RESUMEN
PURPOSE: Polygenic risk scores (PRSs) are a major component of accurate breast cancer (BC) risk prediction but require ethnicity-specific calibration. Ashkenazi Jewish (AJ) population is assumed to be of White European (WE) origin in some commercially available PRSs despite differing effect allele frequencies (EAFs). We conducted a case-control study of WE and AJ women from the Predicting Risk of Cancer at Screening Study. The Breast Cancer in Northern Israel Study provided a separate AJ population-based case-control validation series. METHODS: All women underwent Illumina OncoArray single-nucleotide variation (SNV; formerly single-nucleotide polymorphism [SNP]) analysis. Two PRSs were assessed, SNV142 and SNV78. A total of 221 of 2243 WE women (discovery: cases = 111; controls = 110; validation: cases = 651; controls = 1772) and 221 AJ women (cases = 121; controls = 110) were included from the UK study; the Israeli series consisted of 2045 AJ women (cases = 1331; controls = 714). EAFs were obtained from the Genome Aggregation Database. RESULTS: In the UK study, the mean SNV142 PRS demonstrated good calibration and discrimination in WE population, with mean PRS of 1.33 (95% CI 1.18-1.48) in cases and 1.01 (95% CI 0.89-1.13) in controls. In AJ women from Manchester, the mean PRS of 1.54 (1.38-1.70) in cases and 1.20 (1.08-1.32) in controls demonstrated good discrimination but overestimation of BC relative risk. After adjusting for EAFs for the AJ population, mean risk was corrected (mean SNV142 PRS cases = 1.30 [95% CI 1.16-1.44] and controls = 1.02 [95% CI 0.92-1.12]). This was recapitulated in the larger Israeli data set with good discrimination (area under the curve = 0.632 [95% CI 0.607-0.657] for SNV142). CONCLUSION: AJ women should not be given BC relative risk predictions based on PRSs calibrated to EAFs from the WE population. PRSs need to be recalibrated using AJ-derived EAFs. A simple recalibration using the mean PRS adjustment ratio likely performs well.
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Judíos , Femenino , Humanos , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/etnología , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Judíos/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Población Blanca/genética , Herencia MultifactorialRESUMEN
Reduced clopidogrel effectiveness in preventing recurrent myocardial ischemia following percutaneous coronary intervention has been demonstrated in CYP2C19 loss-of-function carriers. Less is known about the effect of CYP2C19 genotype on the effectiveness of clopidogrel for stroke prevention, particularly in Caucasians. This is a retrospective cohort study, in which we used the Clalit clinical database to follow genotyped clopidogrel initiators, for up to 3 years. Endpoint was a new primary discharge diagnosis of ischemic stroke; secondary endpoints were new primary discharge diagnoses of coronary angioplasty, myocardial infarction (MI), or a composite endpoint of: stroke, MI, or coronary angioplasty. After 3 years of follow up over 628 clopidogrel initiators, 2 out of 12 (16.7%) poor metabolizers, 9 out of 144 intermediate metabolizers (6.3%), and 29 out of 472 (6.1%) normal/rapid/ultrarapid metabolizers have been newly diagnosed with ischemic stroke. Poor metabolizer status was associated with higher risk for ischemic stroke, marginally significant in univariate analysis and in multivariable models; and higher risk for the composite outcome of stroke, myocardial infarction and coronary angioplasty, HR = 3.32 (1.35-8.17) p = 0.009, 2.86 (1.16-7.06) p = 0.02 (univariate and multivariate analyses, respectively). Poor metabolizer status was associated with higher risk for stroke HR = 5.80 (1.33-25.24) p = 0.019, HR = 4.13 (0.94-18.13) p = 0.06 (univariate and multivariate analyses, respectively) in patients who "survived" the first year, and were in the cohort 1-3 years. Caucasian treated with clopidogrel who are homozygote for the CYP2C19 loss-of function allele might be at increased risk for ischemic stroke, and for the composite outcome of ischemic stroke, myocardial infarction and coronary angioplasty.
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Clopidogrel/efectos adversos , Citocromo P-450 CYP2C19/genética , Accidente Cerebrovascular Isquémico/inducido químicamente , Accidente Cerebrovascular Isquémico/genética , Isquemia Miocárdica/inducido químicamente , Isquemia Miocárdica/genética , Inhibidores de Agregación Plaquetaria/efectos adversos , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Clopidogrel/metabolismo , Estudios de Cohortes , Bases de Datos Factuales , Determinación de Punto Final , Femenino , Estudio de Asociación del Genoma Completo , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/genética , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria/metabolismo , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
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.
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Reparación del ADN/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/epidemiología , Estudios de Casos y Controles , Daño del ADN/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/análisis , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Femenino , Fluorescencia , Predisposición Genética a la Enfermedad , Humanos , Leucocitos Mononucleares/citología , Pulmón/enzimología , Pulmón/patología , Neoplasias Pulmonares/genética , Masculino , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
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.
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Neoplasias Pulmonares/epidemiología , Fumar/efectos adversos , Anciano , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Humanos , Israel/epidemiología , Judíos/genética , Neoplasias Pulmonares/etiología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
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.
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Daño del ADN/genética , Reparación del ADN/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas de la Membrana/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , ADN Glicosilasas/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Masculino , Proteínas de la Membrana/genética , Estadificación de Neoplasias , Estrés Oxidativo , PronósticoRESUMEN
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.
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Carcinogénesis , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cromosomas Humanos Par 4/genética , Neoplasias Colorrectales/patología , Etnicidad , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
OBJECTIVE: The use of bisphosphonates has been associated with reduced risk and improved survival of breast and colorectal malignancies. This study was aimed at studying the effects of bisphosphonates on gynecological cancers. METHODS: The Cancer in the Ovary and Uterus Study (CITOUS) is a case-control study of newly diagnosed cases of gynecological malignancies and age/clinic/ethnic-group matched population controls. The use of bisphosphonates prior to, and following, diagnosis was assessed in 424 cases of ovarian and endometrial cancers and 341 controls, all postmenopausal at recruitment, enrolled in Clalit Health Services (CHS), using pharmacy records. RESULTS: The use of bisphosphonates for more than 1 year prior to diagnosis was associated with a significantly reduced risk of ovarian cancer (OR=0.49, 95% CI: 0.26-0.93) and endometrial cancer (OR=0.39, 95% CI: 0.24-0.63). The association with endometrial cancer (OR=0.48, 0.27-0.84) remained statistically significant after adjustment for a variety of putative effect modifiers (RR=0.48, 0.26-0.89). The association with ovarian cancer remained significant when adjusted to statin use (0.46, 0.23-0.90) but not for other modifiers (0.58, 0.29-1.18). A strong negative association was found in an adjusted model for the use of either bisphosphonates or statins for more than 1 year (0.40, 0.23-0.68). CONCLUSION: The use of bisphosphonates, with or without statins, for more than 1 year before diagnosis was associated with reduced risk of endometrial and ovarian cancers.
Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/uso terapéutico , Neoplasias Endometriales/epidemiología , Neoplasias Ováricas/epidemiología , Anciano , Estudios de Casos y Controles , Neoplasias Endometriales/prevención & control , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Persona de Mediana Edad , Neoplasias Ováricas/prevención & control , Factores de RiesgoRESUMEN
PURPOSE: The use of statins has been associated with reduced risk of malignancies in a variety of organ sites. This study was aimed at studying the effects of statins on gynecological cancers. METHODS: The Cancer in The Ovary and Uterus Study (CITOUS) is a case-control study of newly diagnosed cases of gynecological malignancies and age/sex/clinic/ethnic-group matched population controls. Use of statins prior to and following diagnosis was assessed in a subset of 424 cases of ovarian and endometrial cancers and 341 controls, enrolled in Clalit Health Services (CHS), using pharmacy records. RESULTS: The use of statins for more than one year prior to diagnosis was associated with a significantly reduced risk of ovarian cancer (OR=0.56, 95% CI: 0.33-0.94) and of endometrial cancer (OR=0.59, 95% CI: 0.40-0.87). The association with endometrial cancer, but not with ovarian cancer (OR=0.54, 0.26-1.13), remained statistically significant after adjustment for fruit and vegetable consumption, sports activity, family history of endometrial and colorectal cancer, ethnicity, BMI, duration of breast feeding, age at 1st pregnancy and use of menopausal hormones (RR=0.48, 0.26-0.89). Women who used statins only after diagnosis of cancer had a significantly better survival of both ovarian cancer (Log rank test, p=0.021, age adjusted HR=0.47, 0.26-0.85) and endometrial cancer (p=0.06, age adjusted HR=0.45, 0.23-0.87). CONCLUSION: The use of statins for more than one year before diagnosis was associated with a reduction in the risk of endometrial cancer and possibly ovarian cancer. A significantly improved survival of cases of both malignancies was noticed when statins were taken only after diagnosis.
Asunto(s)
Neoplasias Endometriales/epidemiología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neoplasias Ováricas/epidemiología , Anciano , Estudios de Casos y Controles , Intervalos de Confianza , Neoplasias Endometriales/mortalidad , Femenino , Humanos , Israel/epidemiología , Estimación de Kaplan-Meier , Persona de Mediana Edad , Oportunidad Relativa , Neoplasias Ováricas/mortalidad , Modelos de Riesgos Proporcionales , Tasa de SupervivenciaRESUMEN
Among patients treated with irinotecan, homozygous carriers of the UGT1A1*28 allele are at increased risk for neutropenia, but UGT1A1 genotype alone does not account for irinotecan-induced toxicity. Our aim was to study the association between single-nucleotide variants in genes encoding for efflux transporters of irinotecan (ABCG2, ABCB1, and ABCC2) and toxicity in real life. The source population was a cohort of patients with colorectal cancer (CRC) in Northern Israel, who had undergone genome-wide association study. From the source population we chose the patients with CRC prescribed irinotecan, and a comparative cohort of patients with CRC treated with other anticancer systemic therapies. Using Clalit Health Services electronic medical records (including laboratory results) we ascertained hematological and gastrointestinal adverse effects and mortality, within 90 days of the first dose, as a composite outcome. There were 601 patients with CRC who received irinotecan, and 756 patients with CRC treated with other anticancer regimens. The minor allele in rs2231142 (ABCG2) was associated with lower incidence of the composite outcome (odds ratio (OR) = 0.54 (0.33, 0.91); P = 0.02) in irinotecan-treated patients with CRC, but not in patients with CRC treated with other regimens. ABCB1 rs1045642 and ABCC2 rs3740066 were not associated with the composite outcome. In a sensitivity analysis, adjusted for UGT1A1 status and for possible demographic and clinical confounders, adjusted OR was 0.56 (0.33, 0.94) for the association between rs2231142 (ABCG2) and the composite outcome. In conclusion, we describe a novel association between the minor allele of rs2231142 in the efflux transporter gene ABCG2 and protection against severe side effects in CRC patients treating with irinotecan.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Neoplasias Colorrectales , Irinotecán , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Humanos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Estudio de Asociación del Genoma Completo , Genotipo , Glucuronosiltransferasa/genética , Irinotecán/efectos adversos , Proteínas de Transporte de Membrana/genética , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas de Neoplasias/genética , Nucleótidos/uso terapéutico , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Variants of the mutY homolog gene MutYH, a DNA repair gene, are associated with increased risk of colorectal cancer; however, it remains unclear whether these variants also are associated with the risk of other cancers. The authors studied the risk of breast cancer associated with MutYH variants in a unique ethnic group of Sephardi Jews in Israel with a high prevalence of MutYH mutations. METHODS: The study participants were 930 Sephardi Jewish women of North African origin who were recruited into the population-based case-control Breast Cancer in Northern Israel Study (BCINIS) either as breast cancer cases or as healthy controls. All participants contributed a blood sample and completed an interview. Two MutYH variants, a glycine-to-aspartic acid substitution at codon 396 (G396D) and a tyrosine-to-cysteine substitution at codon 179 (Y179C), were studied. RESULTS: In the Sephardi Jews, among the healthy controls, 20 women (3.7%) were homozygote or heterozygote carriers of the G396D variant, and 4 women (0.7%) were heterozygote carriers of the Y179C variant. Breast cancer cases had a 6.7% prevalence of G396D, yielding a significantly elevated risk estimate for breast cancer (odds ratio, 1.86; 95% confidence interval, 1.02-3.39; P = .039). The tumors detected in carriers with MutYH variants were similar in characteristics to those without MutYH variants, as was the age at diagnosis. CONCLUSIONS: Carriers of variants in MutYH, although not very common, may have an increased risk of breast cancer in Jews of North African origin. Identification of such carriers and special surveillance protocols may be warranted.
Asunto(s)
ADN Glicosilasas/genética , Judíos/genética , África del Norte/etnología , Anciano , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Israel , Persona de Mediana Edad , MutaciónRESUMEN
Symptom refractoriness of patients treated with proton pump inhibitors (PPIs) might be explained by polymorphism in CYP2C19. This is a retrospective cohort study in which we used the computerized database of Clalit Health Services to compose a cohort from cancer case-control studies' participants that had been genotyped, and that have been dispensed PPI (January 1, 2002 to November 10, 2020). We retrieved demographic and clinical variables on date of PPI initiation (cohort entry), and studies' questionnaires-reported consumption of foods/beverages known to increase peptic-related symptoms. Primary outcome was an abdominal pain diagnosis; secondary outcome was a composite of abdominal pain, visit to a gastroenterology clinic, change to another PPI, PPI dose increase, or metoclopramide prescription, reflecting symptoms persistence/recurrence; in a 2-year follow-up. We also evaluated the association between genetic groups and hip/wrist/spine fractures, in a long-term follow-up. Of 3,326 PPI initiators, there were 66 (2.0%), 739 (22.2%), 1394 (41.9%), 947 (28.5%), and 180 (5.4%) CYP2C19 poor, intermediate, normal, rapid, and ultra-rapid metabolizers, respectively. Being a poor metabolizer was associated with lower risk for the primary outcome, hazard ratio (HR) = 0.50 (95% confidence interval (CI) 0.27-0.91), HR = 0.52 (95% CI 0.28-0.94); and for the secondary outcome, HR = 0.57 (95% CI 0.38-0.86), HR = 0.58 (95% CI 0.39-0.87), in univariate and multivariable cox regression analyses, respectively. In long-term follow-up with 20,142 person-years of follow-up: 7.6% (5 cases) within the poor metabolizers group, and 11.6%, 12.9%, 12.8%, and 11.1% in the normal, intermediate, rapid, and ultra-rapid metabolizers groups, respectively, had a new fracture (nonsignificant). We conclude that CYP2C19 poor metabolizer status is associated with higher effectiveness of PPIs, and is not associated with higher risk for fractures.
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Citocromo P-450 CYP2C19 , Fracturas Óseas , Inhibidores de la Bomba de Protones , Dolor Abdominal/tratamiento farmacológico , Estudios de Cohortes , Citocromo P-450 CYP2C19/genética , Fracturas Óseas/enzimología , Fracturas Óseas/genética , Humanos , Polimorfismo Genético , Inhibidores de la Bomba de Protones/uso terapéutico , Estudios RetrospectivosRESUMEN
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.
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Neoplasias de la Mama/epidemiología , Neoplasias Colorrectales/epidemiología , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Registros Electrónicos de Salud , Femenino , Humanos , Israel , Persona de Mediana Edad , Análisis Multivariante , Factores de RiesgoRESUMEN
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.
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Aborto Inducido/estadística & datos numéricos , Aborto Espontáneo/epidemiología , Neoplasias Colorrectales/epidemiología , Anticonceptivos Orales/administración & dosificación , Factores de Edad , Anciano , Anciano de 80 o más Años , Árabes/estadística & datos numéricos , Estudios de Casos y Controles , Neoplasias Colorrectales/prevención & control , Femenino , Humanos , Israel/epidemiología , Judíos/estadística & datos numéricos , Menarquia , Menopausia , Persona de Mediana Edad , Oportunidad Relativa , Embarazo , Factores Protectores , Factores de RiesgoRESUMEN
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.
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Proteína C-Reactiva/metabolismo , Neoplasias Colorrectales/epidemiología , Anciano , Proteína C-Reactiva/genética , Causalidad , Neoplasias Colorrectales/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Modelos Logísticos , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Genetic variation in FGFR2 is a newly described risk factor for breast cancer. We estimated the relative risk and contribution of FGFR2 polymorphisms to breast cancer risk in diverse ethnic groups within Jewish and other Middle Eastern populations. We genotyped four FGFR2 single nucleotide polymorphisms (SNP) and tested for association of these SNPs and haplotypes with breast cancer risk in a population-based case-control study of 1,529 women with breast cancer and 1,528 controls. We found significant associations between breast cancer risk and all four studied SNPs in FGFR2 (P trend for all SNPs < 0.0001). In ethnicity-specific analysis, all four SNPs were significantly associated with breast cancer risk in Ashkenazi and Sephardi Jews, with a similar but not significant trend in Arabs. Haplotype analysis identified five common haplotypes (>1%). The previously described AAGT risk haplotype was significantly associated with breast cancer risk in Ashkenazi [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.07-1.45; P = 0.0059] and Sephardi Jews (OR, 1.46; 95% CI, 1.17-1.80; P = 0.0006) compared with the reference GGAC haplotype. The AAAC haplotype was significantly associated with breast cancer risk in Sephardi Jews (OR, 1.97; 95% CI, 1.16-3.35; P = 0.0125) but not in Ashkenazi Jews (OR, 0.83; 95% CI, 0.41-1.62; P = 0.5613) or in Arabs (OR, 1.31; 95% CI, 0.80-2.14; P = 0.2881). Genetic variation in FGFR2, identified by rs1219648, may account for a substantial fraction of breast cancer in Arab (12%), Ashkenazi (15%), and Sephardi Jewish (22%) populations. The identification of population-specific risk haplotypes in FGFR2 is likely to help identify causal variants for breast cancer.
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Árabes/genética , Neoplasias de la Mama/etnología , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Judíos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Femenino , Variación Genética , Genotipo , Haplotipos , Humanos , Israel , Modelos Logísticos , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
UNLABELLED: Growth hormone may be associated with the development of colorectal cancer directly and/or indirectly via increased serum level of insulin-like growth factor (IGF-I). Regular physical activity can decrease insulin resistance and modulates IGF-I production. A common polymorphism in the GH1 gene, rs2665802, was previously shown to be associated with lower IGF-I levels and decreased colorectal cancer (CRC) risk. We investigated the association of this polymorphism and physical activity with colorectal cancer risk in a case-control study. METHODS: The analysis includes 3,041 (1,402 cases and 1,639 controls) participants in the Molecular Epidemiology of Colorectal Cancer study, a population-based case-control study in Northern Israel. Analysis was carried out separately in two sets. The first set included 1,248 subjects (625 cases, 623 controls), and the second validation set consisted of 1,793 subjects (777 cases, 1,016 controls). RESULTS: No association was found between the studied polymorphism and CRC risk. However, evaluation of gene environment interactions revealed an interaction between leisure time physical activity and the GH1 polymorphism, which was consistent in both sets (P(interaction) = 0.005). The genotype AA was associated with decreased risk of CRC among individuals who did not engage in any such activity (odds ratio, 0.76; 95% confidence interval, 0.52-0.98), whereas the same genotype was marginally associated with increased risk among individuals who reported physical activity (odds ratio, 1.38; 95% confidence interval, 0.98-1.94). CONCLUSIONS: We found that the A allele of the rs2665802 polymorphism is associated with reduced risk of CRC only among physically inactive individuals, indicating an interaction between physical activity and the growth hormone/IGF-I system. A replication of the observed findings and further investigation of the underlying mechanism is warranted.
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Neoplasias Colorrectales/genética , Hormona de Crecimiento Humana/genética , Actividad Motora , Anciano , Alelos , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Neoplasias Colorrectales/epidemiología , Femenino , Genotipo , Humanos , Incidencia , Israel/epidemiología , Actividades Recreativas , Modelos Logísticos , Masculino , Polimorfismo Genético , Factores de RiesgoRESUMEN
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.
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Neoplasias de la Mama/tratamiento farmacológico , Difosfonatos/uso terapéutico , Osteoporosis/tratamiento farmacológico , Anciano , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Osteoporosis/patología , Receptor ErbB-2/genéticaRESUMEN
DNA repair is a prime mechanism for preventing DNA damage, mutation, and cancers. Adopting a functional approach, we examined the association with lung cancer risk of an integrated DNA repair score, measured by a panel of three enzymatic DNA repair activities in peripheral blood mononuclear cells. The panel included assays for AP endonuclease 1 (APE1), 8-oxoguanine DNA glycosylase (OGG1), and methylpurine DNA glycosylase (MPG), all of which repair oxidative DNA damage as part of the base excision repair pathways. A blinded population-based case-control study was conducted with 96 patients with lung cancer and 96 control subjects matched by gender, age (±1 year), place of residence, and ethnic group (Jews/non-Jews). The three DNA repair activities were measured, and an integrated DNA repair OMA (OGG1, MPG, and APE1) score was calculated for each individual. Conditional logistic regression analysis revealed that individuals in the lowest tertile of the integrated DNA repair OMA score had an increased risk of lung cancer compared with the highest tertile, with OR = 9.7; 95% confidence interval (CI), 3.1-29.8; P < 0.001, or OR = 5.6; 95% CI, 2.1-15.1; P < 0.001 after cross-validation. These results suggest that pending validation, this DNA repair panel of risk factors may be useful for lung cancer risk assessment, assisting prevention and referral to early detection by technologies such as low-dose computed tomography scanning.
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Biomarcadores de Tumor/metabolismo , ADN Glicosilasas/metabolismo , Reparación del ADN , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Neoplasias Pulmonares/diagnóstico , Proteínas de la Membrana/metabolismo , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/patología , Masculino , Estadificación de Neoplasias , Pronóstico , Factores de RiesgoRESUMEN
MUTYH is associated with colorectal cancer (CRC) risk. We studied the frequency of MUTYH and risk of CRC in Arabs, North African and European Jews. Participants were all 593 Sephardi Moroccan Jews (232 cases, 361 controls) and all 631 Arabs (327 cases, 304 controls) recruited into a population-based study of colorectal cancer in Israel, as well as a random sample of 189 Ashkenazi Jewish cases. Two MUTYH mutations, G396D and Y179C, were studied in 1,413 individuals, with MUTYH sequence analysis in 46 cases with CRC in a sibling or adenoma. No carriers of mutations in MUTYH were identified in Ashkenazi Jews and only one in Arabs. In Sephardi Jews, 28 carriers of G396D, 25 (4.2%) heterozygotes and 3 (0.5%) homozygotes were identified. Four (0.7%) were heterozygote carriers of the Y179C mutation. Two compound heterozygous carriers of Y179C and G396D were identified. Homozygote carriers of G396D had nonsignificantly elevated risk of CRC (OR = 11.0, 95% CI: 0.91-213.9, p = 0.06), and combined bi-allelic carriers of G396D and Y179C had increased risk, OR = 17.4, 95% CI = (1.9-316.7, p = 0.009). Four of five bi-allelic carriers reported a family history of CRC. Sequencing of 46 colorectal cancer cases with family history and additional adenomas, did not identify any other non-founder mutations. MUTYH carriers of the two common founder mutations are profoundly under-represented among both Ashkenazi Jews and Arabs. The prevalence of MUTYH carriers of the common mutations is much higher in Sephardi Jews. Bi-allelic carriers of mutations in MUTYH, are associated with highly risk of colorectal cancer.