandatory registry reporting in four integrated health care systems of the National Cancer Institute-funded Cancer Research Network. METHODS: We documented the distinctive characteristics of lung cancer screening programs, and we provide examples of strategies to facilitate data collection and describe early challenges and possible solutions. In addition, we report preliminary data on use and outcomes of screening with low-dose computed tomography at each of the participating sites. RESULTS: Programs varied in approaches to confirming patient eligibility, ordering screening low-dose computed tomographic scans, and coordinating follow-up care. Most data elements were collected from structured fields in electronic health records, but sites also made use of standardized order templates, local procedure codes, identifiable hashtags in radiology reports, and natural language processing algorithms. Common challenges included incomplete documentation of tobacco smoking history, difficulty distinguishing between scans performed for screening versus diagnosis or surveillance, and variable adherence with use of standardized templates. Adherence with eligibility criteria as well as the accuracy and completeness of data collection appeared to depend at least partly on availability of personnel and other resources to support the successful implementation of screening. CONCLUSIONS: To maximize the effectiveness of lung cancer screening, minimize the burden of data collection, and facilitate research and quality improvement, clinical workflow and information technology should be purposefully designed to ensure that patients meet eligibility criteria and receive appropriate follow-up testing.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Programas de Rastreamento/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Melhoria de Qualidade , Sistema de Registros , Tomografia Computadorizada por Raios X , Estados Unidos
18.
Cancer Epidemiol Biomarkers Prev ; 25(12): 1609-1618, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27587788

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. METHODS: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. RESULTS: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. IMPACT: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Complexo Repressor Polycomb 1/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética
19.
Cancer Epidemiol Biomarkers Prev ; 25(9): 1341-7, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27383774

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk. METHODS: A total of 341 lung cancer cases and 752 volunteer controls, ages 21 to 89 years, participated in a structured interview, standardized CT scan, and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than -950 Hounsfield units on the inspiratory scan (HUI) and percent voxels less than -856 HU on expiratory scan (HUE). RESULTS: The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared with those without, regardless of assessment method; however, in multivariable modeling, only percent voxels <-856 HUE as a continuous measure of air trapping [OR = 1.04; 95% confidence interval (CI), 1.03-1.06] and FEV1/FVC < 0.70 (OR = 1.71; 95% CI, 1.21-2.41) were independent predictors of lung cancer risk. Nearly 10% of lung cancer cases were negative on all objective measures of COPD. CONCLUSION: Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplementary measures at the time of screening for lung cancer. IMPACT: Quantitative measures of air trapping based on imaging provide additional information for the identification of high-risk groups who might benefit the most from lung cancer screening. Cancer Epidemiol Biomarkers Prev; 25(9); 1341-7. ©2016 AACR.


Assuntos
Neoplasias Pulmonares/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Testes de Função Respiratória , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Espirometria , Tomografia Computadorizada por Raios X , Capacidade Vital
20.
Nat Commun ; 7: 10979, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27052111

RESUMO

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.


Assuntos
Afro-Americanos , Epigênese Genética , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Padrões de Herança , Neoplasias da Próstata/genética , Acetilação , Atlas como Assunto , Linhagem Celular Tumoral , Loci Gênicos , Estudo de Associação Genômica Ampla , Histonas/genética , Histonas/metabolismo , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia
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