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1.
BMC Med ; 20(1): 332, 2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36199081

RESUMO

BACKGROUND: Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. METHODS: To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. RESULTS: We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. CONCLUSIONS: Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.


Assuntos
Predisposição Genética para Doença , Neoplasias Primárias Múltiplas , Exoma/genética , Predisposição Genética para Doença/genética , Humanos , Neoplasias Primárias Múltiplas/genética , Fenótipo , Sequenciamento Completo do Exoma
2.
Mol Cancer Res ; 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36125519

RESUMO

The most common somatic event in primary prostate cancer is a fusion between the androgen-related TMPRSS2 gene and the ERG oncogene. Tumors with these fusions, which occur early in carcinogenesis, have a distinctive etiology. A smaller subset of other tumors harbor fusions between TMPRSS2 and members of the ETS transcription factor family other than ERG. To assess the genomic similarity of tumors with non-ERG ETS fusions and those with fusions involving ERG, this study derived a transcriptomic signature of non-ERG ETS fusions and assessed this signature and ERG-related gene expression in 1,050 men with primary prostate cancer from three independent population-based and hospital-based studies. While non-ERG ETS fusions involving ETV1, ETV4, ETV5, or FLI1 were individually rare, they jointly accounted for one in seven prostate tumors. Genes differentially regulated between non-ERG ETS tumors and tumors without ETS fusions showed similar differential expression when ERG tumors and tumors without ETS fusions were compared (differences explained: R2 69-77%), including ETS-related androgen receptor (AR) target genes. Differences appeared to result from similarities among ETS tumors rather than similarities among non-ETS tumors. Gene sets associated with ERG fusions were consistent with gene sets associated with non-ERG ETS fusions, including fatty acid and amino acid metabolism, an observation that was robust across cohorts. Implications: Considering ETS fusions jointly may be useful for etiologic studies on prostate cancer, given that the transcriptome is profoundly impacted by ERG and non-ERG ETS fusions in a largely similar fashion, most notably genes regulating metabolic pathways.

3.
Br J Cancer ; 127(9): 1670-1679, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36028533

RESUMO

BACKGROUND: Individual health behaviours have been associated with fatal prostate cancer (PCa). Their combined association with fatal PCa after diagnosis is unknown. METHODS: This prospective cohort included 4518 men diagnosed with nonmetastatic PCa from the Health Professionals Follow-up Study. Exposures included a three-factor score integrating post-diagnostic fatal PCa risk factors ("2021 PCa Behaviour Score"), six-factor score integrating incident aggressive PCa risk factors ("2015 PCa Behaviour Score"), and two scores integrating recommendations for cancer prevention and survival, respectively. Multivariable Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for fatal PCa. RESULTS: Over a median 10.2 years, we observed 219 PCa deaths. Each additional point of one of the PCa-specific health behaviour scores (2015 PCa Behaviour Score) was associated with a 19% reduced fatal PCa risk (HR: 0.81, 95%CI: 0.68-0.97). The 2021 PCa Behaviour Score and scores integrating national recommendations were not associated with fatal PCa. CONCLUSIONS: While a PCa-specific health behaviour score was associated with a reduced risk of fatal PCa, we did not otherwise observe strong evidence of associations between post-diagnostic scores and fatal PCa. Avoiding tobacco, healthy body size, and physical activity may decrease PCa death risk, but further research is needed to inform cancer survivorship recommendations.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Estudos Prospectivos , Seguimentos , Neoplasias da Próstata/patologia , Modelos de Riscos Proporcionais , Fatores de Risco , Comportamentos Relacionados com a Saúde
4.
Cancers (Basel) ; 14(15)2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35954479

RESUMO

Background: Technology-based interventions are increasingly used to improve physical activity (PA) and diet. Methods: We conducted a systematic review of randomized controlled trials (RCTs) published up to August 2021 that tested mobile health (mHealth) PA and/or dietary interventions among cancer survivors and reported on the feasibility, satisfaction, behavioral change, and/or quality of life (QOL) outcomes. Results: In total, 61 articles were identified on PubMed, and 23 of those met the inclusion criteria. The most common cancers were breast (n = 1000), prostate (n = 713), and colorectal (n = 650). Participants were predominantly White (median: 84%, interquartile range (IQR): 20%) and college-educated (58%). The interventions varied, but the most common combination of components (six studies) was a website/mobile app with an activity tracker and coaching. In terms of duration, 70% (n = 16) of the interventions lasted 12 weeks. The median total tracker wear was 87% of the study days (IQR: 6%) and the median text-message reply rate was 73% (IQR 4%). Most participants (median: 87%; IQR: 16%) were satisfied with at least one intervention component. Eleven out of 18 studies examining behavioral change reported significant between-group differences and six out of 11 studies examining QoL reported significant improvements. Conclusions: mHealth interventions are a promising approach to improving the PA and diets of cancer survivors. Research in racially/ethnically and socioeconomically diverse populations is needed.

5.
Cancer Epidemiol Biomarkers Prev ; 31(9): 1760-1768, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-35767977

RESUMO

BACKGROUND: Inflammatory and insulin pathways have been linked to prostate cancer; postdiagnostic behaviors activating these pathways may lead to poor outcomes. The empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH), and empirical dietary index for insulin resistance (EDIR), and associated lifestyle indices (ELIH, ELIR) predict biomarkers of inflammation (EDIP: IL6, TNFaR2, CRP) and insulin secretion (EDIH/ELIH: c-peptide; EDIR/ELIR: TAG:HDL) from whole foods and behaviors. METHODS: Associations of these indices with time to prostate cancer progression (primary, n = 2,056) and prostate cancer-specific mortality (PCSM; secondary, n = 2,447) were estimated among men diagnosed with nonmetastatic prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavor cohort diet and lifestyle sub-study. Because the true (versus clinically documented) date of progression is unobserved, we used parametric (Weibull) survival models to accommodate interval-censoringand estimated adjusted HR and 95% confidence intervals (CI) for prostate cancer progression per 1-SD increase in index. Cox proportional hazards models were used to estimate PCSM associations. RESULTS: During a median [interquartile range (IQR)] 6.4 years (IQR, 1.3-12.7), 192 progression and 73 PCSM events were observed. Inflammatory (EDIP: HR, 1.27; CI, 1.17-1.37), hyperinsulinemic (EDIH: HR, 1.24; CI, 1.05-1.46. ELIH: HR, 1.34; CI, 1.17-1.54), and insulin-resistant (EDIR: HR, 1.22; CI, 1.00-1.48. ELIR: HR, 1.36; CI, 1.12-1.64) indices were positively associated with risk of prostate cancer progression. There was no evidence of associations between the indices and PCSM. CONCLUSIONS: Both inflammatory and insulinemic dietary and lifestyle patterns are associated with risk of prostate cancer progression. IMPACT: For men with prostate cancer, consuming dietary patterns that limit chronic systemic inflammation and insulin hypersecretion may improve survivorship, especially when coupled with active lifestyle and healthy body weight. See related commentary by Kucuk, p. 1673.


Assuntos
Hiperinsulinismo , Neoplasias da Próstata , Dieta , Humanos , Inflamação , Insulina , Estilo de Vida , Masculino , Neoplasias da Próstata/patologia , Fatores de Risco
6.
Eur Urol ; 82(3): 247-251, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35715363

RESUMO

To disentangle the "obesity paradox" in renal cell carcinoma (RCC), we examined associations of body mass index (BMI) and weight change with RCC risk and survival in the Health Professionals Follow-up Study (HPFS) and Nurses' Health Study (NHS) 1 and 2. We estimated cohort-specific and summary covariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for RCC incidence, as well as RCC-specific survival among cases in the pooled HPFS and NHS data. Cumulative average BMI was associated with a higher risk of total RCC (summary HR 2.16, 95% CI 1.77-2.63 for BMI ≥30 vs 18-<25 kg/m2; p trend <0.001) and fatal RCC (HR 2.03, 95% CI 1.37-3.01; p trend <0.001). Prediagnosis BMI was not associated with RCC death. However, first postdiagnosis BMI (HR 0.51, 95% CI 0.29-0.89; p trend 0.006) and prediagnosis to postdiagnosis weight change (HR 0.52, 95% CI 0.29-0.91; p trend 0.001) were significantly inversely associated with RCC death. These results support obesity as a risk factor for total and fatal RCC. They undermine the obesity paradox by suggesting that weight loss around diagnosis, and not low BMI itself, is associated with worse prognosis. PATIENT SUMMARY: We studied obesity in kidney cancer and found that obesity is associated with getting and dying from the disease. Body mass index at diagnosis is not an ideal factor for predicting prognosis, as patients who have lost weight are likely to have more aggressive cancer.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Índice de Massa Corporal , Seguimentos , Humanos , Incidência , Obesidade/complicações , Obesidade/epidemiologia , Estudos Prospectivos , Fatores de Risco
7.
JAMA Netw Open ; 5(4): e225491, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35377426

RESUMO

Importance: Identifying the youngest age when Alzheimer disease (AD) influences cognition and the earliest affected cognitive domains will improve understanding of the natural history of AD and approaches to early diagnosis. Objective: To evaluate the age at which cognitive differences between individuals with higher compared with lower genetic risk of AD are first apparent and which cognitive assessments show the earliest difference. Design, Setting, and Participants: This cross-sectional study used data from UK Biobank participants of European genetic ancestry, aged 40 years or older, who contributed genotypic and cognitive test data from January 1, 2006, to December 31, 2015. Data analysis was performed from March 10, 2020, to January 4, 2022. Exposure: The AD genetic risk score (GRS), which is a weighted sum of 23 single-nucleotide variations. Main Outcomes and Measures: Seven cognitive tests were administered via touchscreen at in-person visits or online. Cognitive domains assessed included fluid intelligence, episodic memory, processing speed, executive functioning, and prospective memory. Multiple cognitive measures were derived from some tests, yielding 32 separate measures. Interactions between age and AD-GRS for each of the 32 cognitive measures were tested with linear regression using a Bonferroni-corrected P value threshold. For cognitive measures with significant evidence of age by AD-GRS interaction, the youngest age of interaction was assessed with new regression models, with nonlinear specification of age terms. Models with youngest age of interaction from 40 to 70 years, in 1-year increments, were compared, and the best-fitting model for each cognitive measure was chosen. Results across cognitive measures were compared to determine which cognitive indicators showed earliest AD-related change. Results: A total of 405 050 participants (mean [SD] age, 57.1 [7.9] years; 54.1% female) were included. Sample sizes differed across cognitive tests (from 12 455 to 404 682 participants). The AD-GRS significantly modified the association with age on 13 measures derived from the pairs matching (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.5%-11.5%), symbol digit substitution (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.0%-5.8%), and numeric memory tests (difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 8.8%) (P = 1.56 × 10-3). Best-fitting models suggested that cognitive scores of individuals with a high vs low AD-GRS began to diverge by 56 years of age for all 13 measures and by 47 years of age for 9 measures. Conclusions and Relevance: In this cross-sectional study, by early midlife, subtle differences in memory and attention were detectable among individuals with higher genetic risk of AD.


Assuntos
Doença de Alzheimer , Transtornos Cognitivos , Adolescente , Adulto , Idoso , Doença de Alzheimer/diagnóstico , Transtornos Cognitivos/psicologia , Estudos Transversais , Função Executiva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos
8.
Integr Cancer Ther ; 21: 15347354211063500, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35389288

RESUMO

BACKGROUND: Following a prostate cancer (PC) diagnosis, treatment-related symptoms may result in diminished quality of life (QoL). Improved diet and increased exercise may improve QoL in men with PC. METHODS: We conducted a 4-arm pilot randomized trial to assess feasibility and acceptability of a 3-month web-based diet and exercise intervention, among men (>18 years of age) with PC (reported elsewhere). The purpose of this study is to describe the change in QoL measured by surveys (eg, QLQ-C30, PROMIS Fatigue) at enrollment and following the intervention. Men were randomized 1:1:1:1 to increasing levels of web-based behavioral support: Level 1: website; Level 2: Level 1 plus personalized diet and exercise prescription; Level 3: Levels 1-2 plus Fitbit and text messages; Level 4: Levels 1-3 plus 2 30-minute coaching calls. T-tests were used to compare pre-post change in mean QoL scores between each Level and Level 1. RESULTS: Two hundred and two men consented and were randomized (n = 49, 51, 50, 52 for Levels 1-4, respectively). Men were predominantly white (93%), with a median age of 70 years (Intra-quartile Range [IQR]: 65,75) and 3 years (IQR: 1,9) post primary treatment for mostly localized disease (74% with T1-2). There were no meaningful changes in QoL, but there were notable trends. Level 3 participants had small improvements in QLQ-C30 Global Health (5.46; 95% CI: -0.02, 10.95) compared to Level 1. In contrast, Level 2 participants trended toward decreasing Global QoL (-2.31, 95% CI: -8.05, 3.42), which may reflect declines in function (eg, Cognitive: -6.94, 95% CI: -13.76, -0.13) and higher symptom burden (eg, Diarrhea: 4.63, 95% CI: -1.48, 10.74). CONCLUSIONS: This short, web-based intervention did not appear to have an impact on PC survivors' QoL. Most men were several years past treatment for localized disease; the potential for this approach to reduce symptoms and improve QoL in men who have worse health may still be warranted.


Assuntos
Sobreviventes de Câncer , Intervenção Baseada em Internet , Neoplasias da Próstata , Humanos , Masculino , Projetos Piloto , Próstata , Neoplasias da Próstata/terapia , Qualidade de Vida , Sobreviventes
9.
J Gerontol A Biol Sci Med Sci ; 77(6): 1254-1260, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34788817

RESUMO

BACKGROUND: Cancer is inversely associated with dementia. Using simulations, we examined whether this inverse association may be explained by dementia diagnosis timing, including death before dementia diagnosis and differential diagnosis patterns by cancer history. METHODS: We used multistate Markov simulation models to generate cohorts 65 years of age and free of cancer and dementia at baseline; follow-up for incident cancer (all cancers, breast, prostate, and lung cancer), dementia, dementia diagnosis among those with dementia, and death occurred monthly over 30 years. Models specified no true effect of cancer on dementia, and used age-specific transition rates calibrated to U.S. population and cohort data. We varied the average lapse between dementia onset and diagnosis, including nondifferential and differential delays by cancer history, and examined observed incidence rate ratios (IRRs) for the effect of cancer on dementia diagnosis. RESULTS: Nondifferential dementia diagnosis delay introduced minimal bias (IRRs = 0.98-1.02) for all cancer, breast, and prostate models and substantial bias (IRR = 0.78) in lung cancer models. For the differential dementia diagnosis delay model of all cancer types combined, simulation scenarios with ≥20% lower dementia diagnosis rate (additional 4.5-month delay) in those with cancer history versus without yielded results consistent with literature estimates. Longer dementia diagnosis delays in those with cancer and higher mortality in those with cancer and dementia yielded more bias. CONCLUSIONS: Delays in dementia diagnosis may play a role in the inverse cancer-dementia relationship, especially for more fatal cancers, but moderate differential delays in those with cancer were needed to fully explain the literature-reported IRRs.


Assuntos
Demência , Neoplasias Pulmonares , Estudos de Coortes , Diagnóstico Tardio/efeitos adversos , Demência/diagnóstico , Demência/epidemiologia , Demência/etiologia , Humanos , Incidência , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Masculino
10.
Cancer Med ; 10(22): 8058-8070, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34636156

RESUMO

BACKGROUND: Exercise may improve clinical and quality of life outcomes for men with prostate cancer. No randomized controlled trials (RCTs) have examined the feasibility, safety, and acceptability of remote exercise training in men with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: We conducted a pilot RCT (1:1:1 aerobic or resistance exercise 3x/week or usual care) to determine the feasibility, safety, and acceptability of remotely monitored exercise over 12 weeks in 25 men with mCRPC. A prescribed exercise program was based on baseline testing including high- and moderate-intensity aerobic exercise or resistance exercise completed at a local exercise facility. Feasibility was based on attendance, adherence, and tolerance; safety on adverse events; and acceptability on participant interviews. RESULTS: Between March 2016 and March 2020, 25 patients were randomized (8 aerobic, 7 resistance, and 10 control). Twenty-three men (82%) completed the 12-week study. Men who completed the remote intervention attempted 90% and 96% of prescribed aerobic and resistance training sessions, respectively, and 86% and 88% of attempted sessions were completed as or more than prescribed. We observed changes in performance tests that corresponded with the exercise prescription. No safety concerns were identified. Ninety percent of participants interviewed were satisfied with the program and would recommend it to others. CONCLUSIONS: Remotely monitored exercise training is feasible, safe, and acceptable in men with mCRPC; there was no difference in these outcomes by mode of exercise. Through this research, we provide direction and rationale for future studies of exercise and clinical outcomes in patients with metastatic prostate cancer.


Assuntos
Exercício Físico/tendências , Neoplasias de Próstata Resistentes à Castração/terapia , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Projetos Piloto
11.
Cancer Causes Control ; 32(6): 635-644, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33837499

RESUMO

PURPOSE: Post-diagnostic coffee and tea consumption and prostate cancer progression is understudied. METHODS: We examined 1,557 men from the Cancer of the Prostate Strategic Urologic Research Endeavor who completed a food frequency questionnaire a median of 28 months post-diagnosis. We estimated associations between post-diagnostic coffee (total, caffeinated, decaffeinated) and tea (total, non-herbal, herbal) and risk of prostate cancer progression (recurrence, secondary treatment, bone metastases, or prostate cancer death) using Cox proportional hazards regression. We also examined whether smoking (current, former, never) modified these associations. RESULTS: We observed 167 progression events (median follow-up 9 years). Higher coffee intake was associated with higher risk of progression among current smokers (n = 95). The hazard ratio (HR) [95% confidence interval (CI)] for 5 vs 0 cups/day of coffee was 0.5 (CI 0.2, 1.7) among never smokers, but 4.5 (CI 1.1, 19.4) among current smokers (p-interaction: 0.001). There was no association between total coffee intake and prostate cancer progression among never and former smokers. However, we observed an inverse association between decaffeinated coffee (cups/days) and risk of prostate cancer progression in these men (HR > 0 to < 1 vs 0: 1.1 (CI 0.7, 1.8); HR1 to <2 vs 0: 0.7 (CI 0.3, 1.4); HR≥2 vs 0: 0.6 (CI 0.3, 1.1); p-trend = 0.03). There was no association between tea and prostate cancer progression, overall or by smoking status. CONCLUSION: Among non-smoking men diagnosed with localized prostate cancer, moderate coffee and tea consumption was not associated with risk of cancer progression. However, post-diagnostic coffee intake was associated with increased risk of progression among current smokers.


Assuntos
Café , Neoplasias da Próstata/diagnóstico , Fumar/efeitos adversos , Chá , Adulto , Idoso , Sobreviventes de Câncer , Progressão da Doença , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Inquéritos Nutricionais , Modelos de Riscos Proporcionais , Fatores de Risco , Inquéritos e Questionários
12.
Curr Oncol Rep ; 23(3): 37, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33689041

RESUMO

PURPOSE OF REVIEW: This study aimed to summarize evidence published between 1999 and June 2020 examining diet and lifestyle after prostate cancer (PC) diagnosis in relation to risk of biochemical recurrence, PC progression, and PC-specific mortality. RECENT FINDINGS: Secondary prevention is an important research area in cancer survivorship. A growing number of studies have reported associations between post-diagnostic modifiable behaviors and risk of PC outcomes. Evidence on modifiable lifestyle factors and PC remains limited. Where multiple studies exist, findings are often mixed. However, studies consistently suggest that smoking and consumption of whole milk/high-fat dairy are associated with higher risk of PC recurrence and mortality. In addition, physical activity and ½ to 1 glass of red wine/day have been associated with lower risk of recurrence and PC-specific mortality. Greater inclusion of racially/ethnically diverse groups in future research is necessary to understand these relationships in populations most impacted by adverse PC outcomes.


Assuntos
Estilo de Vida , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias da Próstata/terapia , Prevenção Secundária/métodos , Dieta/efeitos adversos , Suplementos Nutricionais , Progressão da Doença , Humanos , Masculino , Neoplasias da Próstata/mortalidade , Abandono do Hábito de Fumar , Prevenção do Hábito de Fumar
13.
Immunity ; 54(2): 367-386.e8, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33567262

RESUMO

Understanding the contribution of the host's genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-ß-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions.


Assuntos
Mutação em Linhagem Germinativa/genética , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Genes BRCA1 , Estudo de Associação Genômica Ampla , Humanos , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Característica Quantitativa Herdável , Proteína p107 Retinoblastoma-Like/genética , Transdução de Sinais/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
14.
Nat Commun ; 12(1): 970, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579919

RESUMO

Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.


Assuntos
Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/genética , Epidemiologia Molecular , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
15.
Alzheimer Dis Assoc Disord ; 35(3): 271-274, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32568784

RESUMO

Cancer diagnoses are associated with better long-term memory in older adults, possibly reflecting a range of social confounders that increase cancer risk but improve memory. We used spouse's memory as a negative control outcome to evaluate this possible confounding, since spouses share social characteristics and environments, and individuals' cancers are unlikely to cause better memory among their spouses. We estimated the association of an individual's incident cancer diagnosis (exposure) with their own (primary outcome) and their spouse's (negative control outcome) memory decline in 3601 couples from 1998 to 2014 in the Health and Retirement Study, using linear mixed-effects models. Incident cancer predicted better long-term memory for the diagnosed individual. We observed no association between an individual's cancer diagnosis and rate of spousal memory decline. This negative control study suggests that the inverse association between incident cancer and rate of memory decline is unlikely to be attributable to social/behavioral factors shared between spouses.


Assuntos
Memória/fisiologia , Neoplasias/diagnóstico , Cônjuges/estatística & dados numéricos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
16.
Cancer Res ; 81(7): 1695-1703, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33293427

RESUMO

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, P = 2.55 × 10-191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.See related commentary by Lachance, p. 1637.


Assuntos
Herança Multifatorial , Neoplasias da Próstata , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética
17.
JAMA Netw Open ; 3(11): e2025515, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33185677

RESUMO

Importance: Observational studies consistently report inverse associations between cancer and Alzheimer disease (AD). Shared inverse etiological mechanisms might explain this phenomenon, but a systematic evaluation of methodological biases in existing studies is needed. Objectives: To systematically review and meta-analyze evidence on the association between cancer and subsequent AD, systematically identify potential methodological biases in studies, and estimate the influence of these biases on the estimated pooled association between cancer and AD. Data Sources: All-language publications were identified from PubMed, Embase, and PsycINFO databases through September 2, 2020. Study Selection: Longitudinal cohort studies and case-control studies on the risk of AD in older adults with a history of any cancer type, prostate cancer, breast cancer, colorectal cancer, or nonmelanoma skin cancer, relative to those with no cancer history. Data Extraction and Synthesis: Two reviewers independently abstracted the data and evaluated study biases related to confounding, diagnostic bias, competing risks, or survival bias. Random-effects meta-analysis was used to provide pooled estimates of the association between cancer and AD. Metaregressions were used to evaluate whether the observed pooled estimate could be attributable to each bias. The study was designed and conducted according to the Preferring Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: Incidence, hazard, or odds ratios for AD comparing older adults with vs without a previous cancer diagnosis. Results: In total, 19 cohort studies and 3 case-control studies of the associations between any cancer type (n = 13), prostate cancer (n = 5), breast cancer (n = 1), and nonmelanoma skin cancer (n = 3) with AD were identified, representing 9 630 435 individuals. In all studies combined, cancer was associated with decreased AD incidence (cohort studies: random-effects hazard ratio, 0.89; 95% CI, 0.79-1.00; case-control studies: random-effects odds ratio, 0.75; 95% CI, 0.61-0.93). Studies with insufficient or inappropriate confounder control or greater likelihood of AD diagnostic bias had mean hazard ratios closer to the null value, indicating that these biases could not explain the observed inverse association. Competing risks bias was rare. Studies with greater likelihood of survival bias had mean hazard ratios farther from the null value. Conclusions and Relevance: The weak inverse association between cancer and AD may reflect shared inverse etiological mechanisms or survival bias but is not likely attributable to diagnostic bias, competing risks bias, or insufficient or inappropriate control for potential confounding factors.


Assuntos
Doença de Alzheimer/epidemiologia , Viés , Neoplasias/epidemiologia , Projetos de Pesquisa , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Estudos Observacionais como Assunto , Razão de Chances , Modelos de Riscos Proporcionais , Neoplasias da Próstata/epidemiologia , Neoplasias Cutâneas/epidemiologia
18.
JMIR Cancer ; 6(2): e19362, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33170126

RESUMO

BACKGROUND: Exercise and a healthy diet can improve the quality of life and prognosis of prostate cancer survivors, but there have been limited studies on the feasibility of web-based lifestyle interventions in this population. OBJECTIVE: This study aims to develop a data-driven grounded theory of web-based engagement by prostate cancer survivors based on their experience in the Community of Wellness, a 12-week randomized clinical trial designed to support healthy diet and exercise habits. METHODS: TrueNTH's Community of Wellness was a four-arm pilot study of men with prostate cancer (N=202) who received progressive levels of behavioral support (level 1: website; level 2: website with individualized diet and exercise recommendations; level 3: website with individualized diet and exercise recommendations, Fitbit, and text messages; and level 4: website with individualized diet and exercise recommendations, Fitbit and text messages, and separate phone calls with an exercise trainer and a registered dietitian). The primary aim of the study is to determine the feasibility and estimate the effects on behaviors (results reported in a separate paper). Following the 12-week intervention, we invited participants to participate in 4 focus groups, one for each intervention level. In this report, we used grounded theory analyses including open, axial, and selective coding to generate codes and themes from the focus group transcripts. Categories were refined across levels using embodied categorization and constant comparative methods. RESULTS: In total, 20 men with prostate cancer participated in the focus groups: 5, 4, 5, and 6 men in levels 1, 2, 3, and 4, respectively. Participants converged on 5 common factors influencing engagement with the intervention: environment (home environment, competing priorities, and other lifestyle programs), motivation (accountability and discordance experienced within the health care system), preparedness (technology literacy, health literacy, trust, and readiness to change), program design (communication, materials, and customization), and program support (education, ally, and community). Each of these factors influenced the survivors' long-term impressions and habits. We proposed a grounded theory associating these constructs to describe the components contributing to the intuitiveness of a web-based lifestyle intervention. CONCLUSIONS: These analyses suggest that web-based lifestyle interventions are more intuitive when we optimize participants' technology and health literacy; tailor interface design, content, and feedback; and leverage key motivators (ie, health care providers, family members, web-based coach) and environmental factors (ie, familiarity with other lifestyle programs). Together, these grounded theory-based efforts may improve engagement with web-based interventions designed to support prostate cancer survivorship.

19.
Nat Commun ; 11(1): 6084, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247094

RESUMO

Cancer risk is determined by a complex interplay of environmental and heritable factors. Polygenic risk scores (PRS) provide a personalized genetic susceptibility profile that may be leveraged for disease prediction. Using data from the UK Biobank (413,753 individuals; 22,755 incident cancer cases), we quantify the added predictive value of integrating cancer-specific PRS with family history and modifiable risk factors for 16 cancers. We show that incorporating PRS measurably improves prediction accuracy for most cancers, but the magnitude of this improvement varies substantially. We also demonstrate that stratifying on levels of PRS identifies significantly divergent 5-year risk trajectories after accounting for family history and modifiable risk factors. At the population level, the top 20% of the PRS distribution accounts for 4.0% to 30.3% of incident cancer cases, exceeding the impact of many lifestyle-related factors. In summary, this study illustrates the potential for improving cancer risk assessment by integrating genetic risk scores.


Assuntos
Predisposição Genética para Doença , Herança Multifatorial/genética , Medição de Risco , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco
20.
Nat Commun ; 11(1): 5116, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037222

RESUMO

Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10-8, tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P < 0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk (P < 0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk.


Assuntos
Densidade da Mama , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Mamografia , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
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