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1.
Cancer Res ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472890

RESUMO

Lung cancer is the leading cause of cancer death globally. An improved risk stratification strategy can increase efficiency of low-dose computed tomography (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. Based on 13,119 lung cancer patients and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK biobank data (N=335,931). Absolute risk was estimated based on age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial, N=50,772 participants). The lung cancer odds ratio (ORs) for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 (95%CI=1.92-3.00, P=1.80x10-14) in the validation set (trend p-value of 5.26 x 10-20). The OR per standard deviation of PRS increase was 1.26 (95%CI=1.20-1.32, P=9.69x10-23) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status and family history. Collectively, these results suggest that Individual's genetic background may inform the optimal lung cancer LDCT screening strategy.

2.
BJU Int ; 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33404154

RESUMO

OBJECTIVE: To contribute to the debate regarding the minimum volume of radical cystectomies (RCs) that a hospital should perform by evaluating the association between hospital volume (HV) and postoperative mortality. PATIENTS AND METHODS: Patients who underwent RC for bladder cancer between 1 January 2008 and 31 December 2018 were retrospectively identified from the Netherlands Cancer Registry. To create a calendar-year independent measure, the HV of RCs was calculated per patient by counting the RCs performed in the same hospital in the 12 months preceding surgery. The relationship of HV with 30- and 90-day mortality was assessed by logistic regression with a non-linear spline function for HV as a continuous variable, which was adjusted for age, tumour, node and metastasis (TNM) stage, and neoadjuvant treatment. RESULTS: The median (interquartile range; range) HV among the 9287 RC-treated patients was 19 (12-27; 1-75). Of all the included patients, 208 (2.2%) and 518 (5.6%) died within 30 and 90 days after RC, respectively. After adjustment for age, TNM stage and neoadjuvant therapy, postoperative mortality slightly increased between an HV of 0 and an HV of 25 RCs and steadily decreased from an HV of 30 onwards. The lowest risks of postoperative mortality were observed for the highest volumes. CONCLUSION: This paper, based on high-quality data from a large nationwide population-based cohort, suggests that increasing the RC volume criteria beyond 30 RCs annually could further decrease postoperative mortality. Based on these results, the volume criterion of 20 RCs annually, as recently recommended by the European Association of Urology Guideline Panel, might therefore be reconsidered.

3.
Eur Urol ; 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33419683

RESUMO

BACKGROUND: The European Association of Urology (EAU) prognostic factor risk groups for non-muscle-invasive bladder cancer (NMIBC) are used to provide recommendations for patient treatment after transurethral resection of bladder tumor (TURBT). They do not, however, take into account the widely used World Health Organization (WHO) 2004/2016 grading classification and are based on patients treated in the 1980s. OBJECTIVE: To update EAU prognostic factor risk groups using the WHO 1973 and 2004/2016 grading classifications and identify patients with the lowest and highest probabilities of progression. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data for primary NMIBC patients were collected from the institutions of the members of the EAU NMIBC guidelines panel. INTERVENTION: Patients underwent TURBT followed by intravesical instillations at the physician's discretion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Cox proportional-hazards regression models were fitted to the primary endpoint, the time to progression to muscle-invasive disease or distant metastases. Patients were divided into four risk groups: low-, intermediate-, high-, and a new, very high-risk group. The probabilities of progression were estimated using Kaplan-Meier curves. RESULTS AND LIMITATIONS: A total of 3401 patients treated with TURBT ± intravesical chemotherapy were included. From the multivariable analyses, tumor stage, WHO 1973/2004-2016 grade, concomitant carcinoma in situ, number of tumors, tumor size, and age were used to form four risk groups for which the probability of progression at 5 yr varied from <1% to >40%. Limitations include the retrospective collection of data and the lack of central pathology review. CONCLUSIONS: This study provides updated EAU prognostic factor risk groups that can be used to inform patient treatment and follow-up. Incorporating the WHO 2004/2016 and 1973 grading classifications, a new, very high-risk group has been identified for which urologists should be prompt to assess and adapt their therapeutic strategy when necessary. PATIENT SUMMARY: The newly updated European Association of Urology prognostic factor risk groups for non-muscle-invasive bladder cancer provide an improved basis for recommending a patient's treatment and follow-up schedule.

4.
Cancer Treat Res Commun ; 25: 100266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33316557

RESUMO

BACKGROUND: With the introduction of new therapeutic options, the landscape of metastatic bladder cancer (mBC) management is shifting. We describe current clinical practice and outcomes of mBC patients as a benchmark for translation of developments into clinical practice in the near future. PATIENTS AND METHODS: Nation-wide population-based cohort study including all patients diagnosed with synchronous metastatic bladder cancer in the Netherlands in 2016-2017, identified through the Netherlands Cancer Registry (NCR). Clinical data on patient and disease characteristics, treatments and survival from the NCR were supplemented with specific information from electronic health records and descriptively analyzed. This study was part of the Prospective Bladder Cancer Infrastructure. RESULTS: Synchronous metastatic bladder cancer was diagnosed in 636 patients in the Netherlands in 2016 and 2017. 35% (221 patients) received systemic treatment, of whom 88 received multiple treatment lines. Most common first-line regimen was carboplatin-based chemotherapy (49%), followed by cisplatin-based chemotherapy (41%) and immunotherapy (8%). Factors associated with systemic treatment were: young age, <2 comorbidities, adequate renal function and performance-status (WHO-0-1/Karnofsky-80-100), urothelial carcinoma and lymph node only metastases. Median overall survival was 4.4 months for the total cohort, and 12.3, 12.9 and 11.1 months for patients treated with first-line immunotherapy, cisplatin-based and carboplatin-based chemotherapy, respectively. CONCLUSIONS: Many mBC patients received no systemic treatment or received carboplatin-based chemotherapy, partly because of cisplatin-ineligibility. Observed survival corresponded relatively well with rates reported from trials among chemotherapy-treated patients. These data can serve as a benchmark for future studies evaluating the application of immunotherapy outside a trial setting.

5.
Cancer Treat Res Commun ; 25: 100264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33316558

RESUMO

BACKGROUND: Despite treatment with radical cystectomy, patients with muscle invasive bladder cancer (MIBC) have a poor survival. It has been reported that survival is worse in NMIBC patients who progressed to MIBC in comparison to patients with de novo MIBC. The objective of this study was to compare survival of progressive versus de novo MIBC. Secondary objective was to explain this difference in survival by clinicopathological factors. METHODS: 431 patients with MIBC who underwent radical cystectomy between 1998 and 2016 in the Radboudumc, Nijmegen, were retrospectively analyzed. 313 patients were identified with de novo MIBC and 118 with progressive MIBC. RESULTS: 5- and 10-year overall survival (OS) of patients with progressive MIBC was 37% and 20%, respectively. Patients with de novo MIBC had significantly better survival, with a 5- and 10-year OS of 49% and 39%, respectively. Patients with progressive MIBC were more frequently diagnosed with concomitant carcinoma in situ and positive surgical margins in bladder, ureters or urethra. In multivariable analysis that adjusted for these factors, progressive MIBC was associated with a hazard ratio of 1.40 (0.99 - 1.98). Kaplan-Meier survival curves show a detrimental effect of progressive MIBC in patients with pT2 versus pT3-4 tumors and in patients with negative versus positive surgical margins. In multivariable analysis, this effect modification disappeared. CONCLUSIONS: Progressive MIBC is associated with poorer survival than de novo MIBC. Because most patients with progressive MIBC had a history of high risk NMIBC, considering radical cystectomy is most important in the highest risk NMIBC.

6.
Front Med ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32889700

RESUMO

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

7.
J Med Genet ; 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994281

RESUMO

BACKGROUND: Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%-40% of familial cases carry a pathogenic variant in a known high-risk melanoma susceptibility gene. We investigated whether a melanoma-specific Polygenic Risk Score (PRS) is associated with melanoma risk in patients with genetically unexplained familial melanoma. METHODS: Dutch familial melanoma cases (n=418) were genotyped for 46 SNPs previously identified as independently associated with melanoma risk. The 46-SNP PRS was calculated and standardised to 3423 healthy controls (sPRS) and the association between PRS and melanoma risk was modelled using logistic regression. Within the case series, possible differences were further explored by investigating the PRS in relation to (1) the number of primary melanomas in a patient and (2) the extent of familial clustering of melanoma. RESULTS: The PRS was significantly associated with melanoma risk, with a per-SD OR of 2.12 (95% CI 1.90 to 2.35, p<0.001), corresponding to a 5.70-fold increased risk (95% CI 3.93 to 8.28) when comparing the top 90th to the middle 40-60th PRS percentiles. The mean PRS was significantly higher in cases with multiple primary melanomas than in cases with a single melanoma (sPRS 1.17 vs 0.71, p=0.001). Conversely, cases from high-density melanoma families had a lower (but non-significant) mean PRS than cases from low-density families (sPRS 0.60 vs 0.94, p=0.204). CONCLUSION: Our work underlines the significance of a PRS in determining melanoma susceptibility and encourages further exploration of the diagnostic value of a PRS in genetically unexplained melanoma families.

8.
Genet Epidemiol ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924180

RESUMO

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

9.
Urol Oncol ; 38(12): 935.e9-935.e16, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32917503

RESUMO

OBJECTIVES: Radical cystectomies (RCs) are increasingly centralized, but bladder cancer can be diagnosed in every hospital The aim of this study is to assess the variation between hospitals of diagnosis in a patient's chance to undergo a RC before and after the volume criteria for RCs, to identify factors associated with this variation and to assess its effect on survival. METHODS AND MATERIALS: Patients diagnosed with muscle-invasive bladder cancer (cT2-4a,N0/X,M0/X) without nodal or distant metastases between 2008 and 2016 were identified through the Netherlands Cancer Registry. Multilevel logistic regression analysis was used to investigate the hospital specific probability of undergoing a cystectomy. Cox proportional hazard regression analysis was used to assess the case-mix adjusted effect of hospital-specific probabilities on survival. RESULTS: Of the 9,215 included patients, 4,513 (49%) underwent a RC. The percentage of RCs varied between 7% and 83% by hospital of diagnosis before the introduction of the first volume criteria (i.e., 2008-2009; minimum of 10 RCs). This variation decreased slightly to 17%-77% after establishment of the second volume criteria (i.e., 2015-2016; minimum of 20 RCs). Age, cT-stage and comorbidity were inversely and socioeconomic status was positively associated with RC. Both being diagnosed in a community hospital and/or being diagnosed in a hospital fulfilling the RC volume criteria were associated with increased use of RC compared to academic hospitals and hospitals not fulfilling the volume criteria. For each 10% increase in the percentage of RC in the hospital of diagnosis, 2-year case-mix adjusted survival increased 4% (hazard ratio 0.96, 95% confidence interval 0.94-0.98). CONCLUSION: Probability of RC varied between hospitals of diagnosis and affected 2-year overall survival. Undergoing a RC was associated with age, cT-stage, socioeconomic status, type of hospital, and whether the hospital of diagnosis fulfilled the RC volume criteria. Future research is needed to identify patient, tumor, and hospital characteristics affecting utilization of curative treatment as this may benefit overall survival.

10.
Int J Cancer ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32914876

RESUMO

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10-4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = .011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = .036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.

11.
Nat Commun ; 11(1): 3981, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769997

RESUMO

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.


Assuntos
Pleiotropia Genética , Estudo de Associação Genômica Ampla , Neoplasias da Glândula Tireoide/genética , Tireotropina/genética , Loci Gênicos , Predisposição Genética para Doença , Bócio/genética , Humanos , Análise da Randomização Mendeliana , Herança Multifatorial/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Mapeamento Físico do Cromossomo , Prevalência , Fatores de Risco , Tireoglobulina/genética , Neoplasias da Glândula Tireoide/epidemiologia
12.
Cancer Med ; 9(18): 6888-6895, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32710528

RESUMO

BACKGROUND: Concerns have been raised about the accessibility and quality of cancer-related care for people with intellectual disabilities (ID). However, there is limited insight into cancer incidence and the utilization of cancer care at the ID population level to inform targeted cancer control strategies. Therefore, we aimed to examine differences in the utilization of cancer-related care between people with and without ID, identified through diagnostic codes on health insurance claims. METHODS: In a population-based cohort study, Dutch individuals of all ages who received residential care through the Chronic Care Act due to an ID (n = 65 183) and an age and sex-matched sample of persons without ID (1:2 ratio), who were cancer-free at enrollment in 2013 were followed through 2015. Incidence rates (IRs) of newly started cancer care and IR ratios (IRRs) with 95% CIs were used to compare groups. Separate analyses were performed per cancer type. RESULTS: Individuals with ID received less cancer-related care than individuals without (IRR = 0.64, 95% CI 0.62-0.66). Differences increased with age and were larger for females than for males. Utilization of care for cancers within the national screening program (female breast, cervical, and colon cancer) was lower for people with ID compared to people without ID. CONCLUSION: Cancer may be underdiagnosed and/or undertreated in people with ID, or cancer is truly less prevalent in this population. In particular, the differences detected between males and females with ID, and the potential underutilization of national screening programs, require urgent follow-up investigations.

13.
Cancer Epidemiol Biomarkers Prev ; 29(8): 1654-1664, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32467345

RESUMO

BACKGROUND: Urothelial carcinoma is the predominant (95%) bladder cancer subtype in industrialized nations. Animal and epidemiologic human studies suggest that hormonal factors may influence urothelial carcinoma risk. METHODS: We used an analytic cohort of 333,919 women from the European Prospective Investigation into Cancer and Nutrition Cohort. Associations between hormonal factors and incident urothelial carcinoma (overall and by tumor grade, tumor aggressiveness, and non-muscle-invasive urothelial carcinoma) risk were evaluated using Cox proportional hazards models. RESULTS: During a mean of 15 years of follow-up, 529 women developed urothelial carcinoma. In a model including number of full-term pregnancies (FTP), menopausal status, and menopausal hormone therapy (MHT), number of FTP was inversely associated with urothelial carcinoma risk (HR≥5vs1 = 0.48; 0.25-0.90; P trend in parous women = 0.010) and MHT use (compared with nonuse) was positively associated with urothelial carcinoma risk (HR = 1.27; 1.03-1.57), but no dose response by years of MHT use was observed. No modification of HRs by smoking status was observed. Finally, sensitivity analyses in never smokers showed similar HR patterns for the number of FTP, while no association between MHT use and urothelial carcinoma risk was observed. Association between MHT use and urothelial carcinoma risk remained significant only in current smokers. No heterogeneity of the risk estimations in the final model was observed by tumor aggressiveness or by tumor grade. A positive association between MTH use and non-muscle-invasive urothelial carcinoma risk was observed. CONCLUSIONS: Our results support that increasing the number of FTP may reduce urothelial carcinoma risk. IMPACT: More detailed studies on parity are needed to understand the possible effects of perinatal hormone changes in urothelial cells.

14.
Cancer Epidemiol Biomarkers Prev ; 29(7): 1423-1429, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32277007

RESUMO

BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. RESULTS: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10-6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3). CONCLUSIONS: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. IMPACT: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.

15.
PLoS One ; 15(3): e0229384, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210471

RESUMO

BACKGROUND: Non-muscle invasive bladder cancer patients are at high risk for tumour recurrence and progression, hence an intensive follow-up procedure is recommended which is costly. Identification of factors that are associated with the risk of recurrence and progression may enable personalized follow-up schedules. Obesity and diabetes mellitus may be associated with a worse prognosis, but the evidence is limited and inconsistent. Our objective was to determine the associations of BMI and diabetes mellitus with risks of recurrence and progression among non-muscle invasive bladder cancer patients. METHODS: A population-based cohort of patients diagnosed with non-muscle invasive bladder cancer between 1995 and 2010 was retrospectively identified from the Netherlands Cancer Registry and invited to participate in the Nijmegen Bladder Cancer Study (n = 1,433). Average weight during adult life, height, and diabetes mellitus diagnosis were self-reported by use of a questionnaire. Clinical follow-up data were retrieved from medical files. Associations were quantified using proportional hazard analyses. For all analyses, minimal adjustment sets were selected using a Directed Acyclic Graph. RESULTS: Fourteen percent of the patients indicated to be diagnosed with diabetes mellitus, and more than half was overweight (45%) or obese (9%). Compared to healthy weight, overweight and obesity were not associated with risk of recurrence (adjusted hazard ratio (HR) = 1.02; 95% confidence interval (CI): 0.86-1.22, and HR = 1.02; 95% CI: 0.76-1.38, respectively) and overall progression (HR = 1.04; 95% CI: 0.74-1.44, and HR = 1.20; 95% CI: 0.69-2.09, respectively). Also, no clear associations of diabetes mellitus with risk of recurrence (HR = 1.22; 95% CI: 0.98-1.54) and overall progression (HR = 1.16; 95% CI: 0.76-1.76) were found. CONCLUSION: Average BMI during adult life and diabetes mellitus were not clearly associated with risk of recurrence or progression in non-muscle invasive bladder cancer. Prospective cohort studies with detailed information on BMI and diabetes mellitus before and after diagnosis are needed to confirm these findings.


Assuntos
Índice de Massa Corporal , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Recidiva Local de Neoplasia/epidemiologia , Obesidade/complicações , Sobrepeso/complicações , Neoplasias da Bexiga Urinária/epidemiologia , Adulto , Idoso , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/patologia , Países Baixos/epidemiologia , Prognóstico , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/patologia
16.
Proc Natl Acad Sci U S A ; 117(11): 5997-6002, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32132206

RESUMO

Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points (P ≤ 1.0 × 10-9). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC.


Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Herança Multifatorial , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudo de Associação Genômica Ampla , Humanos , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Penetrância , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Curva ROC , Medição de Risco/métodos , Fatores de Risco , Câncer Papilífero da Tireoide/epidemiologia , Câncer Papilífero da Tireoide/patologia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologia , Reino Unido/epidemiologia , Estados Unidos/epidemiologia
17.
Am J Psychiatry ; 177(6): 526-536, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32046534

RESUMO

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with intellectual disability, and shared overlapping genetics have been suggested. The aim of this study was to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to intellectual disability contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using Drosophila melanogaster. METHODS: Common genetic variants in a diagnostic gene panel of 396 autosomal intellectual disability genes were tested for association with ADHD risk through gene set and gene-wide analyses, using ADHD meta-analytic data from the Psychiatric Genomics Consortium for discovery (N=19,210) and ADHD data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research for replication (N=37,076). The significant genes were functionally validated and characterized in Drosophila by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits. RESULTS: The intellectual disability gene set was significantly associated with ADHD risk in the discovery and replication data sets. The three genes most consistently associated were MEF2C, ST3GAL3, and TRAPPC9. Performing functional characterization of the two evolutionarily conserved genes in Drosophila melanogaster, the authors found that their knockdown in dopaminergic (dMEF2) and circadian neurons (dTRAPPC9) resulted in increased locomotor activity and reduced sleep, concordant with the human phenotype. CONCLUSIONS: This study reveals that a large set of intellectual disability-related genes contribute to ADHD risk through effects of common alleles. Utilizing this continuity, the authors identified TRAPPC9, MEF2C, and ST3GAL3 as novel ADHD candidate genes. Characterization in Drosophila suggests that TRAPPC9 and MEF2C contribute to ADHD-related behavior through distinct neural substrates.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Locomoção/genética , Fatores de Regulação Miogênica/genética , Sialiltransferases/genética , Adulto , Idoso , Animais , Ritmo Circadiano , Neurônios Dopaminérgicos/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Deficiência Intelectual/genética , Fatores de Transcrição MEF2/genética , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Sono/genética
18.
Psychol Med ; : 1-10, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32102724

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a common mood disorder, with a heritability of around 34%. Molecular genetic studies made significant progress and identified genetic markers associated with the risk of MDD; however, progress is slowed down by substantial heterogeneity as MDD is assessed differently across international cohorts. Here, we used a standardized online approach to measure MDD in multiple cohorts in the Netherlands and evaluated whether this approach can be used in epidemiological and genetic association studies of depression. METHODS: Within the Biobank Netherlands Internet Collaboration (BIONIC) project, we collected MDD data in eight cohorts involving 31 936 participants, using the online Lifetime Depression Assessment Self-report (LIDAS), and estimated the prevalence of current and lifetime MDD in 22 623 unrelated individuals. In a large Netherlands Twin Register (NTR) twin-family dataset (n ≈ 18 000), we estimated the heritability of MDD, and the prediction of MDD in a subset (n = 4782) through Polygenic Risk Score (PRS). RESULTS: Estimates of current and lifetime MDD prevalence were 6.7% and 18.1%, respectively, in line with population estimates based on validated psychiatric interviews. In the NTR heritability estimates were 0.34/0.30 (s.e. = 0.02/0.02) for current/lifetime MDD, respectively, showing that the LIDAS gives similar heritability rates for MDD as reported in the literature. The PRS predicted risk of MDD (OR 1.23, 95% CI 1.15-1.32, R2 = 1.47%). CONCLUSIONS: By assessing MDD status in the Netherlands using the LIDAS instrument, we were able to confirm previously reported MDD prevalence and heritability estimates, which suggests that this instrument can be used in epidemiological and genetic association studies of depression.

19.
Nat Commun ; 11(1): 27, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911640

RESUMO

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.


Assuntos
Neoplasias Pulmonares/genética , Pulmão/fisiopatologia , Adulto , Idoso , Feminino , Volume Expiratório Forçado , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Testes de Função Respiratória , Capacidade Vital
20.
Dermatology ; 236(3): 228-236, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31505496

RESUMO

OBJECTIVE: Previous studies regarding cigarette smoking causing a lower risk of melanoma are inconclusive. Here, we re-examined melanoma risk in relation to cigarette smoking in a large, case-control study. METHODS: In total 1,157 patients with melanoma diagnosed between 2003 and 2011 in the Netherlands and 5,595 controls from the Nijmegen Biomedical Study were included. Information concerning smoking habits and known risk factors for melanoma were obtained through self-administered questionnaires. Logistic regression analyses stratified by gender were performed to study the risk of cigarette smoking on melanoma risk, adjusted for age, marital status, highest level of education, skin type, sun vacation, use of solarium, time spent outdoors, and sun protective measures. RESULTS: Among men, current and former smokers did not have a higher risk of melanoma compared to never smokers: adjusted odds ratio (OR) = 0.56 (95% confidence interval [CI]: 0.40-0.79) and adjusted OR = 0.50 (95% CI: 0.39-0.64), respectively. With an increasing number of years smoked the risk of melanoma decreased: <20 years: OR = 0.61 (95% CI: 0.46-0.80); 21-40 years: OR = 0.50 (95% CI: 0.37-0.68); >40 years: OR = 0.26 (95% CI: 0.15-0.44). No clear trend was found for the number of cigarettes smoked. Results for females were less clear and not statistically significant (current smoker: adjusted OR = 0.96, 95% CI: 0.74-1.26, former smoker: adjusted OR = 0.89, 95% CI: 0.73-1.08). CONCLUSION: This study shows a strong inverse association between cigarette smoking and melanoma risk in men. Fundamental laboratory research is necessary to investigate the biological relation between smoking cigarettes and melanoma.


Assuntos
Fumar Cigarros/epidemiologia , Melanoma/epidemiologia , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Fumar Cigarros/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fatores de Risco
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