RESUMEN
The cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of testosterone. Functional changes in this enzyme may influence endogenous hormone exposure, which has been associated with risk of breast cancer. To assess potential associations between two functional polymorphisms CYP2B6_516_G>T (rs3745274) and CYP2B6_785_A>G (rs2279343) and breast cancer risk, we established a specific matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assay. The GENICA breast cancer case-control study showed associations between the variant genotypes CYP2B6_516_TT and CYP2B6_785_GG and breast cancer risk with odds ratios (ORs) of 1.34 (p = 0.001) and 1.31 (p = 0.002), respectively. A similar effect was observed for carriers of the CYP2B6_516_T allele in a validation study including four independent studies from Germany, Sweden and USA. In a pooled analysis of all five studies involving 4,638 breast cancer cases and 3,594 controls of European ancestry, carriers of the CYP2B6_516_G and the CYP2B6_785_G variant had an increased breast cancer risk with ORs of 1.10 (p = 0.027) and 1.10 (p = 0.031), respectively. We conclude that the genetic variants CYP2B6_516_G and CYP2B6_785_G (designated CYP2B6*6), which are known to decrease activity of the CYP2B6 enzyme, contribute to an increased breast cancer risk.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/etiología , Predisposición Genética a la Enfermedad , Polimorfismo Genético/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Citocromo P-450 CYP2B6 , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Metaanálisis como Asunto , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Small ubiquitin-like modifier (SUMO) proteins are covalently attached to target proteins to modify their function. SUMO conjugation participates in processes tightly linked to tumorigenesis. Recently USPL1 (ubiquitin-specific peptidase-like (1) was identified as a SUMO isopeptidase. We report here on the first exploratory study investigating the relationship between genetic variability in USPL1 and breast cancer. Three potentially functional nonsynonymous coding SNPs (rs3742303, rs17609459, rs7984952) were genotyped in 1,021 breast cancer cases and 1,015 controls from the population-based GENICA study. We took advantage of multiple genotype imputation based on HapMap and the 1000 Genomes Project data to refine the association screening in the investigated region. Public genetic databases were also used to investigate the relationship with USPL1 expression in lymphoblastoid cell lines and breast tissue. Women homozygous for the minor C allele of rs7984952 showed a lower risk of Grade 3 breast tumors compared to TT homozygotes (OR 0.50, 95% CI 0.30-0.81). Case-only analyses confirmed the association between rs7984952 and tumor grade (OR 0.60, 95% CI 0.39-0.93). Imputation results in a 238 kb region around rs7984952 based on HapMap and the 1000 Genomes Project data were similar. No imputed variant showed an association signal stronger than rs7984952. USPL1 expression in tumor breast tissue increased with the number of C alleles. The present study illustrates the contribution of multiple imputation of genotypes using public data repositories to standard genotyping laboratory. The provided information may facilitate the design of independent studies to validate the association between USPL1 rs7984952 and risk of Grade 3 breast tumors.
Asunto(s)
Neoplasias de la Mama/genética , Endopeptidasas/genética , Regulación Neoplásica de la Expresión Génica , Polimorfismo de Nucleótido Simple , Alelos , Índice de Masa Corporal , Estudios de Casos y Controles , Línea Celular Tumoral , Bases de Datos Genéticas , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Homocigoto , Humanos , Sitios de Carácter Cuantitativo , Análisis de Regresión , Análisis de Secuencia de ADN , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Factores de Tiempo , Proteasas Ubiquitina-EspecíficasRESUMEN
17ß-hydroxysteroid dehydrogenase type 1 (HSD17B1) plays an important role in the biosynthesis of 17ß-estradiol. The current study aimed at confirming the reduced risk of breast cancer in carriers of the non-synonymous HSD17B1_937_A>G (rs605059) polymorphism who used any hormone replacement therapy (HRT) for 10 years or longer. We performed an independent association study using four breast cancer case-control studies from Australia, Germany, and Sweden. In all, 5,777 cases and 8,189 age-matched controls of European descent were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and TaqMan. Risk estimates were calculated by interaction analysis and main effect analysis adjusted for age and study. Main effect analyses for women using any HRT for 10 years or longer (1,428 cases versus 1,724 controls) revealed a protective effect of the HSD17B1_937_G allele on breast cancer risk (OR 0.86, 95 % CI: 0.73-0.99; p = 0.048). Thus, our previous finding of a protective effect of the HSD17B1_937_G allele on HRT-associated breast cancer risk has now been confirmed both in independent large patient cohorts and a comprehensive pooled analysis supporting the hypothesis that a HSD17B1-mediated decreased conversion of estrone to the more potent 17ß-estradiol may reduce the estrogenic effects, thereby reducing the risk of developing breast cancer during long-term HRT use.
Asunto(s)
Neoplasias de la Mama/genética , Estradiol Deshidrogenasas/genética , Terapia de Reemplazo de Estrógeno/efectos adversos , Polimorfismo de Nucleótido Simple , Neoplasias de la Mama/inducido químicamente , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Posmenopausia , Factores de RiesgoRESUMEN
The human homolog of the Drosophila Scribble (SCRIB) tumor suppressor gene encodes a protein that regulates apical-basolateral polarity in mammalian epithelia and controls cell proliferation. Due to the role of cell polarity proteins in human cancers, we investigated whether genetic variability in SCRIB impacts breast carcinogenesis and tumor pathology. Five genetic variants were analyzed for an association with breast cancer risk and histopathological tumor parameters using a single nucleotide polymorphism (SNP) tagging approach. Genotyping of five tag SNPs was performed by TaqMan allelic discrimination and RFLP-based PCR using the GENICA population-based breast cancer case-control collection including 1,021 cases and 1,015 age-matched controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by ordinal logistic regression. None of the tag SNPs was associated with breast cancer risk or tumor characteristics. Our findings suggest that genetic variability in the SCRIB polarity gene does not contribute to breast cancer development.
Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Neoplasias de la Mama/patología , Femenino , Orden Génico , Alemania/epidemiología , Humanos , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
Organic anion transporter polypeptides (OATPs, SLCOs) are involved in the uptake of conjugates steroid hormones such as estrone-3-sulfate. It has been suggested that the expression of OATPs in breast tissues could impact breast carcinogenesis and tumor pathology. The nuclear receptor pregnane X receptor (PXR) is involved in the regulation of SLCO1A2 expression. We investigated 31 variants located in PXR, SLCO1A2, SLCO1B1, SLCO1B3, and SLCO2B1 for an association with breast cancer risk and/or histo-pathological tumor characteristics. Polymorphisms were selected on the basis of a known or potential functional consequence and an allele frequency >2%. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using the GENICA population-based breast cancer case-control collection comprising 1,021 cases and 1,015 age-matched controls. Statistical analysis was performed by SAS, and all tests were two-sided. None of the 31 analyzed transporter and PXR polymorphisms showed an association with breast cancer risk or tumor characteristics. Our data suggest that among the many known transporters common variations of PXR, SLCO1A2, SLCO1B1, SLCO1B3, and SLCO2B1 do not contribute to breast carcinogenesis.
Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple , Receptores de Esteroides/genética , Femenino , Expresión Génica , Frecuencia de los Genes , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado , Transportadores de Anión Orgánico Sodio-Independiente/genética , Receptor X de Pregnano , Riesgo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones OrgánicosRESUMEN
Genetic polymorphisms of human ABC-transporter genes have been suggested to modulate breast cancer risk in the general population. In particular ABCC11 (MRP8), which is highly expressed in breast cancer tissue and involved in the efflux of conjugated estrogen metabolites such as estrone-3-sulfate and estradiol-17beta-glucuronide, has recently been proposed as a potential risk factor for female breast cancer. The wet earwax-associated G-allele of the c.538G>A polymorphism was associated with an increased risk for breast cancer in Japanese women. In contrast, no evidence for such an association could be observed in Caucasian women. We aimed to confirm/refute the association of the c.538G>A variant in ABCC11 with breast cancer risk and/or histo-pathological tumor characteristics in an independent population-based breast cancer case-control study from Germany comprising 1021 cases and 1015 age-matched controls. No association for allele and genotype frequencies of the 538G>A variant in ABCB11 with breast cancer risk was found. Our data suggest that the c.538G>A variation in ABCC11 does not contribute to breast carcinogenesis in women of European descent.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Neoplasias de la Mama/genética , Cerumen/fisiología , Población Blanca/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Anciano , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Alemania , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Breast cancer is a complex disease and in recent years a number of breast cancer susceptibility genes have been identified, but the role of low penetrance susceptibility genes has not been completely resolved. Glutathione S-transferases (GSTs) are phase II xenobiotic metabolizing enzymes involved in the detoxification of chemical carcinogens and environmental pollutants and play an important role in cell defense mechanisms against oxidative stress. They have been in the spot light for the investigation of a potential association with breast cancer risk but so far, sparse or even no data for a potential contribution of GSTA2, GSTM2, GSTO, and GSTZ to breast cancer risk are available. We genotyped GSTA2_448_C > G (rs2180314), GSTA2_742_A > C (rs6577), GSTM2_-832_T > C (rs638820), GSTO1_-1242_G > A (rs2164624), GSTO1_419_A > C (rs4925), GSTO2_-183_A > G (rs2297235), GSTO2_342_A > G (rs156697), GSTZ1_-4378_A > G (rs1046428), and GSTZ1_94_G > A (rs3177427) by MALDI-TOF MS in the German GENICA breast cancer case-control collection of 1021 cases and 1015 controls and performed breast cancer risk association in general and with respect to the stratifications: menopausal status, family history of breast or ovarian cancer, use of oral contraceptives, use of hormone therapy, body mass index, and smoking as well as histopathological tumor characteristics including hormone receptor status, grade, histology, and node status. We did not observe any breast cancer risk associations and conclude that it is unlikely that glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 participate in breast cancer susceptibility.
Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Isoenzimas/genética , Neoplasias de la Mama/enzimología , Femenino , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
SUMOylation consists in the covalent conjugation of small ubiquitin-related modifiers to target proteins. SUMOylation participates in processes that are tightly linked to tumorigenesis, and genetic variability in the SUMO-conjugating system may influence the development of breast cancer. We recently reported that variation in the UBC9 gene encoding the SUMO-conjugating enzyme may affect the grade of breast tumors. Following comprehensive in silico analyses for detection of putative functional polymorphisms in 14 genes of the SUMO system, we selected one coding SNP in PIAS3 and seven tag SNPs in UBC9 for association analyses. Results were based on 1,021 cases, and 1,015 matched controls from the population-based GENICA study. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by conditional logistic regression. To explore the association with polymorphisms closely linked to the genotyped variants, multiple imputation based on HapMap data was applied. The study revealed associations of four UBC9 polymorphisms with risk of grade 1 tumors. Comparison of genotype and haplotype models indicated that the best representation of risk solely relied on rs7187167 under dominant penetrance. Women carrying the rare allele showed an increased risk of grade 1 tumors compared with common homozygotes (OR 1.87, 95% CI 1.18-2.95). This effect appeared to be stronger in women with a family history of breast or ovarian cancer. Imputation of polymorphisms in a 300-kb region around the genotyped polymorphisms identified no variants with stronger associations. Our findings suggest that genetic variation in UBC9 may affect the risk of grade 1 breast tumors.
Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Chaperonas Moleculares/genética , Polimorfismo de Nucleótido Simple , Proteínas Inhibidoras de STAT Activados/genética , Enzimas Ubiquitina-Conjugadoras/genética , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos , Humanos , Persona de Mediana Edad , Chaperonas Moleculares/metabolismo , Proteínas Inhibidoras de STAT Activados/metabolismo , Factores de Riesgo , Proteína SUMO-1/genética , Proteína SUMO-1/metabolismo , Enzimas Ubiquitina-Conjugadoras/metabolismo , Adulto JovenRESUMEN
Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast tumors is associated with bad prognosis. Therefore, it is highly relevant to further improve understanding of the regulatory mechanisms of HER2 expression. In addition to gene amplification, transcriptional regulation plays a crucial role in HER2 overexpression. In this study, we analyzed 3 polymorphisms E2F2_-5368_A>G, CCND1_870_A>G and CCND3_-677_C>T located in genes involved in cell cycle regulation in the GENICA population-based and age-matched breast cancer case-control study from Germany. We genotyped 1,021 cases and 1,015 controls by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Statistical analyses were performed by conditional logistic regression. We observed no differences in genotype frequencies between breast cancer cases and controls. Subgroup analysis showed associations between carriers of the E2F2_-5368_G allele (OR: 0.60, 95% CI: 0.42-0.85), carriers of the CCND1_870_G allele (OR: 0.66, 95% CI: 0.45-0.96) and carriers of the CCND3_-677_T allele (OR: 1.72, 95% CI: 1.20-2.49) and HER2 expression in breast tumors. This finding points to an association of an increased expression of these cell cycle regulators with lower expression of HER2. An explanation for this observation might be that low expression of E2F2, CCND1 and CCND3 decrease levels of factors down-regulating HER2. We conclude that the analyzed polymorphisms located in E2F2, CCND1 and CCND3 are potential markers for HER2 status of breast tumors.
Asunto(s)
Neoplasias de la Mama/genética , Ciclina D1/genética , Ciclinas/genética , Factor de Transcripción E2F2/genética , Polimorfismo Genético/genética , Receptor ErbB-2/genética , Sitios de Unión , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Ciclina D1/metabolismo , Ciclina D3 , Ciclinas/metabolismo , Análisis Mutacional de ADN , Factor de Transcripción E2F2/metabolismo , Femenino , Genotipo , Alemania , Humanos , Técnicas para Inmunoenzimas , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Receptor ErbB-2/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Factores de Transcripción/metabolismoRESUMEN
UBC9 encodes a protein that conjugates small ubiquitin-related modifier (SUMO) to target proteins resulting in a change of their localization, activity or stability. Genetic variability may affect expression and activity of UBC9 and may have an impact on breast tumor progression. We investigated associations between UBC9 genotypes and histopathological parameters in 1,021 breast cancer cases of the GENICA collection using a single nucleotide polymorphism (SNP) tagging approach. Genotyping analyses were performed by TaqMan(R) allelic discrimination. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by ordinal logistic regression. Multiple imputation based on HapMap data was applied to boost the power of the study. The study revealed significant associations of three UBC9 SNPs with histological grade (rs7187167, p(trend) = 0.001; rs11248866, p(trend) = 0.009; rs8052688, p(trend) = 0.008). Model selection identified a recessive penetrance model for rs7187167 as the best representation of tumor grade (global p = 0.001). This model did not improve by inclusion of additional SNPs in linkage disequilibrium. Imputation of SNPs in a 300 kb region around the genotyped SNPs supported rs7187167 as a major contributor to tumor grade. Compared with common allele carriers, rare homozygotes presented less frequently with high grade tumors (G3 vs. G1: OR 0.26, 95% CI 0.11-0.62; G3 vs. G2: OR 0.45, 95% CI 0.23-0.86). In addition to tumor size, nodal status and estrogen receptor status, multivariate analyses confirmed an independent role of rs7187167 as predictor of tumor grade (p = 0.0003). The present results underline the value of genetic variation in UBC9 for breast cancer prognosis.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Polimorfismo de Nucleótido Simple , Proteína SUMO-1/metabolismo , Enzimas Ubiquitina-Conjugadoras/genética , Adulto , Anciano , Análisis de Varianza , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Variación Genética , Genotipo , Humanos , Desequilibrio de Ligamiento , Metástasis Linfática , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Receptores de Estrógenos/metabolismoRESUMEN
Cytochrome P450 2C19 (CYP2C19) plays an important role in the metabolism of xenobiotics and drugs and contributes to the catabolism of endogenous substrates like estradiol. Genetic variability impacts expression and activity of CYP2C19 and therefore can influence catabolism of estrogens. In the present study we analyzed the association of three polymorphisms of CYP2C19 namely CYP2C19*2 (CYP2C19_681_G>A, rs4244285), CYP2C19*3 (CYP2C19_636_G>A, rs57081121) and CYP2C19*17 (CYP2C19_-806_C>T, rs12248560), with breast cancer susceptibility. We genotyped 1,015 breast cancer cases and 1,021 age-matched, population-based controls of the German GENICA study by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Risk estimates were calculated by logistic regression. All tests were two-sided. We observed a decreased breast cancer risk for carriers of the CYP2C19*17 allele (OR 0.77, 95% CI: 0.65-0.93; P = 0.005). In subgroup analysis we observed a significant decreased breast cancer risk for women using hormone therapy for ten years or longer who were carriers of the CYP2C19*17 allele (OR 0.57, 95% CI: 0.39-0.83; P = 0.003). Since CYP2C19*17 defines an ultra rapid metabolizer phenotype we suggest that an increased catabolism of estrogens by CYP2C19 may lead to decreased estrogen levels and therefore reduces breast cancer risk. This protective effect seems to be stronger in combination with long-term intake of supplemental estrogens during hormone therapy.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Estudios de Casos y Controles , Citocromo P-450 CYP2C19 , Femenino , Genotipo , Haplotipos , Humanos , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
A significant number of HER-2 amplified breast cancers is effectively treated by trastuzumab and further shows receptor-enhanced chemosensitivity. Recent studies have postulated transactivation of HER-2 also in tumors expressing phosphorylated/activated HER-2 (pHER-2) and of the HER-3/HER-4 ligand heregulin (HRG), independent of HER-2 amplification. As a consequence, a subset of tumors without HER-2 overexpression would be sensitive to trastuzumab chemotherapy. To investigate the potential transactivation of HER-2, in 171 breast cancers from the GENICA study with negative/low expression of HER-2 we analyzed the expression of pHER-2, HRG, HER-3 and HER-4 by immunohistochemistry. None of the tumors examined displayed expression of pHER-2. Moderate or strong cytoplasmic staining of HRG, HER-3 and HER-4 was observed in 44 (26%), 67 (39%) and 33 (19%) cases, respectively. No association of HRG, HER-3 and HER-4 with the survival of patients or with known prognostic clinical factors was seen. In conclusion, our data obtained on a well-characterized cohort of breast cancers provide no evidence of HER-2-activation in the absence of HER-2 overexpression. The biological function and clinical implications of HRG, HER-3 and HER-4 in this group of tumors remain unclear. Our results cannot support the hypothesis of a transactivation of HER-2 and thus a possible therapeutic benefit of trastuzumab in HER-2 negative breast cancers.
Asunto(s)
Neoplasias de la Mama/metabolismo , Receptores ErbB/biosíntesis , Neurregulina-1/biosíntesis , Receptor ErbB-2/biosíntesis , Receptor ErbB-3/biosíntesis , Adulto , Anciano , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Estadificación de Neoplasias , Fosforilación , Receptor ErbB-4 , Activación TranscripcionalRESUMEN
Iron overload has been noticed as a feature of human breast cancer. Cellular iron uptake is regulated by the hemochromatosis and transferrin receptor system, mutations of which cause the iron storage disease hereditary hemochromatosis. To understand the role of hemochromatosis and transferrin receptor system mutations in breast cancer, we analyzed 19 sequence variations at HFE, TFR1, TFR2, and FPN1 and compared genotype frequencies between cases and controls in a German population. There were 688 breast cancer patients and 724 population-based and age-matched controls. For genotyping, we applied the Hemochromatosis Strip Assay and TaqMan allelic discrimination analyses. In addition to genotype frequencies, we established frequencies of compound genotypes. The frequencies of HFE at His63Asp, Ser65Cys, and Cys282Tyr, and of TFR1 at Ser142Gly minor alleles in this German population were 15.9%, 1.8%, 5.6%, and 46.0%, respectively. No rare variants at 15 more loci at HFE, TFR2, and FPN1 were observed in breast cancer patients. There were no significant differences of allele and genotype frequencies between cases and controls. Triple and quadruple compound genotypes at HFE_His63_Cys282-TFR1_Ser142Gly and HFE_His63_Ser65_Cys282-TFR1_Ser142Gly showed a nonsignificant increase in cases. Although limited by low numbers, an increased prevalence of the HFE Tyr282 minor allele was observed in breast cancer cases with a high number of affected lymph nodes (P = 0.032). Our data suggest that variants of the hemochromatosis-transferrin receptor system have no direct effect on the incidence of breast cancer in Germany. Possible effects on tumor progression and prognosis remain elusive.
Asunto(s)
Neoplasias de la Mama/genética , Variación Genética , Hemocromatosis/genética , Polimorfismo Genético , Adulto , Anciano , Neoplasias de la Mama/sangre , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Alemania/epidemiología , Hemocromatosis/epidemiología , Humanos , Incidencia , Hierro/metabolismo , Modelos Logísticos , Menopausia , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Factores de RiesgoRESUMEN
CHEK2*1100delC is associated with a twofold increased breast cancer risk. This was shown in a collaborative analysis of European populations, but not in other populations from Europe and the US. Accordingly, there is a need to clarify the role of CHEK2*1100delC in breast cancer. We established its prevalence in two German populations GENICA (Northrhine-Westphalia, n = 724) and KORA (Bavaria, n = 600) and in women with breast cancer. The latter included cases (n = 688) from the GENICA breast cancer case-control study, patients with early-onset breast cancer (n = 86) and patients with familial breast cancer (n = 71). The latter patient groups were previously investigated for BRCA1/2-mutations and tested negative. Mutation analysis was performed by combined PCR/DHPLC methodology. CHEK2*1100delC was found in 0.9% of GENICA controls and was absent in the KORA controls indicating a significant difference between the two populations (P= 0.03). The frequency of CHEK2*1100delC in age-matched cases of the GENICA collection was 0.8% and thus not different from controls (OR 0.88, 95% CI 0.21-3.50). In patients with early-onset disease CHEK2*1100delC was found at a frequency of 2.3% referring to an increased breast cancer risk of 2.56 (95% CI 0.25-14.58). In patients with familial disease the frequency was 1.4% referring to an increased risk of 1.53 (95% CI 0.03-12.93). Our data showed variations in CHEK2*1100delC prevalence within German populations suggesting possible inaccuracies in breast cancer risk assessments from non population-based studies. In patients with a high-risk profile however, CHEK2*1100delC was indicative for this risk and highest for early-onset breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Quinasa de Punto de Control 2 , Femenino , Genes BRCA1 , Genes BRCA2 , Genotipo , Alemania , Humanos , Mutación , Linaje , Prevalencia , Factores de RiesgoAsunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/psicología , Glucuronosiltransferasa/genética , Acontecimientos que Cambian la Vida , Estrés Psicológico/complicaciones , Neoplasias de la Mama/enzimología , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Alemania , Humanos , Modelos Logísticos , Oportunidad Relativa , Fenotipo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Medición de Riesgo , Factores de RiesgoRESUMEN
The polygenic concept of breast cancer susceptibility calls for the identification of genetic variants that contribute to breast cancer risk. Reduced DNA repair proficiencies in women with breast cancer pointed to a possible role of DNA repair enzymes in the risk to develop the disease. The nucleotide excision repair enzyme encoded by the excision repair cross-complementing group 2 gene ERCC2 (formerly XPD) known to cause skin cancer by germ line mutations has multiple regulatory cellular functions, including nucleotide excision repair, basal transcription, cell cycle control, and apoptosis. ERCC2 polymorphisms ERCC2_6540_G>A (Asp(312)Asn) and ERCC2_18880_A>C (Lys(751)Gln) within the coding region of this evolutionarily highly conserved gene have been of functional relevance and therefore are potential candidates to confer breast cancer susceptibility. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we analyzed genotype frequencies in constitutional DNA of study participants of a German case-control study that included 688 cases of incident breast cancer and 724 population-based, age-matched controls. We identified ERCC2_6540_GG (Asp(312)Asp) as an at-risk genotype [odds ratio (OR), 2.06; 95% confidence interval (95% CI), 1.39-3.07]. The ERCC2_6540_GG-associated breast cancer risk was even higher in women who were also carriers of the ERCC2_18880_CC (Gln(751)Gln) genotype (OR, 3.69; 95% CI, 1.76-7.74). We identified ERCC2_6540_G/ERCC2_18880_C (Asp(312)/Gln(751)) as the most potent risk-conferring haplotype (OR, 3.49; 95% CI, 2.30-5.28). To our knowledge, this is the first study assigning breast cancer risk to both the ERCC2 genotype encoding Asp(312)Asp and the haplotype encoding Asp(312)/Gln(751).
Asunto(s)
Neoplasias de la Mama/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Factores de Transcripción/genética , Adulto , Anciano , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/etiología , Estudios de Casos y Controles , Análisis Mutacional de ADN , Reparación del ADN , Femenino , Genotipo , Alemania/epidemiología , Haplotipos , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Proteína de la Xerodermia Pigmentosa del Grupo DRESUMEN
OBJECTIVES: The role of genetic variants and environmental factors in breast cancer etiology has been intensively studied in the last decades. Gene-environment interactions are now increasingly being investigated to gain more insights into the development of breast cancer, specific subtypes, and therapeutics. Recently, night shift work that involves circadian disruption has gained rising interest as a potential non-genetic breast cancer risk factor. Here, we analyzed genetic polymorphisms in genes of cellular clocks, melatonin biosynthesis and signaling and their association with breast cancer as well as gene-gene and gene-night work interactions in a German case-control study on breast cancer. METHODS: GENICA is a population-based case-control study on breast cancer conducted in the Greater Region of Bonn. Associations between seven polymorphisms in circadian genes (CLOCK, NPAS2, ARTNL, PER2 and CRY2), genes of melatonin biosynthesis and signaling (AANAT and MTNR1B) and breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders for 1022 cases and 1014 controls. Detailed shift-work information was documented for 857 breast cancer cases and 892 controls. Gene-gene and gene-shiftwork interactions were analyzed using model-based multifactor dimensionality reduction (mbMDR). RESULTS: For combined heterozygotes and rare homozygotes a slightly elevated breast cancer risk was found for rs8150 in gene AANAT (OR 1.17; 95% CI 1.01-1.36), and a reduced risk for rs3816358 in gene ARNTL (OR 0.82; 95% CI 0.69-0.97) in the complete study population. In the subgroup of shift workers, rare homozygotes for rs10462028 in the CLOCK gene had an elevated risk of breast cancer (OR for AA vs. GG: 3.53; 95% CI 1.09-11.42). Shift work and CLOCK gene interactions were observed in the two-way interaction analysis. In addition, gene-shiftwork interactions were detected for MTNR1B with NPAS2 and ARNTL. CONCLUSIONS: In conclusion, the results of our population-based case-control study support a putative role of the CLOCK gene in the development of breast cancer in shift workers. In addition, higher order interaction analyses suggest a potential relevance of MTNR1B with the key transcriptional factor NPAS2 with ARNTL. Hence, in the context of circadian disruption, multivariable models should be preferred that consider a wide range of polymorphisms, e.g. that may influence chronotype or light sensitivity. The investigation of these interactions in larger studies is needed.
Asunto(s)
Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Relojes Circadianos/genética , Polimorfismo de Nucleótido Simple , Tolerancia al Trabajo Programado , Factores de Transcripción ARNTL/genética , Adulto , Anciano , Anciano de 80 o más Años , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Neoplasias de la Mama/epidemiología , Proteínas CLOCK/genética , Estudios de Casos y Controles , Epistasis Genética , Femenino , Alemania/epidemiología , Humanos , Persona de Mediana Edad , Modelos Genéticos , Análisis Multivariante , Proteínas del Tejido Nervioso/genética , Receptor de Melatonina MT2/genética , Adulto JovenRESUMEN
OBJECTIVES: The potential mechanisms that link night-shift work with breast cancer have been extensively discussed. Exposure to light at night (LAN) depletes melatonin that has oncostatic and anti-estrogenic properties and may lead to a modified expression of estrogen receptor (ER) α. Here, we explored the association between shift work and breast cancer in subgroups of patients with ER-positive and -negative tumors. METHODS: GENICA (Gene-ENvironment Interaction and breast CAncer) is a population-based case-control study on breast cancer with detailed information on shift work from 857 breast cancer cases and 892 controls. ER status was assessed by immunohistochemical staining. Associations between night-shift work and ER-positive and -negative breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders. RESULTS: ER status was assessed for 827 cases and was positive in 653 and negative in 174 breast tumors. Overall, 49 cases and 54 controls were "ever employed" in shift work including night shifts for ≥ 1 year. In total, "ever shift work" and "ever night work" were not associated with an elevated risk of ER-positive or -negative breast tumors. Night work for ≥ 20 years was associated with a significantly elevated risk of ER-negative breast cancer [odds ratio (OR) 4.73, 95% confidence interval (95% CI) 1.22-18.36]. CONCLUSIONS: Our case-control study suggests that long-term night-shift work is associated with an increased risk of ER-negative breast cancers. Further studies on histological subtypes and the analysis of other potentially relevant factors are crucial for discovering putative mechanisms.
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Neoplasias de la Mama/metabolismo , Receptores de Estrógenos/metabolismo , Tolerancia al Trabajo Programado , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Alemania , Humanos , Persona de Mediana EdadRESUMEN
Validation of an association between the UGT1A6_19_T>G (rs6759892) polymorphism and overall breast cancer risk. A pilot study included two population-based case-control studies from Germany (MARIE-GENICA). An independent validation study comprised four independent breast cancer case-control studies from Finland (KBCP, OBCS), Germany (BBCC), and Sweden (SASBAC). The pooled analysis included 7418 cases and 8720 controls from all six studies. Participants were of European descent. Genotyping was done by MALDI-TOF MS and statistical analysis was performed by logistic regression adjusted for age and study. The increased overall breast cancer risk for women with the UGT1A6_19_GG genotype which was observed in the pilot study was confirmed in the set of four independent study collections (OR 1.13, 95% CI 1.05-1.22; p = 0.001). The pooled study showed a similar effect (OR 1.09, 95% CI 1.04-1.14; p = 0.001). The risk effect on the basis of allele frequencies was highly significant, the pooled analysis showed an OR of 1.11 (95% CI 1.06-1.16; p = 5.8 × 10(-6)). We confirmed the association of UGT1A6_19_GG with increased overall breast cancer risk and conclude that our result from a well powered multi-stage study adds a novel candidate to the panel of validated breast cancer susceptibility loci.