RESUMEN
PURPOSE: Breast cancer (BC) in women under 45 is rare yet often aggressive. We aim to analyze loco-regional recurrences (LR), distant recurrences (DR), second breast cancers, and mortality in young BC patients. METHODS: We enrolled 776 women with non-metastatic BC ≤45 years diagnosed from 1970 to 2012. Variables included age, family history, tumor stage/grade, and treatment. We used multivariate Cox regression and competing risk models. RESULTS: Among the participants, 37.0% were diagnosed before the age of 40. Most had stage I or II, grade II, ER- and PR-positive, HER2-negative tumors. Over a median follow-up of 8.7 years, 10.1% experienced LR, 13.7% developed DR, and 10.8% died, primarily due to BC. The majority of recurrences occurred within the first five years. Older age (>40) significantly reduced the risk of LR and DR. Advanced disease stage, certain surgical strategies, and positive margins increased DR risk. In the cohort diagnosed between 2001 and 2012, recent diagnosis, triple-negative cancer, and hormonal therapy were associated with reduced LR risk. Breast-conserving surgery appeared to offer protective effects against DR. CONCLUSION: This study highlights that BC in young women carries a significant risk of early recurrence, with age, tumor characteristics, and treatment modalities influencing outcomes. The findings emphasize the need for tailored treatment strategies for young BC patients, focusing on surgical precision and aggressive adjuvant therapy for high-risk cases. This research contributes valuable insights into managing BC in younger patients, aiding in improving long-term outcomes.
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Neoplasias de la Mama , Recurrencia Local de Neoplasia , Humanos , Femenino , Neoplasias de la Mama/terapia , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/epidemiología , Adulto , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Adulto Joven , Factores de Edad , Factores de Riesgo , Clasificación del Tumor , Estudios de SeguimientoRESUMEN
Rationale: Millions of workers around the world are exposed to respirable crystalline silica. Although silica is a confirmed human lung carcinogen, little is known regarding the cancer risks associated with low levels of exposure and risks by cancer subtype. However, little is known regarding the disease risks associated with low levels of exposure and risks by cancer subtype.Objectives: We aimed to address current knowledge gaps in lung cancer risks associated with low levels of occupational silica exposure and the joint effects of smoking and silica exposure on lung cancer risks.Methods: Subjects from 14 case-control studies from Europe and Canada with detailed smoking and occupational histories were pooled. A quantitative job-exposure matrix was used to estimate silica exposure by occupation, time period, and geographical region. Logistic regression models were used to estimate exposure-disease associations and the joint effects of silica exposure and smoking on risk of lung cancer. Stratified analyses by smoking history and cancer subtypes were also performed.Measurements and Main Results: Our study included 16,901 cases and 20,965 control subjects. Lung cancer odds ratios ranged from 1.15 (95% confidence interval, 1.04-1.27) to 1.45 (95% confidence interval, 1.31-1.60) for groups with the lowest and highest cumulative exposure, respectively. Increasing cumulative silica exposure was associated (P trend < 0.01) with increasing lung cancer risks in nonsilicotics and in current, former, and never-smokers. Increasing exposure was also associated (P trend ≤ 0.01) with increasing risks of lung adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Supermultiplicative interaction of silica exposure and smoking was observed on overall lung cancer risks; superadditive effects were observed in risks of lung cancer and all three included subtypes.Conclusions: Silica exposure is associated with lung cancer at low exposure levels. An exposure-response relationship was robust and present regardless of smoking, silicosis status, and cancer subtype.
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Adenocarcinoma del Pulmón/epidemiología , Carcinoma de Células Pequeñas/epidemiología , Carcinoma de Células Escamosas/epidemiología , Neoplasias Pulmonares/epidemiología , Exposición Profesional/estadística & datos numéricos , Dióxido de Silicio , Silicosis/epidemiología , Adulto , Anciano , Canadá/epidemiología , Fumar Cigarrillos , Europa (Continente)/epidemiología , Femenino , Humanos , Exposición por Inhalación , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana EdadRESUMEN
Rationale: Although the carcinogenicity of diesel engine exhaust has been demonstrated in multiple studies, little is known regarding exposure-response relationships associated with different exposure subgroups and different lung cancer subtypes.Objectives: We expanded on a previous pooled case-control analysis on diesel engine exhaust and lung cancer by including three additional studies and quantitative exposure assessment to evaluate lung cancer and subtype risks associated with occupational exposure to diesel exhaust characterized by elemental carbon (EC) concentrations.Methods: We used a quantitative EC job-exposure matrix for exposure assessment. Unconditional logistic regression models were used to calculate lung cancer odds ratios and 95% confidence intervals (CIs) associated with various metrics of EC exposure. Lung cancer excess lifetime risks (ELR) were calculated using life tables accounting for all-cause mortality. Additional stratified analyses by smoking history and lung cancer subtypes were performed in men.Measurements and Main Results: Our study included 16,901 lung cancer cases and 20,965 control subjects. In men, exposure response between EC and lung cancer was observed: odds ratios ranged from 1.09 (95% CI, 1.00-1.18) to 1.41 (95% CI, 1.30-1.52) for the lowest and highest cumulative exposure groups, respectively. EC-exposed men had elevated risks in all lung cancer subtypes investigated; associations were strongest for squamous and small cell carcinomas and weaker for adenocarcinoma. EC lung cancer exposure response was observed in men regardless of smoking history, including in never-smokers. ELR associated with 45 years of EC exposure at 50, 20, and 1 µg/m3 were 3.0%, 0.99%, and 0.04%, respectively, for both sexes combined.Conclusions: We observed a consistent exposure-response relationship between EC exposure and lung cancer in men. Reduction of workplace EC levels to background environmental levels will further reduce lung cancer ELR in exposed workers.
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Adenocarcinoma del Pulmón/epidemiología , Carcinoma de Células Grandes/epidemiología , Carcinoma de Células Pequeñas/epidemiología , Carcinoma de Células Escamosas/epidemiología , Fumar Cigarrillos/epidemiología , Neoplasias Pulmonares/epidemiología , Exposición Profesional/estadística & datos numéricos , Emisiones de Vehículos , Adulto , Anciano , Canadá/epidemiología , Carbono , Europa (Continente)/epidemiología , Femenino , Humanos , Exposición por Inhalación , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores SexualesRESUMEN
At present, analysis of diet and bladder cancer (BC) is mostly based on the intake of individual foods. The examination of food combinations provides a scope to deal with the complexity and unpredictability of the diet and aims to overcome the limitations of the study of nutrients and foods in isolation. This article aims to demonstrate the usability of supervised data mining methods to extract the food groups related to BC. In order to derive key food groups associated with BC risk, we applied the data mining technique C5.0 with 10-fold cross-validation in the BLadder cancer Epidemiology and Nutritional Determinants study, including data from eighteen case-control and one nested case-cohort study, compromising 8320 BC cases out of 31 551 participants. Dietary data, on the eleven main food groups of the Eurocode 2 Core classification codebook, and relevant non-diet data (i.e. sex, age and smoking status) were available. Primarily, five key food groups were extracted; in order of importance, beverages (non-milk); grains and grain products; vegetables and vegetable products; fats, oils and their products; meats and meat products were associated with BC risk. Since these food groups are corresponded with previously proposed BC-related dietary factors, data mining seems to be a promising technique in the field of nutritional epidemiology and deserves further examination.
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Minería de Datos , Alimentos , Neoplasias de la Vejiga Urinaria/epidemiología , Algoritmos , Estudios de Casos y Controles , Dieta , Femenino , Humanos , Incidencia , Internacionalidad , Masculino , Factores de RiesgoRESUMEN
BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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Carcinoma de Células Renales/etiología , Neoplasias Renales/etiología , Obesidad/complicaciones , Glucemia/análisis , Presión Sanguínea , Índice de Masa Corporal , Carcinoma de Células Renales/genética , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Insulina/sangre , Neoplasias Renales/genética , Lípidos/sangre , Masculino , Análisis de la Aleatorización Mendeliana , Obesidad/genética , Factores de RiesgoRESUMEN
BACKGROUND: Inconsistent results for coffee consumption and bladder cancer (BC) risk have been shown in epidemiological studies. This research aims to increase the understanding of the association between coffee consumption and BC risk by bringing together worldwide case-control studies on this topic. METHODS: Data were collected from 13 case-control comprising of 5,911 cases and 16,172 controls. Pooled multivariate odds ratios (ORs), with corresponding 95% confidence intervals (CIs), were obtained using multilevel logistic regression models. Furthermore, linear dose-response relationships were examined using fractional polynomial models. RESULTS: No association of BC risk was observed with coffee consumption among smokers. However, after adjustment for age, gender, and smoking, the risk was significantly increased for never smokers (ever vs. never coffee consumers: ORmodel2 1.30, 95% CI 1.06-1.59; heavy (> 4 cups/day) coffee consumers vs. never coffee consumers: ORmodel2 1.52, 95% CI 1.18-1.97, p trend = 0.23). In addition, dose-response analyses, in both the overall population and among never smokers, also showed a significant increased BC risk for coffee consumption of more than four cups per day. Among smokers, a significant increased BC risk was shown only after consumption of more than six cups per day. CONCLUSION: This research suggests that positive associations between coffee consumption and BC among never smokers but not smokers.
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Café , Fumar/epidemiología , Neoplasias de la Vejiga Urinaria/epidemiología , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de RiesgoRESUMEN
Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
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Cromosomas Humanos Par 13 , Cromosomas Humanos Par 20 , Neoplasias de la Vejiga Urinaria/genética , Población Blanca/genética , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Neoplasias de la Vejiga Urinaria/etnologíaRESUMEN
Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10(-9)) and rs907611 on 11p15.5 (P = 4.11 × 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 × 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
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Sitios Genéticos , Estudio de Asociación del Genoma Completo , Neoplasias de la Vejiga Urinaria/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Desequilibrio de Ligamiento , Metaanálisis como Asunto , Polimorfismo de Nucleótido Simple , Riesgo , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Bladder cancer is a very heterogeneous disease as regards natural history. Environmental exposures, constitutional genetic and/or epigenetic background may affect not only the likelihood of bladder tumor occurrence, but also the histologic type of cancer and its outcome. Currently, only a few data are available to study the prognostic role of genetic and environmental factors. Likewise, data on the economic burden of bladder cancer and the longitudinal impact of the disease and the treatments on patient quality of life are scarce. METHODS: COBLAnCE is a large French-based clinical cohort study on bladder cancer. Newly diagnosed patients are enrolled prospectively in 12 public hospitals and 5 private for profits hospitals. The target sample size is 2,000 patients. All patients are to be followed for 6 years. Information on patient characteristics and lifestyle is collected during a face-to-face interview at enrollment. Clinical information on disease presentation, diagnosis, and treatment is extracted from medical records for the primary tumor and for all subsequent local and distant recurrences. Quality of life and resource use is collected at recruitment and during follow-up. In parallel, 4 types of biological samples (blood, tumor tissue, urine and nail) are collected, at baseline and during follow-up. DNA, RNA and PBMLs are extracted from blood samples, DNA and RNA from stabilized urine, proteins from frozen urine, DNA, RNA and proteins from frozen tumor tissues, and DNA and RNA from formalin-fixed paraffin-embedded tumor tissues. All derived products are stored at -80 °C or in liquid nitrogen. Main endpoints are gene-environment interactions, molecular classification, biomarker discovery, therapeutic innovation, treatment patterns, healthcare resource use, bladder cancer outcomes and quality of life. DISCUSSION: The COBLAnCE cohort will provide considerable insight into the biology of bladder cancer and the mechanisms through which genetic and environmental factors may influence the prognosis. It may allow the discovery of emerging biomarkers. Finally, economic data will be useful for future cost-effectiveness studies of immunotherapy drugs or other therapeutics in bladder cancer.
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Ensayos Clínicos como Asunto/métodos , Selección de Paciente , Proyectos de Investigación , Neoplasias de la Vejiga Urinaria/terapia , Humanos , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Calidad de VidaRESUMEN
DNA repair pathways are good candidates for upper aerodigestive tract cancer susceptibility because of their critical role in maintaining genome integrity. We have selected 13 pathways involved in DNA repair representing 212 autosomal genes. To assess the role of these pathways and their associated genes, two European data sets from the International Head and Neck Cancer Epidemiology consortium were pooled, totaling 1954 cases and 3121 controls, with documented demographic, lifetime alcohol and tobacco consumption information. We applied an innovative approach that tests single nucleotide polymorphism (SNP)-sets within DNA repair pathways and then within genes belonging to the significant pathways. We showed an association between the polymerase pathway and oral cavity/pharynx cancers (P-corrected = 4.45 × 10(-) (2)), explained entirely by the association with one SNP, rs1494961 (P = 2.65 × 10(-) (4)), a missense mutation V306I in the second exon of HELQ gene. We also found an association between the cell cycle regulation pathway and esophagus cancer (P-corrected = 1.48 × 10(-) (2)), explained by three SNPs located within or near CSNK1E gene: rs1534891 (P = 1.27 × 10(-) (4)), rs7289981 (P = 3.37 × 10(-) (3)) and rs13054361 (P = 4.09 × 10(-) (3)). As a first attempt to investigate pathway-level associations, our results suggest a role of specific DNA repair genes/pathways in specific upper aerodigestive tract cancer sites.
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Enzimas Reparadoras del ADN/genética , Reparación del ADN/genética , Estudio de Asociación del Genoma Completo , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Consumo de Bebidas Alcohólicas/genética , Estudios de Casos y Controles , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Fumar/genéticaRESUMEN
The study's purpose was to assess whether individuals who developed a second malignant neoplasm (SMN) after treatment for a first malignant neoplasm (FMN) had a lower ability to repair DNA double-strand breaks (DSBs) using a bioassay with γH2AX intensity as a surrogate endpoint. In a case-control study nested in a cohort of childhood cancer survivors, lymphoblastoid cell lines (LCLs) were established from blood samples collected from 94 cases (SMN) and 94 matched controls (FMN). LCLs were irradiated with ionizing radiation (2 and 5 Gy) and γH2AX intensities measured 1, 3, 5 and 24h post-irradiation. Differences in mean γH2AX intensity between cases and controls were compared using Kruskal-Wallis tests. Generalized linear models for repeated measures and conditional logistic regressions for SMN risk estimates were performed. The mean baseline γH2AX intensity measured without irradiation was 9.1 [95% confidence interval (95% CI): 8.5-9.7] in the LCLs from cases and 6.4 (95% CI: 6.0-6.8) from controls (P < 0.001). Markedly higher γH2AX intensity, particularly at 1 h post-irradiation, was also found in the LCLs from the cases compared with the controls for all FMNs and for different types of FMN. Chemotherapy and radiation doses received by bone marrow and thymus for FMN treatment showed a non-significant effect on γH2AX intensity. This case-control study shows that higher baseline and post-irradiation levels of DNA DSBs, as measured by γH2AX intensity, are associated with the risk of SMN in childhood cancer survivors. Further investigations in a prospective setting are warranted to confirm this association.
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Roturas del ADN de Doble Cadena/efectos de la radiación , Neoplasias Inducidas por Radiación/etiología , Neoplasias Primarias Secundarias/etiología , Sobrevivientes , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Citometría de Flujo , Estudios de Seguimiento , Histonas/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Estadificación de Neoplasias , Neoplasias Inducidas por Radiación/diagnóstico , Neoplasias Inducidas por Radiación/mortalidad , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/mortalidad , Pronóstico , Radiación Ionizante , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Células Tumorales Cultivadas , Adulto JovenRESUMEN
Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10(-) (5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 × 10(-) (7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 × 10(-) (7)). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.
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Biomarcadores de Tumor/genética , Interacción Gen-Ambiente , Genoma Humano , Polimorfismo de Nucleótido Simple/genética , Fumar/efectos adversos , Neoplasias de la Vejiga Urinaria/etiología , Adulto , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Humanos , Metaanálisis como Asunto , Pronóstico , Factores de RiesgoRESUMEN
Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21-6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10(-16)), 6p21 (P = 2.3 × 10(-14)) and 15q25 (P = 2.2 × 10(-63)). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16(INK4A)/p14(ARF)/CDKN2B/p15(INK4B)/ANRIL; rs1333040, P = 3.0 × 10(-7)) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10(-8)). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer.
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Variación Genética , Estudio de Asociación del Genoma Completo , Neoplasias Pulmonares/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , Humanos , Neoplasias Pulmonares/epidemiología , Polimorfismo de Nucleótido Simple , Riesgo , Población Blanca/genéticaRESUMEN
Genetic counseling and BRCA1/BRCA2 genes testing are routinely offered in a clinical setting. However, no data are available on the proportion of breast cancer patients with a positive family history undergoing genetic counseling. By linking databases of the Oncogenetics and Cancer Prevention Unit at the Geneva University Hospitals and the population-based Geneva Cancer Registry, we evaluated the uptake of genetic counseling among 1709 breast cancer patients with familial risk of breast cancer and the determinants of such a consultation process. We also studied the impact of genetic counseling on contralateral breast cancer occurrence and survival. Overall, 191 (11.2 %) breast cancer patients had genetic counseling; this proportion was 25.1 % within the high familial risk group. Recent period of diagnosis, early-onset breast cancer, female offspring, high familial risk, tumor size, and chemotherapy treatment were statistically significantly associated with genetic counseling uptake in multivariate analysis. More than 2 % of patients had developed contralateral metachronous breast cancer. An increased risk of contralateral breast cancer of borderline significance was found for patients who had genetic counseling versus those who had not (Cox model adjusted hazard ratio 2.2, 95 % confidence intervals 1.0-5.2, P = 0.063). Stratification by BRCA1/BRCA2 mutation status showed that the occurrence of contralateral breast cancer was 8-fold higher among mutation carriers compared with non-carriers. Age-adjusted overall survival and breast cancer-specific survival were not significantly different between patients who underwent genetic counseling and those who did not. In conclusion, we observed a significant increase in the use of genetic counseling over time and found that breast cancer patients with high familial risk had more often genetic counseling than those with moderate familial risk. A more thorough evaluation of sociodemographic and clinical predictors to attend the cancer genetic unit may help improving the use of genetic counseling services for at-risk individuals at a population level.
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Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Asesoramiento Genético/métodos , Anciano , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Riesgo , Factores de Riesgo , Suiza/epidemiologíaRESUMEN
Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
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Cromosomas Humanos Par 15/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias Pulmonares/genética , Subunidades de Proteína/genética , Receptores Nicotínicos/genética , Europa (Continente) , Genotipo , Humanos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10â»7). Two novel variants were identified, a 4q21 variant (rs1494961, pâ=â1×10â»8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10â»8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10â»8); rs1229984-ADH1B, p = 7 × 10â»9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
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Estudio de Asociación del Genoma Completo , Neoplasias de Cabeza y Cuello/genética , Adulto , Anciano , Aldehído Deshidrogenasa/genética , Biomarcadores de Tumor/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Variación Genética , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Grupos Raciales , Factores de RiesgoRESUMEN
Second malignant neoplasm (SMN) is one of the most severe long-term risks for childhood cancer survivors (CCS), significantly impacting long-term patient survival. While radiotherapy and chemotherapy are known risk factors, the observed inter-individual variability suggests a genetic component contributing to the risk of SMN. This article aims to conduct a systematic review of genetic factors implicated in the SMN risk among CCS. Searches were performed in PubMed, Scopus, and Web of Sciences. Eighteen studies were included (eleven candidate gene studies, three genome-wide association studies, and four whole exome/genome sequencing studies). The included studies were based on different types of first cancers, investigated any or specific types of SMN, and focused mainly on genes involved in drug metabolism and DNA repair pathways. These differences in study design and methods used to characterize genetic variants limit the scope of the results and highlight the need for further extensive and standardized investigations. However, this review provides a valuable compilation of SMN risk-associated variants and genes, facilitating efficient replication and advancing our understanding of the genetic basis for this major risk for CCS.
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Neoplasias Primarias Secundarias , Humanos , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/epidemiología , Niño , Predisposición Genética a la Enfermedad , Factores de Riesgo , Neoplasias/genética , Supervivientes de Cáncer/estadística & datos numéricos , Estudio de Asociación del Genoma CompletoRESUMEN
BACKGROUND: Molecular understanding of muscle-invasive (MIBC) and non-muscle-invasive (NMIBC) bladder cancer is currently based primarily on transcriptomic and genomic analyses. OBJECTIVE: To conduct proteogenomic analyses to gain insights into bladder cancer (BC) heterogeneity and identify underlying processes specific to tumor subgroups and therapeutic outcomes. DESIGN, SETTING, AND PARTICIPANTS: Proteomic data were obtained for 40 MIBC and 23 NMIBC cases for which transcriptomic and genomic data were already available. Four BC-derived cell lines harboring FGFR3 alterations were tested with interventions. INTERVENTION: Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), second mitochondrial-derived activator of caspases mimetic (birinapant), pan-FGFR inhibitor (erdafitinib), and FGFR3 knockdown. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Proteomic groups from unsupervised analyses (uPGs) were characterized using clinicopathological, proteomic, genomic, transcriptomic, and pathway enrichment analyses. Additional enrichment analyses were performed for FGFR3-mutated tumors. Treatment effects on cell viability for FGFR3-altered cell lines were evaluated. Synergistic treatment effects were evaluated using the zero interaction potency model. RESULTS AND LIMITATIONS: Five uPGs, covering both NMIBC and MIBC, were identified and bore coarse-grained similarity to transcriptomic subtypes underlying common features of these different entities; uPG-E was associated with the Ta pathway and enriched in FGFR3 mutations. Our analyses also highlighted enrichment of proteins involved in apoptosis in FGFR3-mutated tumors, not captured through transcriptomics. Genetic and pharmacological inhibition demonstrated that FGFR3 activation regulates TRAIL receptor expression and sensitizes cells to TRAIL-mediated apoptosis, further increased by combination with birinapant. CONCLUSIONS: This proteogenomic study provides a comprehensive resource for investigating NMIBC and MIBC heterogeneity and highlights the potential of TRAIL-induced apoptosis as a treatment option for FGFR3-mutated bladder tumors, warranting a clinical investigation. PATIENT SUMMARY: We integrated proteomics, genomics, and transcriptomics to refine molecular classification of bladder cancer, which, combined with clinical and pathological classification, should lead to more appropriate management of patients. Moreover, we identified new biological processes altered in FGFR3-mutated tumors and showed that inducing apoptosis represents a new potential therapeutic option.
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Neoplasias Vesicales sin Invasión Muscular , Proteogenómica , Neoplasias de la Vejiga Urinaria , Humanos , Proteómica , Ligandos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Apoptosis , Factor de Necrosis Tumoral alfa , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8p21.1 with p value = 7.4 × 10(-6)), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.
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Variación Genética/genética , Estudio de Asociación del Genoma Completo , Neoplasias Pulmonares/genética , Población Blanca/genética , Alelos , Canadá/epidemiología , Estudios de Casos y Controles , Europa (Continente)/epidemiología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Inflamación/genética , Funciones de Verosimilitud , Neoplasias Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Polimorfismo de Nucleótido Simple/genética , Riesgo , Estados Unidos/epidemiologíaRESUMEN
The gene cyclin-dependent kinase inhibitor 2A (CDKN2A) is frequently inactivated by deletion in bladder carcinoma. However, its role in bladder tumourigenesis remains unclear. We investigated the role of CDKN2A deletion in urothelial carcinogenesis, as a function of FGFR3 mutation status, a marker for one of the two pathways of bladder tumour progression, the Ta pathway. We studied 288 bladder carcinomas: 177 non-muscle-invasive (123 Ta, 54 T1) and 111 muscle-invasive (T2-4) tumours. CDKN2A copy number was determined by multiplex ligation-dependent probe amplification, and FGFR3 mutations by SNaPshot analysis. FGFR3 mutation was detected in 124 tumours (43.1%) and CDKN2A homozygous deletion in 56 tumours (19.4%). CDKN2A homozygous deletion was significantly more frequent in FGFR3-mutated tumours than in wild-type FGFR3 tumours (p = 0.0015). This event was associated with muscle-invasive tumours within the FGFR3-mutated subgroup (p < 0.0001) but not in wild-type FGFR3 tumours. Similar findings were obtained for an independent series of 101 bladder carcinomas. The impact of CDKN2A deletions on recurrence-free and progression-free survival was then analysed in 89 patients with non-muscle-invasive FGFR3-mutated tumours. Kaplan-Meier survival analysis showed that CDKN2A losses (hemizygous and homozygous) were associated with progression (p = 0.0002), but not with recurrence, in these tumours. Multivariate Cox regression analysis identified CDKN2A loss as a predictor of progression independent of stage and grade. These findings highlight the crucial role of CDKN2A loss in the progression of non-muscle-invasive FGFR3-mutated bladder carcinomas and provide a potentially useful clinical marker for adapting the treatment of such tumours, which account for about 50% of cases at initial clinical presentation.