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1.
Transl Oncol ; 14(1): 100934, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33186889

RESUMO

PURPOSE: A substantial fraction of all non-small cell lung cancers(NSCLC) carry a mutation in the EGFR gene for which an effective treatment with anti-tyrosine kinases(TKIs) is available. We studied the long term survival of these patients following the introduction of TKIs. EXPERIMENTAL DESIGN: All consecutive cases of NSCLC newly diagnosed with advanced disease were referred for free tumor EGFR mutation testing at Clalit's national personalized medicine laboratory. Mutations and deletions in target codons 18-21 of EGFR were sought using RT-PCR and fragment analysis. Comprehensive EMRs were used to collect full data on treatments and clinical status. RESULTS: A cohort of 3,062 advanced NSCLC cases, included 481(15.7%) somatic EGFR mutation carriers (17.5% of all adenocarcinomas, 26.7% of females with adenocarcinomas). TKIs treatment to EGFR mutation carriers was provided to 85% of all eligible. After a median follow up period of 15.9 months for EGFR mutated cases the hazard ratio for overall survival of EGFR-mutated NSCLC treated with TKIs was 0.55(0.49-0.63, p<0.0001) when compared with EGFR wild-type(WT) tumors under usual care. After adjusting for age, sex, ethnicity, smoking history and tumor histology, all of which had an independently significant effect on survival, the HR for TKI-treated, EGFR-mutated tumors, was 0.63 (0.55-0.71, p<0.0001). Treating EGFR-WT cases with TKIs yielded a high HR=1.32 (1.19-1.48). CONCLUSIONS: TKIs given to EGFR mutated advanced NSCLC demonstrated a substantial survival benefit for at least five years. Squamous histology, smoking, male sex and Arab ethnicity were associated with higher NSCLC mortality hazard. Treating non-EGFR-mutated NSCLC with TKIs seems detrimental. Statement of Significance: • TKIs given to EGFR mutated advanced NSCLC demonstrated a substantial survival benefit for at least five years but not much longer. • Treating non-EGFR-mutated NSCLC with TKIs seems detrimental and should probably be avoided. • Squamous histology of non-small cell lung cancer, smoking history, male sex and Arab ethnicity were associated with altogether higher NSCLC mortality hazard.

2.
Acta Paediatr ; 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32649794

RESUMO

AIM: We investigated the prevalence of elevated liver aminotransferases (ALT) and additional comorbidities in a large cohort of Israeli children and adolescents with overweight and obesity. METHODS: This study included data from medical records of 2- to 18-year-old children and adolescents, with body mass index (BMI) in the overweight or obesity range (WHO definitions), for whom ALT testing was performed. RESULTS: Overweight was present in 50 418 (10.7%) and obesity in 70 515 (15.0%). Elevated ALT, above 30 IU/L (0.51 µkat/L), was reported in 2245 (7.2%) of children with overweight and 5475 (16.8%) of children with obesity (P < .0001). Compared to children with overweight and obesity and ALT within normal range, children with elevated ALT were older (11.9 ± 4.2 vs 10.9 ± 4.2, P < .001), mostly male (68.0% vs 49.4%, P < .001) and had higher BMI (27.3 ± 6.1vs 24.0 ± 4.8, P < .001). They also had a more unfavourable cardiometabolic profile with significantly higher either systolic or diastolic blood pressure, total cholesterol and triglycerides, and had more than three criteria defining metabolic syndrome. CONCLUSION: In this large cohort, abnormally elevated ALT was present in a high number of individuals with overweight or obesity. The children and adolescents with abnormal ALT had higher BMI, were older, male and had more cardiometabolic risk factors.

3.
Diabetes Res Clin Pract ; 165: 108232, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32446797

RESUMO

BACKGROUND: Diabetes has been associated with increased risk of cancer, including breast cancer and colorectal cancer. Metformin, an oral hypoglycemic drug, but not other anti-diabetic drugs, has been associated with reduced risk of breast and of colon cancers in some, but not in other, studies. METHODS: Data from two large-scale, population-based, case-control studies of breast and colorectal cancers etiology, conducted in Northern Israel since 1998 were analyzed to evaluate the association between regular use (>3 times) of metformin prior to diagnosis and risk of developing cancer. The multivariate analyses for both cancer sites included age, family history of breast/colorectal cancer, history of diabetes, sports participation, fruits/vegetables consumption, aspirin and statins use, and for breast cancer, also included use of oral contraceptives and postmenopausal hormones and number of pregnancies. Use of metformin and diabetes status were determined based on valid electronic medical records of the participants. RESULTS: Metformin use prior to diagnosis of cancer was associated with a decrease in risk of both breast cancer (OR = 0.821, 0.726-0.928, p = 0.002) and colorectal cancer (OR = 0.754, 0.623-0.912, p = 0.004). An inverse association was not identified with use of other anti-diabetic medications. Diabetes was found to be associated with risk of colorectal cancer (OR = 1.204, 1.014-1.431, p = 0.034) but not of breast cancer. No dose response by years of use of metformin was found. CONCLUSION: These analyses of large population-based studies provide evidence of a strong inverse association of metformin with breast and, even more so, with colorectal cancer risk.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias Colorretais/epidemiologia , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/tratamento farmacológico , Registros Eletrônicos de Saúde , Feminino , Humanos , Israel , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco
4.
J Natl Cancer Inst ; 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32324875

RESUMO

BACKGROUND: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. METHODS: We tested multiplicative statistical interactions between BMI (per 5 kg·m2) and approximately 2.7 million single nucleotide polymorphisms (SNPs) with colorectal cancer risk among 14,059 colorectal cancer case (53.2% women) and 14,416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included two-step (i.e., Cocktail method) and single-step (i.e., case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. RESULTS: Each 5 kg·m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR]: 1.14; 95% confidence intervals [CI]: 1.11-1.18; p-value: 9.75 x 10-17) than for men (OR: 1.26; 95% CI: 1.20-1.32; p-value: 2.13 x 10-24). The two-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; p-observed: 0.0009; p-threshold: 0.005). A joint 2-degree of freedom test was consistent with this finding for women (joint p-value: 2.43 x 10-10). Each 5 kg·m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR: 1.24; 95% CI: 1.16-1.32; p-value: 2.60 x 10-10) than for women with the CT (OR: 1.14; 95% CI: 1.09-1.19; p-value: 1.04 x 10-8) or TT (OR: 1.07; 95% CI: 1.01-1.14; p-value: 0.02) genotypes. CONCLUSION: These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.

5.
Eur J Cancer Prev ; 29(3): 229-237, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31714342

RESUMO

Females differ from males in incidence and clinical characteristics of colorectal cancer. Understanding the differences can lead to development of preventive approaches. To identify reproductive factors currently associated with the risk of colorectal cancer. Consecutively diagnosed female colorectal cancer cases and randomly chosen colorectal cancer-free controls matched on age/ethnicity/primary care clinic within the molecular epidemiology of colorectal cancer study, a population-based case-control study in Northern Israel, were included. A total of 2867 female cases and 2333 controls participated in this analysis. Participants were interviewed on reproductive history: ages at menarche, menopause, first birth, terminations of pregnancies, miscarriages, births, use of oral contraceptives. Among 5200 women, spontaneous miscarriages (odds ratio = 0.71, 0.61-0.83 for ever/never in Jews; odds ratio = 0.76, 0.53-1.08 in Arabs) and number of miscarriages, but not termination of pregnancies, as well as use, and duration of use, of oral contraceptives (Jews: odds ratio = 0.49, 0.39-0.62 for ever/never; Arabs: odds ratio = 0.14, 0.04-0.47) were strongly inversely associated with colorectal cancer risk. Up to 5 pregnancies were associated with increased risk while ages at menarche, at menopause and at first birth were not associated with colorectal cancer risk. Miscarriages but not terminations of pregnancy or full-term pregnancies, and use of oral contraceptives, were strongly associated with reduced odds of developing colorectal cancer suggesting unique hormonal influences on colorectal cancer.

6.
Eur J Cancer Prev ; 28(4): 287-293, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30640205

RESUMO

To examine the association between red meat subtypes intake and risk of colorectal cancer (CRC) among Jewish and Arabs populations in a unique Mediterranean environment. The Molecular Epidemiology of Colorectal Cancer study (n=10 026) is a prospective population-based case-control study in northern Israel. Participants were interviewed in-person about their dietary intake and lifestyle using a questionnaire that included a food-frequency questionnaire. Red meat consumption in Israel was found to be especially low in the Jewish population (1.29±1.45 servings/week), but higher in Arabs (3.0±1.98 servings/week) (P<0.001). Beef was the most commonly consumed red meat by Jews (1.15/1.29 servings/week, 89%) and proportionally less so by Arabs (2.00/3.00, 67%). Processed meat consumption (mostly pork free) was lower among Arabs (0.9±1.56 servings/week) compared with Jews (1.97±2.97 servings/week) (P<0.001). The adjusted odds of CRC per one serving/week of red meat were 1.05 (95% confidence interval: 1.01-1.08) in Jews and 0.94 (0.88-1.01) in Arabs. Compared with no consumption, beef consumption was associated with odds ratio (OR)=0.96 (0.86-1.07) in Jews and 0.94 (0.61-1.45) in Arabs, lamb consumption with OR=1.28 (1.10-1.5) and 1.01 (0.75-1.37), pork consumption with OR=1.44 (1.24-1.67) and 1.07 (0.73-1.56), and processed meat consumption with OR=1.22 (1.10-1.35) and 1.04 (0.82-1.33) in Jews and Arabs, respectively. Overall red meat consumption was associated weakly with CRC risk, significant only for lamb and pork, but not for beef, irrespective of tumor location. Processed meat was associated with mild CRC risk.


Assuntos
Neoplasias Colorretais/epidemiologia , Comportamento Alimentar/etnologia , Carne Vermelha/efeitos adversos , Adulto , Animais , Estudos de Casos e Controles , Bovinos , Neoplasias Colorretais/etiologia , Inquéritos sobre Dietas/estatística & dados numéricos , Feminino , Humanos , Incidência , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de Risco , Ovinos , Suínos
7.
Int J Epidemiol ; 48(3): 767-780, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476131

RESUMO

BACKGROUND: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. METHODS: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. RESULTS: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. CONCLUSIONS: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.


Assuntos
Proteína C-Reativa/metabolismo , Neoplasias Colorretais/epidemiologia , Idoso , Proteína C-Reativa/genética , Causalidade , Neoplasias Colorretais/genética , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
8.
Neurology ; 91(5): e400-e409, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-29970405

RESUMO

OBJECTIVE: To examine the association between statin exposure in a dose-dependent manner and intracerebral hemorrhage (ICH) in a large nationwide study. METHODS: The computerized database of the largest health care provider in Israel was used to identify diagnosed ICH among new users of statins, who started statin treatment between 2005 and 2010. We assessed a dose-response relationship between ICH and statins, using the average atorvastatin equivalent daily dose (AAEDD). Multivariable Cox proportional hazard regression models, adjusted for baseline disease risk score, were applied to estimate the hazard ratio of ICH. RESULTS: Of the 345,531 included patients, 1,304 were diagnosed with ICH during a median follow-up of 9.5 years (interquartile range 7.6-11.0). Overall, 75.3% of patients had AAEDD <10 mg/d, 19.0% had AAEDD 0-19.9 mg/d, and 5.7% had AAEDD ≥20 mg/d. The corresponding proportions were 81.0%, 15.0%, 4.0% among ICH cases, and 75.3%, 19.0%, 5.7% among non-ICH cases. Compared to those with AAEDD <10 mg/d (reference), the adjusted hazard ratio (HR) for ICH was 0.68 (95% confidence interval [CI] 0.58-0.79) in those with AAEDD 10-19.9 mg/d, and 0.62 (0.47-0.81) in those with AAEDD ≥20 mg/d. Compared to the lowest baseline total cholesterol quartile, the adjusted HR for ICH was 0.71 (95% CI 0.62-0.82), 0.55 (0.47-0.64), and 0.57 (0.49-0.67) in those in the second, third, and highest quartiles, respectively. The results were similar and robust among highly persistent statin users and after controlling for the change in cholesterol level. CONCLUSIONS: This study confirms that the risk of ICH decreases with increasing cholesterol levels, but suggests that statin use might be associated with decreased risk of ICH.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Idoso , Hemorragia Cerebral/diagnóstico , Estudos de Coortes , Bases de Dados Factuais/tendências , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento
9.
PLoS One ; 13(1): e0190324, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29324747

RESUMO

BACKGROUND: An association between atrial fibrillation (AF) and risk of cancer has been suggested in several studies, including prospective cohort studies. However, the magnitude and the temporal nature of this association remain unclear. METHODS: Data from two large prospective population-based case-control studies, the Molecular Epidemiology of Colorectal Cancer (MECC, n = 8,383) and the Breast Cancer in Northern Israel Study (BCINIS, n = 11,608), were used to better understand the nature and temporality of a possible association between cancer diagnosis and AF events before and after cancer diagnosis. A case-control study approach was employed to study prior AF as a risk factor for cancer, and a cohort study approach was employed to study incident cancer as a risk factor for AF. RESULTS: AF was associated with a significant reduced odds of cancer as reflected in the case-control approach, with an adjusted OR = 0.77 (95% CI, 0.65-0.91), while cancer was not found to be significantly associated with elevated risk of AF in the cohort approach, with an adjusted HR = 1.10 (0.98-1.23). The immediate period (90 days) after an AF event was associated with a 1.85 times increased risk of cancer, and the immediate period after the diagnosis of cancer was associated with a 3.4 fold increased risk of AF. These findings probably reflect both the effect of acute transient conditions associated with new cancer diagnosis and detection bias. Similar results were identified with colorectal and breast cancer cases. CONCLUSIONS: Atrial fibrillation of longer than 90 days duration is associated with reduced odds of new cancer diagnosis. The results of this study suggest that an association observed in prior research may be due to instances related to cancer diagnosis and detection bias rather than a causal relationship. However, there may be bias in the sampling and residual confounding that distort the associations.


Assuntos
Fibrilação Atrial/complicações , Neoplasias/complicações , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
10.
Clin Cancer Res ; 23(7): 1684-1689, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27683176

RESUMO

Purpose: Bisphosphonates are used for treatment or prevention of osteoporosis and of bone metastases. The use of oral bisphosphonates was suggested to be associated with reduced risk of developing breast cancer, and their positive influence on breast cancer survival was only demonstrated with third-generation bisphosphonates. We studied the association of use of oral bisphosphonates after breast cancer diagnosis on overall and breast cancer survival.Experimental Design: A nested case-control analysis was performed using data from the population-based Breast Cancer in Northern Israel Study (BCINIS). Participants were postmenopausal women with newly diagnosed breast cancer insured by Clalit. Use of second-generation bisphosphonates (alendronate and/or risedronate) was identified using computerized prescription records. The analysis was restricted to women who did not use bisphosphonates prior to diagnosis.Results: In a cohort of 3,731 postmenopausal women with breast cancer, followed up for an average of 70 months, there were 799 cases of death which were matched to 15,915 control periods of living breast cancer cases. Use of bisphosphonates after diagnosis for at least 18 months was significantly more common among survivors than among their matched controls who died, adjusted for tumor stage/grade (overall survival: OR = 0.63, 0.41-0.96, P = 0.03; breast cancer-specific survival: OR = 0.28, 0.09-0.91, P = 0.035). A similar advantageous effect, but statistically underpowered, was found in estrogen receptor (ER)-positive, ER-negative, and HER2neu-positive tumors.Conclusions: The use of oral bisphosphonates, by postmenopausal, probably osteoporotic, women initiated after diagnosis of breast cancer was associated with a significant improvement in overall and breast-specific odds of survival. Clin Cancer Res; 23(7); 1684-9. ©2016 AACR.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Osteoporose/patologia , Receptor ErbB-2/genética
11.
J Natl Cancer Inst ; 108(8)2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27172903

RESUMO

BACKGROUND: While clinical outcomes from colorectal cancer (CRC) are influenced by stage at diagnosis and treatment, mounting evidence suggests that an enhanced lymphocytic reaction to a tumor may also be an informative prognostic indicator. METHODS: The roles of intratumoral T lymphocyte infiltration (TIL), peritumoral Crohn's-like lymphoid reaction (CLR), microsatellite instability (MSI), and clinicopathological characteristics in survival from CRC were examined using 2369 incident CRCs from a population-based case-control study in northern Israel. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in multivariable models adjusted for age, sex, ethnicity, grade, stage, and MSI. All statistical tests were two-sided. RESULTS: Tumors with TIL/high-powered field (HPF) of 2 or greater were associated with a statistically significant increase in CRC-specific (P < .001) and overall survival (P < .001) compared with tumors with TIL/HPF of less than 2. Similarly, tumors with a prominent CLR experienced better CRC-specific (P < .001) and overall survival (P < .001) as compared with those with no response. High TILs (HR = 0.76, 95% CI = 0.64 to 0.89, P < .001) and a prominent CLR (HR = 0.71, 95% CI = 0.62 to 0.80, P < .001), but not MSI, were associated with a statistically significant reduction in all-cause mortality after adjustment for established prognostic factors. CONCLUSIONS: TILs and CLR are both prognostic indicators for CRC after adjusting for traditional prognostic indicators.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Instabilidade de Microssatélites , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Causas de Morte , Neoplasias Colorretais/genética , Doença de Crohn/imunologia , Feminino , Humanos , Imunidade Celular , Israel/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida
12.
Cancer Epidemiol Biomarkers Prev ; 25(4): 634-9, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-27196095

RESUMO

BACKGROUND: Coffee contains several bioactive compounds relevant to colon physiology. Although coffee intake is a proposed protective factor for colorectal cancer, current evidence remains inconclusive. METHODS: We investigated the association between coffee consumption and risk of colorectal cancer in 5,145 cases and 4,097 controls from the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based case-control study in northern Israel. We also examined this association by type of coffee, by cancer site (colon and rectum), and by ethnic subgroup (Ashkenazi Jews, Sephardi Jews, and Arabs). Coffee data were collected by interview using a validated, semi-quantitative food frequency questionnaire. RESULTS: Coffee consumption was associated with 26% lower odds of developing colorectal cancer [OR (drinkers vs. non-drinkers), 0.74; 95% confidence interval (CI), 0.64-0.86; P < 0.001]. The inverse association was also observed for decaffeinated coffee consumption alone (OR, 0.82; 95% CI, 0.68-0.99; P = 0.04) and for boiled coffee (OR, 0.82; 95% CI, 0.71-0.94; P = 0.004). Increasing consumption of coffee was associated with lower odds of developing colorectal cancer. Compared with <1 serving/day, intake of 1 to <2 servings/day (OR, 0.78; 95% CI, 0.68-0.90; P < 0.001), 2 to 2.5 servings/day (OR, 0.59; 95% CI, 0.51-0.68; P < 0.001), and >2.5 servings/day (OR, 0.46; 95% CI, 0.39-0.54; P < 0.001) were associated with significantly lower odds of colorectal cancer (Ptrend < 0.001), and the dose-response trend was statistically significant for both colon and rectal cancers. CONCLUSIONS: Coffee consumption may be inversely associated with risk of colorectal cancer in a dose-response manner. IMPACT: Global coffee consumption patterns suggest potential health benefits of the beverage for reducing the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 634-9. ©2016 AACR.


Assuntos
Café/química , Neoplasias Colorretais/prevenção & controle , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Humanos , Fatores de Risco
13.
PLoS One ; 11(1): e0146435, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26751797

RESUMO

We tested for germline variants showing association to colon cancer metastasis using a genome-wide association study that compared Ashkenazi Jewish individuals with stage IV metastatic colon cancers versus those with stage I or II non-metastatic colon cancers. In a two-stage study design, we demonstrated significant association to developing metastatic disease for rs60745952, that in Ashkenazi discovery and validation cohorts, respectively, showed an odds ratio (OR) = 2.3 (P = 2.73E-06) and OR = 1.89 (P = 8.05E-04) (exceeding validation threshold of 0.0044). Significant association to metastatic colon cancer was further confirmed by a meta-analysis of rs60745952 in these datasets plus an additional Ashkenazi validation cohort (OR = 1.92; 95% CI: 1.28-2.87), and by a permutation test that demonstrated a significantly longer haplotype surrounding rs60745952 in the stage IV samples. rs60745952, located in an intergenic region on chromosome 4q31.1, and not previously associated with cancer, is, thus, a germline genetic marker for susceptibility to developing colon cancer metastases among Ashkenazi Jews.


Assuntos
Cromossomos Humanos Par 4/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Mutação em Linhagem Germinativa , Metástase Neoplásica/genética , Idoso , Estudos de Coortes , Neoplasias do Colo/etnologia , Feminino , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Judeus , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Metástase Neoplásica/patologia , Razão de Chances , Polimorfismo de Nucleotídeo Único
15.
Nat Commun ; 6: 7138, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26151821

RESUMO

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único
16.
Carcinogenesis ; 36(9): 982-91, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26045303

RESUMO

The key role of DNA repair in removing DNA damage and minimizing mutations makes it an attractive target for cancer risk assessment and prevention. Here we describe the development of a robust assay for apurinic/apyrimidinic (AP) endonuclease 1 (APE1; APEX1), an essential enzyme involved in the repair of oxidative DNA damage. APE1 DNA repair enzymatic activity was measured in peripheral blood mononuclear cell protein extracts using a radioactivity-based assay, and its association with lung cancer was determined using conditional logistic regression with specimens from a population-based case-control study with 96 lung cancer cases and 96 matched control subjects. The mean APE1 enzyme activity in case patients was 691 [95% confidence interval (CI) = 655-727] units/ng protein, significantly lower than in control subjects (mean = 793, 95% CI = 751-834 units/ng protein, P = 0.0006). The adjusted odds ratio for lung cancer associated with 1 SD (211 units) decrease in APE1 activity was 2.0 (95% CI = 1.3-3.1; P = 0.002). Comparison of radioactivity- and fluorescence-based assays showed that the two are equivalent, indicating no interference by the fluorescent tag. The APE1Asp148Glu SNP was associated neither with APE1 enzyme activity nor with lung cancer risk. Taken together, our results indicate that low APE1 activity is associated with lung cancer risk, consistent with the hypothesis that 'bad DNA repair', rather than 'bad luck', is involved in cancer etiology. Such assays may be useful, along with additional DNA repair biomarkers, for risk assessment of lung cancer and perhaps other cancers, and for selecting individuals to undergo early detection techniques such as low-dose CT.


Assuntos
Reparo do DNA/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/epidemiologia , Estudos de Casos e Controles , Dano ao DNA/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/análise , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Feminino , Fluorescência , Predisposição Genética para Doença , Humanos , Leucócitos Mononucleares/citologia , Pulmão/enzimologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Masculino , Polimorfismo de Nucleotídeo Único , Risco
17.
Int J Cancer ; 137(9): 2155-62, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25924736

RESUMO

Lung cancer rates in Israeli Jews have remained stable over the last five decades and are much lower than in most developed countries despite high historical smoking rates. We compared lung cancer risk in Jews and non-Jews in Israel and in the United States. Data were derived from a population-based, case-control study in Israel (638 cases, 496 controls) to estimate lung cancer risk associated with smoking. Data were also acquired from a case-control study in the United States with information on religious affiliation (5,093 cases, 4,735 controls). Smoking was associated with lung cancer risk in all religion/gender groups in both studies. However, major differences in risk magnitude were noted between Jews and non-Jews; ever smoking was associated with a moderately elevated risk of lung cancer in Jewish men and women in Israel (OR = 4.61, 2.90-7.31 and OR = 2.10, 1.36-3.24, respectively), and in Jewish men and women in the United States (OR = 7.63, 5.34-10.90 and OR = 8.50, 5.94-12.17) but were significantly higher in Israeli non-Jewish men (OR = 12.96, 4.83-34.76) and US non-Jewish men and women (OR = 11.33, 9.09-14.12 and OR = 12.78, 10.45-15.63). A significant interaction between smoking and religion was evident in light, moderate and heavy male and female smokers. The differences in risk level between Israeli Jews and non-Jews could not be explained by lung cancer genetic risk variants which were identified in GWAS (genes in the CHRNA5, TERT and CLPTM1L regions). Data from the two studies support the notion of a reduced risk of lung cancer in Jewish compared to non-Jewish smokers in different areas of the world.


Assuntos
Neoplasias Pulmonares/epidemiologia , Fumar/efeitos adversos , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Israel/epidemiologia , Judeus/genética , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Estados Unidos/epidemiologia
18.
Cancer Epidemiol Biomarkers Prev ; 24(1): 65-72, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25342389

RESUMO

BACKGROUND: miRNAs act as post-transcriptional regulators of gene expression. Genetic variation in miRNA-encoding sequences or their corresponding binding sites may affect the fidelity of the miRNA-mRNA interaction and subsequently alter the risk of cancer development. METHODS: This study expanded the search for miRNA-related polymorphisms contributing to the etiology of colorectal cancer across the genome using a novel platform, the Axiom miRNA Target Site Genotyping Array (237,858 markers). After quality control, the study included 596 cases and 429 controls from the Molecular Epidemiology of Colorectal Cancer study, a population-based case-control study of colorectal cancer in northern Israel. The association between each marker and colorectal cancer status was examined assuming a log-additive genetic model using logistic regression adjusted for sex, age, and two principal components. RESULTS: Twenty-three markers had P values less than 5.0E-04, and the most statistically significant association involved rs2985 (chr6:34845648; intronic of UHRF1BP1; OR = 0.66; P = 3.7E-05). Furthermore, this study replicated a previously published risk locus, rs1051690, in the 3'-untranslated region of the insulin receptor gene INSR (OR = 1.38; P = 0.03), with strong evidence of differences in INSR gene expression by genotype. CONCLUSIONS: This study is the first to examine associations between genetic variation in miRNA target sites and colorectal cancer using a genome-wide approach. Functional studies to identify allele-specific effects on miRNA binding are needed to confirm the regulatory capacity of genetic variation to influence risk of colorectal cancer. IMPACT: This study demonstrates the potential for an miRNA-targeted genome-wide association study to identify candidate susceptibility loci and prioritize them for functional characterization.


Assuntos
Neoplasias Colorretais/genética , Idoso , Feminino , Humanos , Masculino , MicroRNAs , Polimorfismo Genético , Risco
19.
Carcinogenesis ; 35(12): 2763-70, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25355292

RESUMO

DNA repair is a major mechanism for minimizing mutations and reducing cancer risk. Here, we present the development of reproducible and specific enzymatic assays for methylpurine DNA glycosylase (MPG) repairing the oxidative lesions 1,N6-ethenoadenine (εA) and hypoxanthine (Hx) in peripheral blood mononuclear cells protein extracts. Association of these DNA repair activities with lung cancer was determined using conditional logistic regression with specimens from a population-based case-control study with 96 lung cancer cases and 96 matched control subjects. The mean MPG-εA in case patients was 15.8 units/µg protein (95% CI 15.3-16.3), significantly higher than in control subjects-15.1 (14.6-15.5), *P = 0.011. The adjusted odds ratio for lung cancer associated with a one SD increase in MPG-εA activity (2.48 units) was significantly bigger than 1 (OR = 1.6, 95% CI = 1.1-2.4; *P = 0.013). When activity of OGG1, a different DNA repair enzyme for oxidative damage, was included in the model, the estimated odds ratio/SD for a combined MPG-εA-OGG1 score was 2.6 (95% CI 1.6-4.2) *P = 0.0001, higher than the odds ratio for each single assay. The MPG enzyme activity assays described provide robust functional risk biomarkers, with increased MPG-εA activity being associated with increased lung cancer risk, similar to the behavior of MPG-Hx. This underscores the notion that imbalances in DNA repair, including high DNA repair, usually perceived as beneficial, can cause cancer risk. Such DNA repair risk biomarkers may be useful for risk assessment of lung cancer and perhaps other cancer types, and for early detection techniques such as low-dose CT.


Assuntos
Dano ao DNA/genética , Reparo do DNA/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , DNA Glicosilases/metabolismo , Feminino , Seguimentos , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Masculino , Proteínas de Membrana/genética , Estadiamento de Neoplasias , Estresse Oxidativo , Prognóstico
20.
Carcinogenesis ; 35(11): 2512-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25023989

RESUMO

Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genome-wide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10(-9); nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.


Assuntos
Carcinogênese , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cromossomos Humanos Par 4/genética , Neoplasias Colorretais/patologia , Grupos Étnicos , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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