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1.
PLoS Genet ; 17(3): e1009254, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33667223

RESUMO

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.

2.
Gut ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632709

RESUMO

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

3.
Nat Commun ; 11(1): 6071, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247085

RESUMO

The independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.

4.
Cancer Epidemiol Biomarkers Prev ; 29(12): 2441-2453, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33033144

RESUMO

Biomarkers have a wide range of applications in the clinical management of cancer, including screening and therapeutic management. Tumor DNA released from neoplastic cells has become a particularly active area of cancer biomarker development due to the critical role somatic alterations play in the pathophysiology of cancer and the ability to assess released tumor DNA in accessible clinical samples, in particular blood (i.e., liquid biopsy). Many of the early applications of tumor DNA as a biomarker were pioneered in colorectal cancer due to its well-defined genetics and common occurrence, the effectiveness of early detection, and the availability of effective therapeutic options. Herein, in the context of colorectal cancer, we describe how the intended clinical application dictates desired biomarker test performance, how features of tumor DNA provide unique challenges and opportunities for biomarker development, and conclude with specific examples of clinical application of tumor DNA as a biomarker with particular emphasis on early detection.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

5.
Brief Bioinform ; 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32844230

RESUMO

Alternative polyadenylation (APA) in breast tumor samples results in the removal/addition of cis-regulatory elements such as microRNA (miRNA) target sites in the 3'-untranslated region (3'-UTRs) of genes. Although previous computational APA studies focused on a subset of genes strongly affected by APA (APA genes), we identify miRNAs of which widespread APA events collectively increase or decrease the number of target sites [probabilistic inference of microRNA target site modification through APA (PRIMATA-APA)]. Using PRIMATA-APA on the cancer genome atlas (TCGA) breast cancer data, we found that the global APA events change the number of the target sites of particular microRNAs [target sites modified miRNA (tamoMiRNA)] enriched for cancer development and treatments. We also found that when knockdown (KD) of NUDT21 in HeLa cells induces a different set of widespread 3'-UTR shortening than TCGA breast cancer data, it changes the target sites of the common tamoMiRNAs. Since the NUDT21 KD experiment previously demonstrated the tumorigenic role of APA events in a miRNA dependent fashion, this result suggests that the APA-initiated tumorigenesis is attributable to the miRNA target site changes, not the APA events themselves. Further, we found that the miRNA target site changes identify tumor cell proliferation and immune cell infiltration to the tumor microenvironment better than the miRNA expression levels or the APA events themselves. Altogether, our computational analyses provide a proof-of-concept demonstration that the miRNA target site information indicates the effect of global APA events with a potential as predictive biomarker.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32411683

RESUMO

Shortening of 3'UTRs (3'US) through alternative polyadenylation is a post-transcriptional mechanism that regulates the expression of hundreds of genes in human cancers. In breast cancer, different subtypes of tumor samples, such as estrogen receptor positive and negative (ER+ and ER-), are characterized by distinct molecular mechanisms, suggesting possible differences in the post-transcriptional regulation between the subtype tumors. In this study, based on the profound tumorigenic role of 3'US interacting with competing-endogenous RNA (ceRNA) network (3'US-ceRNA effect), we hypothesize that the 3'US-ceRNA effect drives subtype-specific tumor growth. However, we found that the subtypes are available in different sample sizes, biasing the ceRNA network size and disabling the fair comparison of the 3'US-ceRNA effect. Using normalized Laplacian matrix eigenvalue distribution, we addressed this bias and built tumor ceRNA networks comparable between the subtypes. Based on the comparison, we identified a novel role of housekeeping (HK) genes as stable and strong miRNA sponges (sponge HK genes) that synchronize the ceRNA networks of normal samples (adjacent to ER+ and ER- tumor samples). We further found that distinct 3'US events in the ER- tumor break the stable sponge effect of HK genes in a subtype-specific fashion, especially in association with the aggressive and metastatic phenotypes. Knockdown of NUDT21 further suggested the role of 3'US-ceRNA effect in repressing HK genes for tumor growth. In this study, we identified 3'US-ceRNA effect on the sponge HK genes for subtype-specific growth of ER- tumors.

7.
Sci Rep ; 10(1): 92, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919420

RESUMO

Melanoma patients' plasma contains exosomes produced by malignant and normal cells. Plasma exosomes were isolated and separated by immunocapture into two fractions: melanoma cell-derived exosomes (MTEX) and normal cell-derived exosomes (non-MTEX). Immunosuppressive effects of MTEX on primary human immune cells were evaluated. Exosomes were isolated from plasma of 12 melanoma patients and six healthy donors (HDs). Expression levels of 19 immunoregulatory proteins in MTEX, non-MTEX and HDs exosomes were evaluated by on-bead flow cytometry. Functional/phenotypic changes induced in CD8+ T or natural killer (NK) cells by MTEX or non-MTEX were compared. Plasma protein levels were higher in patients than HDs (P < 0.0009). In patients, MTEX accounted for 23-66% of total exosomes. MTEX were enriched in immunosuppressive proteins (P = 0.03). MTEX, but not HDs exosomes, inhibited CD69 expression (P ≤ 0.0008), induced apoptosis (P ≤ 0.0009) and suppressed proliferation (P ≤ 0.002) in CD8+ T cells and downregulated NKG2D expression in NK cells (P = 0.001). Non-MTEX were enriched in immunostimulatory proteins (P = 0.002) and were only weakly immunosuppressive. Elevated MTEX/total exosome ratios and, surprisingly, non-MTEX ability to induce apoptosis of CD8+ T cells emerged as positive correlates of disease stage. MTEX emerge as the major mechanism of tumor-induced immune suppression and as an underestimated barrier to successful melanoma immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Micropartículas Derivadas de Células/imunologia , Exossomos/patologia , Tolerância Imunológica/imunologia , Melanoma/imunologia , Estudos de Casos e Controles , Exossomos/genética , Exossomos/imunologia , Humanos , Células Matadoras Naturais/imunologia , Melanoma/genética , Melanoma/patologia
8.
Gastrointest Endosc ; 91(3): 634-640, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31521778

RESUMO

BACKGROUND AND AIMS: Guidelines recommend colonoscopy after an episode of diverticulitis to exclude neoplasia but the effectiveness of testing is uncertain. Patients with complicated diverticulitis may be at higher risk for neoplasia, but most patients have uncomplicated disease. We examined the incidence of colorectal cancer (CRC) and advanced adenoma (AA) in patients with diverticulitis compared with patients undergoing screening colonoscopy. METHODS: CT scans from January 1, 2008, to May 1, 2013, at the University of Pittsburgh Medical Center (UPMC) were reviewed to identify those with confirmed acute diverticulitis. Subsequent surgical, colonoscopy, and pathology reports were abstracted to identify those with a diagnosis of AA and CRC. The incidence of neoplasia was compared with that reported for screening colonoscopy from a meta-analysis (n = 68,324), and from colonoscopy examinations at UPMC between 2013 and 2015 (n = 28,573). RESULTS: A total of 5167 abdominal/pelvic CT scan reports identified 978 patients with acute diverticulitis, among which 474 (48.5%) patients had undergone at least 1 colonoscopy or gastrointestinal surgery to April 2015. The CRC rate in patients with diverticulitis (13/474, 2.7%) was significantly higher (P < .0001) compared with both the meta-analysis (0.8%) and UPMC (0.3%). The AA rate (19/474, 4.0%) was similar to the rate in the meta-analysis (5.0%, P = .39) but significantly lower than at UPMC (7.7%, P = .003). The incidence of AA or CRC in complicated diverticulitis (10/141, 7.1%) did not differ significantly (P = .85) from the incidence of AA or CRC in uncomplicated diverticulitis (22/332, 6.6%). CONCLUSIONS: CRC after diverticulitis was significantly higher than that observed at screening colonoscopy and was not limited to complicated disease. Colonoscopy is advisable after the diagnosis of diverticulitis.

9.
J Cancer Educ ; 35(6): 1219-1226, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31388974

RESUMO

Recent cancer care delivery models and clinical practice guidelines have expanded the role of primary care providers (PCPs) in routine follow-up of cancer survivors. We conducted a cross-sectional survey of PCPs affiliated with a large healthcare system to (1) examine practices, attitudes, and beliefs regarding preparedness to provide survivorship care and (2) explore predictors of confidence managing cancer survivors. We distributed a self-administered online survey to 1069 clinical affiliates providing primary care services within the University of Pittsburgh Medical Center system. Associations between PCPs' professional characteristics and attitudes and preparedness were evaluated. Multiple logistic regression explored predictors of confidence monitoring common cancer treatment-related symptoms. One hundred twenty-seven eligible PCPs responded. The sample was split between academic and community practice (48.0% vs. 52.0%, respectively), predominantly comprised of physicians (81.8%), and 64.6% had > 15 years direct patient care experience. The majority agreed that PCPs play a valuable role in surveillance and adverse event monitoring in survivors, though less than 25% felt their professional training prepared them to perform each of these domains. Physicians were significantly more likely than advanced practice providers to be among the 65% of PCPs who were confident monitoring ≥ 1 symptom in each of the 5 evaluated symptom clusters (OR 3.6, 95% CI 1.2-10.8). PCPs appear willing to assume an enhanced role in cancer survivorship care but feel unprepared to do so. Enhanced training and dissemination of clinical practice guidelines are needed to facilitate effective implementation of PCP-delivered survivorship care.

10.
Clin Breast Cancer ; 19(4): 304-310, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30827763

RESUMO

BACKGROUND: Of women diagnosed with metastatic breast cancer (MBC), 20% to 30% survive ≥5 years. We evaluated data from a large breast cancer program to identify features associated with MBC survival. PATIENTS AND METHODS: Women diagnosed with MBC in or after 1999 were included. Long-term MBC survival was defined as ≥5 years from date of MBC diagnosis (n = 122), short-term MBC survival as ≤2 years (n = 191). Differences were assessed using t tests, Wilcoxon-Mann-Whitney tests, χ2, and Fisher exact tests. Odds ratios (ORs) were calculated using multivariate logistic regression models. RESULTS: Long-term survivors were significantly (P < .05) younger, premenopausal, partnered, had estrogen receptor (ER)-positive, progesterone receptor-positive, and HER2-positive disease, lower Charlson Comorbidity Index, lower rates of visceral metastases, and higher household income. After adjustment for potential confounders, de novo MBC, premenopausal status, ER-positive status, and HER2-positive status remained significantly positively associated with long-term survival (respectively: OR, 2.68 [95% confidence interval (CI), 1.48-4.88]; OR, 1.96 [95% CI, 1.02-3.79]; OR, 3.74 [95% CI, 1.72-8.14]; OR, 2.88 [95% CI, 1.61-5.14]). Triple-negative status, visceral with bone metastases, and brain metastases remained negatively associated with long-term survival (respectively: OR, 0.12 [95% CI, 0.05-0.29]; OR, 0.18 [95% CI, 0.07-0.47]; OR, 0.16 [95% CI, 0.04-0.60]). Partner status and household income were significant in univariate but not multivariate analyses. CONCLUSION: Diagnosis of de novo MBC, premenopausal status, ER-positive status, and HER2-positive status were positively associated whereas triple-negative status, brain metastases, and visceral with bone metastases were inversely associated with long-term survival. These findings can be applied to better prognosticate survival for MBC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/mortalidade , Neoplasias Encefálicas/mortalidade , Neoplasias da Mama/mortalidade , Sobreviventes/estatística & dados numéricos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/mortalidade , Carcinoma Lobular/secundário , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
11.
Cancer Causes Control ; 30(5): 537-547, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30905014

RESUMO

PURPOSE: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated. METHODS: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (n = 7,022). Using age- and stage-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors. RESULTS: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR = 1.37; 95% CI 1.10-1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR = 1.28; 95% CI 1.08-1.52, and HR = 1.26; 95% CI 1.04-1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS. CONCLUSIONS: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients' survival.


Assuntos
Carcinoma Epitelial do Ovário/epidemiologia , Neoplasias Ovarianas/epidemiologia , Comportamento Sedentário , Fumar/epidemiologia , Feminino , Humanos , Atividade Motora , Obesidade/complicações , Neoplasias Ovarianas/mortalidade , Sobrepeso/complicações , Modelos de Riscos Proporcionais , Fatores de Risco , Fumar/efeitos adversos , Ganho de Peso
12.
Oncol Nurs Forum ; 46(1): 83-91, 2019 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-30547962

RESUMO

OBJECTIVES: To determine the incidence of financial toxicity among women with metastatic breast cancer, as well as the relationships among financial toxicity, quality of life, and overall cancer-related distress in members of this patient population. SAMPLE & SETTING: 145 women with metastatic breast cancer receiving care at an urban outpatient breast cancer clinic. METHODS & VARIABLES: A cross-sectional analysis of women with metastatic breast cancer was performed. Data were collected on patient characteristics, quality of life, cancer-related distress, and financial toxicity using self-administered questionnaires. RESULTS: Financial toxicity is common among women with metastatic breast cancer and more common among low-income women with the disease. In addition, financial toxicity is correlated with worse quality of life and overall cancer-related distress. IMPLICATIONS FOR NURSING: Nurses should consider financial toxicity for all patients receiving treatment for cancer. Understanding the concerns of specific patient populations and patients with different stages of cancer is necessary to tailor assessment and mitigation strategies.


Assuntos
Neoplasias da Mama/economia , Neoplasias da Mama/psicologia , Efeitos Psicossociais da Doença , Qualidade de Vida/psicologia , Estresse Psicológico/economia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Inquéritos e Questionários , Estados Unidos
13.
Int J Epidemiol ; 48(3): 751-766, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30059977

RESUMO

BACKGROUND: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. METHODS: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. RESULTS: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. CONCLUSIONS: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.


Assuntos
Adenocarcinoma de Pulmão/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Leucócitos/metabolismo , Neoplasias Pulmonares/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Homeostase do Telômero/genética , Telômero/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade
14.
Free Radic Biol Med ; 120: 170-180, 2018 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-29545070

RESUMO

Increased reactive species (RS; reactive oxygen and nitrogen species) are a byproduct of both enzymatic and non-enzymatic systems, and critical in cancer development, including breast tumorigenesis. To investigate the role of RS-related genes in breast cancer, expression levels of the most common annotated genes involved in regulating cellular RS levels and proteins that are substrates of RS in specific subtypes of breast cancer 9 were evaluated using public data bases. Based on the premise that increased RS promote tumor formation, and breast cancer subtypes vary in aggressiveness, we hypothesized that specific RS gene expression signatures are associated with breast cancer aggressiveness and patient survival. We identified a group of genes (GSTK1, PRDX2, PRDX3 and SLC36A1) that differentiate Luminal B tumors in two clusters and predict survival of patients with Luminal B breast cancers. Furthermore, network analyses of these four genes revealed an overlap of known LumB related pathways with those of RS-related signaling, which included regulation of M-phase and mitochondrial functions.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Espécies Reativas de Oxigênio/metabolismo , Transcriptoma , Sistemas de Transporte de Aminoácidos/genética , Análise por Conglomerados , Feminino , Glutationa Transferase/genética , Humanos , Estimativa de Kaplan-Meier , Oxirredução , Peroxirredoxina III/genética , Peroxirredoxinas/genética , Simportadores/genética
15.
Am J Respir Crit Care Med ; 198(2): 187-196, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29437466

RESUMO

RATIONALE: Gene promoter hypermethylation detected in sputum assesses the extent of field cancerization and predicts lung cancer (LC) risk in ever-smokers. A rapid decline of FEV1 is a major driver for development of airway obstruction. OBJECTIVES: To assess the effects of methylation of 12 genes on FEV1 decline and of FEV1 decline on subsequent LC incidence using two independent, longitudinal cohorts (i.e., LSC [Lovelace Smokers Cohort] and PLuSS [Pittsburgh Lung Screening Study]). METHODS: Gene methylation was measured in sputum using two-stage nested methylation-specific PCR. The linear mixed effects model was used to assess the effects of studied variables on FEV1 decline. MEASUREMENTS AND MAIN RESULTS: A dose-dependent relationship between number of genes methylated and FEV1 decline was identified, with smokers with three or more methylated genes having 27.8% and 10.3% faster FEV1 decline than smokers with zero to two methylated genes in the LSC and PLuSS cohort, respectively (all P < 0.01). High methylation in sputum was associated with a shorter latency for LC incidence (log-rank P = 0.0048) and worse all-cause mortality (log-rank P < 0.0001). Smokers with subsequent LC incidence had a more rapid annual decline of FEV1 (by 5.2 ml, P = 0.038) than smoker control subjects. CONCLUSIONS: Gene methylation detected in sputum predicted FEV1 decline, LC incidence, and all-cause mortality in smokers. Rapid FEV1 decline may be a risk factor for LC incidence in smokers, which may explain a greater prevalence of airway obstruction seen in patients with LC.


Assuntos
Metilação de DNA/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Neoplasias Pulmonares/genética , Regiões Promotoras Genéticas , Fumar/efeitos adversos , Fumar/genética , Escarro/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Fatores de Risco
16.
Cancer Causes Control ; 29(2): 201-212, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29327114

RESUMO

PURPOSE: Multiple studies have examined the role of anthropometric characteristics in ovarian cancer risk and survival; however, their results have been conflicting. We investigated the associations between weight change, height and height change and risk and outcome of ovarian cancer using data from a large population-based case-control study. METHODS: Data from 699 ovarian cancer cases and 1,802 controls who participated in the HOPE study were included. We used unconditional logistic regression adjusted for age, race, number of pregnancies, use of oral contraceptives, and family history of breast or ovarian cancer to examine the associations between self-reported height and weight and height change with ovarian cancer risk. Cox proportional hazards regression models adjusted for age and stage were used to examine the association between the exposure variables and overall and progression-free survival among ovarian cancer cases. RESULTS: We observed an increased risk of ovarian cancer mortality and progression for gaining more than 20 pounds between ages 18-30, HR 1.36; 95% CI 1.05-1.76, and HR 1.31; 95% CI 1.04-1.66, respectively. Losing weight and gaining it back multiple times was inversely associated with both ovarian cancer risk, OR 0.78; 95% CI 0.63-0.97 for 1-4 times and OR 0.73; 95% CI 0.54-0.99 for 5-9 times, and mortality, HR 0.63; 95% CI 0.40-0.99 for 10-14 times. Finally, being taller during adolescence and adulthood was associated with increased risk of mortality. Taller stature and weight gain over lifetime were not related to ovarian cancer risk. CONCLUSIONS: Our results suggest that height and weight and their change over time may influence ovarian cancer risk and survival. These findings suggest that biological mechanisms underlying these associations may be hormone driven and may play an important role in relation to ovarian carcinogenesis and tumor progression.


Assuntos
Antropometria , Neoplasias Ovarianas/epidemiologia , Adulto , Idoso , Índice de Massa Corporal , Peso Corporal , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Ganho de Peso
17.
Ann Am Thorac Soc ; 15(5): 615-621, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29328885

RESUMO

RATIONALE: Osteoporosis is common in individuals with chronic obstructive pulmonary disease. Lung-specific factors, including radiographic emphysema, independently associate with low bone mineral density in cross-sectional smoking cohorts. However, factors associated with progressive bone loss in smokers are understudied and largely unknown. OBJECTIVES: To determine the relationship between radiographic emphysema, circulating bone metabolism markers, and pulmonary function and accelerated bone mineral density loss in smokers. METHODS: Two hundred and forty male and female current and former smokers, 40 years of age or older, underwent baseline and 2-year assessments of pulmonary function, computed tomography-assessed emphysema, dual X-ray absorptiometry-measured bone mineral density, and circulating bone metabolism biomarker levels (type I collagen C-telopeptide [CTX], amino-terminal propeptide of type I procollagen [P1NP]). The association of radiographic emphysema, bone metabolism biomarker levels, and pulmonary function with accelerated hip bone mineral density loss, defined by the 75th percentile of annual hip bone mineral density decline, was determined by logistic regression modeling with adjustment for age, sex, inhaled and intermittent steroid use, active smoking, body mass index, and the presence of baseline low hip bone mineral density. RESULTS: Of those participants with accelerated hip bone mineral density loss, 22% had moderate or severe visually assessed emphysema compared with 7.2% of smokers without accelerated bone mineral density decline. Moderate to severe visually assessed emphysema (odds ratio, 2.84; 95% confidence interval, 1.01-7.98 compared with trace/mild or no visually assessed emphysema) and the 75th percentile of CTX levels (odds ratio, 2.38; 95% confidence interval, 1.20-4.72 compared with CTX levels below the 75th percentile), a marker of bone resorption, were associated with accelerated hip bone mineral density decline after adjustment for covariates and the presence of baseline low hip bone mineral density. FEV1% predicted was not associated with accelerated bone mineral density decline after adjustment for covariates. Multivariate modeling showed moderate to severe visually assessed emphysema, and the 75th percentiles of CTX were independently associated with accelerated hip bone mineral density decline after adjustment for covariates. CONCLUSIONS: Emphysema and elevated markers of bone resorption are independently associated with progressive bone mineral density loss in smokers. These clinical markers may guide targeted bone mineral density screening and monitoring in smokers at highest risk.


Assuntos
Densidade Óssea , Colágeno Tipo I/sangue , Osteoporose/sangue , Enfisema Pulmonar/diagnóstico , Fumar/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Absorciometria de Fóton , Adulto , Biomarcadores/sangue , Estudos Transversais , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etiologia , Enfisema Pulmonar/sangue , Enfisema Pulmonar/complicações , Estudos Retrospectivos , Fatores de Risco , Fumar/sangue
18.
J Thorac Oncol ; 13(3): 399-412, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29233790

RESUMO

INTRODUCTION: A hormonal role in NSCLC development is well documented. We previously showed that the aromatase inhibitor (AI) anastrozole decreased development of tobacco carcinogen-induced lung tumors in a murine lung cancer prevention model and that aromatase and estrogen receptor were expressed in pulmonary inflammatory cells. METHODS: We utilized a tobacco carcinogen-induced lung tumor mouse model by treatment with 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), to determine whether an AI combined with nonsteroidal anti-inflammatory drugs results in greater lung tumor prevention effects compared to single-agent treatment. RESULTS: Combination of anastrozole (0.1 mg/kg/d) with aspirin (25 mg/kg/d) after NNK exposure resulted in significantly fewer and smaller lung tumors than did single-agent treatments and was accompanied by maximum decreases in circulating ß-estradiol (E2) and interleukin-6, tumor-infiltrating macrophages, and tumoral Ki67, phospho-mitogen-activated protein kinase, phospho-signal transducer and activator of transcription 3, and interleukin-17A expression. Preneoplasia arising after combination treatment showed the lowest Sox-2 expression, suggesting an inhibitory effect on proliferative capacity in the airways by blocking both E2 and inflammation. Anastrozole combined with ibuprofen instead of aspirin also showed enhanced antitumor effects. Moreover, male mice treated with NNK that received E2 in their drinking water showed greater levels of pulmonary macrophages and inflammatory markers than did the control, confirming an E2 effect on inflammation in the microenvironment. CONCLUSIONS: Our results suggest a benefit to joint targeting of the estrogen and inflammatory pathways for NSCLC prevention. Combining AIs with nonsteroidal anti-inflammatory drugs reduces circulating E2, proinflammatory cytokines, and macrophage recruitment in the lung microenvironment after tobacco exposure. This strategy could be particularly effective in women who have underlying pulmonary inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Tabaco/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores da Aromatase/farmacologia , Carcinógenos , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos
19.
Cancer Epidemiol Biomarkers Prev ; 26(9): 1470-1473, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28864456

RESUMO

Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470-3. ©2017 AACR.


Assuntos
Neoplasias Ovarianas/mortalidade , Comorbidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Ovarianas/epidemiologia , Análise de Sobrevida
20.
Br J Cancer ; 117(7): 1063-1069, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28817835

RESUMO

BACKGROUND: Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited. METHODS: We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all-cause survival among women diagnosed with invasive ovarian cancer. RESULTS: Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97-1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19-3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03-1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival. CONCLUSIONS: In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival.


Assuntos
Hipertireoidismo/epidemiologia , Hipotireoidismo/epidemiologia , Neoplasias Ovarianas/mortalidade , Idoso , Feminino , Humanos , Hipertireoidismo/tratamento farmacológico , Hipotireoidismo/tratamento farmacológico , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Fatores de Tempo
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