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1.
Eur J Clin Pharmacol ; 74(10): 1317-1325, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29909576

RESUMO

PURPOSE: The pivotal trials for stroke prevention in non-valvular atrial fibrillation (NVAF) compared rivaroxaban, dabigatran, and apixaban with warfarin, as did most claims-based studies. Comparisons with phenprocoumon, the most frequently used vitamin K antagonist (VKA) in Germany, are scarce. METHODS: Risk of bleeding, ischemic stroke, and all-cause mortality in patients with NVAF were analyzed using data for 2010 to 2014 from a large German claims database. New users of oral anticoagulants from January 2012 to December 2013 were included and observed over 1 year. Baseline characteristics were adjusted using propensity score matching and logistic regression. Several sensitivity analyses were carried out. RESULTS: Fifty-nine thousand four hundred forty-nine rivaroxaban, 23,654 dabigatran, 4894 apixaban, and 87,997 matched phenprocoumon users were included. Adjusted hazard ratios (95% confidence intervals) compared with phenprocoumon were as follows: hospitalized bleedings: rivaroxaban 1.04 (0.97; 1.11), dabigatran 0.87 (0.77; 0.98), and apixaban 0.65 (0.50; 0.86); ischemic stroke: rivaroxaban 1.05 (0.94; 1.17), dabigatran 1.14 (0.96; 1.35), and apixaban 1.84 (1.20; 2.84); all-cause mortality: rivaroxaban 1.17 (1.11; 1.22), dabigatran 1.04 (0.95; 1.13), and apixaban 1.14 (0.97; 1.34). CONCLUSIONS: With rivaroxaban, no significant differences were observed compared to phenprocoumon with regard to hospitalized bleedings or ischemic strokes. Dabigatran was associated with fewer bleedings and a similar risk of ischemic strokes compared to phenprocoumon. Apixaban was also associated with fewer bleedings but was unexpectedly associated with more ischemic strokes, possibly reflecting selective prescribing. The association of rivaroxaban with higher all-cause mortality unrelated to bleedings or strokes has been described previously but remains to be explained.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Femprocumona/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/mortalidade , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/prevenção & controle , Bases de Dados Factuais , Feminino , Seguimentos , Alemanha , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Femprocumona/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Vitamina K/antagonistas & inibidores , Adulto Jovem
3.
PLoS Genet ; 9(3): e1003284, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23544014

RESUMO

Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥ 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 × 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.


Assuntos
Neoplasias da Mama/genética , Interação Gene-Ambiente , Estudos de Associação Genética , Alelos , Neoplasias da Mama/patologia , Caspase 8/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , População Branca
4.
Scand J Gastroenterol ; 49(11): 1325-35, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25259808

RESUMO

OBJECTIVE: A worldwide increase in prevalence of inflammatory bowel disease (IBD) has been reported. For Germany, latest publications not restricted to actively treated disease present data of the 1980s. This study estimates the administrative 1-year period IBD prevalence in 2010 and investigates the trend in prevalence of actively treated disease between 2001 and 2010. MATERIAL AND METHODS: Utilizing an insurance-based cohort (n = 311,001 in 2001 to 265,102 in 2010), case definition was based on ICD-10 codes. The prevalence of active treatment was based on internally validated IBD cases of the respective year. The 1-year period prevalence in 2010 accounts for cases actively treated in at least one of the years between 2001 and 2010. Estimates were directly standardized by age and sex to the population of Germany. The change in prevalence of actively treated disease over the years was evaluated by means of Poisson regression. RESULTS: The IBD prevalence in 2010 was 744 (95% confidence interval [CI]: 707-775) per 100,000 (Crohn's disease: 322 [95% CI: 302-346], ulcerative colitis: 412 [95% CI: 389-436] per 100,000). The prevalence of actively treated disease increased significantly between 2001 (344 [95% CI: 324-364] per 100,000) and 2010 (493 [95% CI: 464-519] per 100,000; increase in prevalence by 42% [95% CI: 31%-53%], p trend = 6.0 × 10(-19)). CONCLUSION: In line with worldwide reports, our results based on a large insurance cohort suggest a considerable increase in IBD prevalence in Germany since the 1980s. The significant increase in prevalence of actively treated disease in our cohort highlights the need to adapt healthcare services and deal with the burden associated with increasing numbers of IBD patients.


Assuntos
Doenças Inflamatórias Intestinais/epidemiologia , Seguradoras/estatística & dados numéricos , Cobertura do Seguro , Sistema de Registros/estatística & dados numéricos , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos
5.
Hum Mol Genet ; 20(23): 4693-706, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21852249

RESUMO

A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 1/genética , Proteínas de Ligação a DNA/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Alelos , Estudos de Casos e Controles , Intervalos de Confiança , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos , Razão de Chances , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Fatores de Risco
6.
Breast Cancer Res Treat ; 138(2): 529-542, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23423446

RESUMO

Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10(-6) for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10(-7)) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Terapia de Reposição de Estrogênios/efeitos adversos , Neoplasias da Mama/induzido quimicamente , Carcinoma Ductal de Mama/induzido quimicamente , Carcinoma Lobular/induzido quimicamente , Estudos de Casos e Controles , Cromossomos Humanos , Estrogênios/efeitos adversos , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Progestinas/efeitos adversos , Fatores de Risco , Análise de Sequência de DNA
7.
Lancet Oncol ; 13(4): 385-94, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22361336

RESUMO

BACKGROUND: Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer. METHODS: Data from 13 ovarian cancer case-control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models. FINDINGS: 13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13 226 controls, odds ratio 3·05, 95% CI 2·43-3·84, p<0·0001), low-grade serous (31 [9·2%] of 336 cases, 2·11, 1·39-3·20, p<0·0001), and endometrioid invasive ovarian cancers (169 [13·9%] of 1220 cases, 2·04, 1·67-2·48, p<0·0001). No association was noted between endometriosis and risk of mucinous (31 [6·0%] of 516 cases, 1·02, 0·69-1·50, p=0·93) or high-grade serous invasive ovarian cancer (261 [7·1%] of 3659 cases, 1·13, 0·97-1·32, p=0·13), or borderline tumours of either subtype (serous 103 [9·0%] of 1140 cases, 1·20, 0·95-1·52, p=0·12, and mucinous 65 [8·5%] of 767 cases, 1·12, 0·84-1·48, p=0·45). INTERPRETATION: Clinicians should be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer. FUNDING: Ovarian Cancer Research Fund, National Institutes of Health, California Cancer Research Program, California Department of Health Services, Lon V Smith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation.


Assuntos
Endometriose/complicações , Endometriose/patologia , Invasividade Neoplásica/patologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Endometriose/epidemiologia , Etnicidade , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/epidemiologia , Fatores de Risco
8.
Hum Mutat ; 33(7): 1123-32, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22461340

RESUMO

A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 11/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , População Branca
9.
Int J Cancer ; 131(5): E841-8, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22234881

RESUMO

Copy number variations (CNVs) of the glutathione-S-transferase θ-1 (GSTT1) and glutathione-S-transferase µ-1 (GSTM1) gene loci can lead to complete lack of enzyme and have been associated with colorectal cancer (CRC) risk. As GSTs are involved in the detoxification of xenobiotics, CNVs may modify CRC risk associated with smoking exposure and menopausal hormone therapy (MHT) use. We investigated CRC risk associated with GSTT1 and GSTM1 CNVs and their interaction with smoking in 1,796 cases and 1,806 age-, sex- and residence-matched controls from a German population-based case-control study (DACHS). The interaction with MHT was assessed in the subset of 684 postmenopausal female cases and 681 controls. Trimodular genotypes (0/0, 1/0 and 1/1) were determined with relative quantification based on multiplex real-time polymerase chain reaction. The associations with CRC risk as well as possible effect modifications were evaluated using conditional logistic regression analysis. CNVs of GSTT1 and GSTM1 were not significantly associated with CRC risk. Compared to the 1/1 genotype, odds ratios (ORs) for the 0/1 genotype and the 0/0 genotype were 0.89 [95% confidence interval (CI): 0.77-1.04] and 0.97 (95% CI: 0.80-1.18) for GSTT1, and 0.99 (95% CI: 0.78-1.27) and 1.03 (95% CI: 0.81-1.31) for GSTM1. Compared to the non-null genotype, ORs for the null-genotype were 1.04 (95% CI: 0.87-1.23) for GSTT1 and 1.03 (95% CI: 0.91-1.18) for GSTM1. No significant interaction with smoking and MHT use was observed. Our study does not provide evidence for a strong association between CRC risk and CNVs of GSTT1 or GSTM1 or for an effect modification of smoking or MHT use.


Assuntos
Neoplasias Colorretais/etiologia , Variações do Número de Cópias de DNA , Glutationa Transferase/genética , Terapia de Reposição Hormonal , Polimorfismo Genético/genética , Fumar/genética , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco
10.
BMC Med Genet ; 13: 94, 2012 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-23036011

RESUMO

BACKGROUND: The majority of non-syndromic colorectal cancers (CRCs) can be described as a complex disease. A two-stage case-control study on CRC susceptibility was conducted to assess the influence of the ancestral alleles in the polymorphisms previously associated with nutrition-related complex diseases. METHODS: In stage I, 28 single nucleotide polymorphisms (SNPs) were genotyped in a hospital-based Czech population (1025 CRC cases, 787 controls) using an allele-specific PCR-based genotyping system (KASPar(®)). In stage II, replication was carried out for the five SNPs with the lowest p values. The replication set consisted of 1798 CRC cases and 1810 controls from a population-based German study (DACHS). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between genotypes and CRC risk were estimated using logistic regression. To identify signatures of selection, Fay-Wu's H and Integrated Haplotype Score (iHS) were estimated. RESULTS: In the Czech population, carriers of the ancestral alleles of AGT rs699 and CYP3A7 rs10211 showed an increased risk of CRC (OR 1.26 and 1.38, respectively; two-sided p≤0.05), whereas carriers of the ancestral allele of ENPP1 rs1044498 had a decreased risk (OR 0.79; p≤0.05). For rs1044498, the strongest association was detected in the Czech male subpopulation (OR 0.61; p=0.0015). The associations were not replicated in the German population. Signatures of selection were found for all three analyzed genes. CONCLUSIONS: Our study showed evidence of association for the ancestral alleles of polymorphisms in AGT and CYP3A7 and for the derived allele of a polymorphism in ENPP1 with an increased risk of CRC in Czechs, but not in Germans. The ancestral alleles of these SNPs have previously been associated with nutrition-related diseases hypertension (AGT and CYP3A7) and insulin resistance (ENPP1). Future studies may shed light on the complex genetic and environmental interactions between different types of nutrition-related diseases.


Assuntos
Distúrbios Nutricionais/genética , Neoplasias Colorretais/genética , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
11.
Twin Res Hum Genet ; 15(5): 615-623, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22794196

RESUMO

Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small-effect variants.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Idoso , Austrália , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Tamanho da Amostra
12.
Breast Cancer Res ; 13(4): R74, 2011 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-21791049

RESUMO

INTRODUCTION: Vitamin D has been postulated to be involved in cancer prognosis. Thus far, only two studies reported on its association with recurrence and survival after breast cancer diagnosis yielding inconsistent results. Therefore, the aim of our study was to assess the effect of post-diagnostic serum 25-hydroxyvitamin D [25(OH)D] concentrations on overall survival and distant disease-free survival. METHODS: We conducted a prospective cohort study in Germany including 1,295 incident postmenopausal breast cancer patients aged 50-74 years. Patients were diagnosed between 2002 and 2005 and median follow-up was 5.8 years. Cox proportional hazards models were stratified by age at diagnosis and season of blood collection and adjusted for other prognostic factors. Fractional polynomials were used to assess the true dose-response relation for 25(OH)D. RESULTS: Lower concentrations of 25(OH)D were linearly associated with higher risk of death (hazard ratio (HR) = 1.08 per 10 nmol/L decrement; 95% confidence interval (CI), 1.00 to 1.17) and significantly higher risk of distant recurrence (HR = 1.14 per 10 nmol/L decrement; 95%CI, 1.05 to 1.24). Compared with the highest tertile (≥ 55 nmol/L), patients within the lowest tertile (< 35 nmol/L) of 25(OH)D had a HR for overall survival of 1.55 (95%CI, 1.00 to 2.39) and a HR for distant disease-free survival of 2.09 (95%CI, 1.29 to 3.41). In addition, the association with overall survival was found to be statistically significant only for 25(OH)D levels of blood samples collected before start of chemotherapy but not for those of samples taken after start of chemotherapy (P for interaction = 0.06). CONCLUSIONS: In conclusion, lower serum 25(OH)D concentrations may be associated with poorer overall survival and distant disease-free survival in postmenopausal breast cancer patients.


Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Pós-Menopausa/metabolismo , Vitamina D/análogos & derivados , Idoso , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Alemanha , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Vitamina D/sangue
13.
Int J Cancer ; 129(6): 1467-76, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21792883

RESUMO

Breast cancer is the most frequent cancer type among women in western countries. In addition to established risk factors like hormone replacement therapy, oxidative stress may play a role in carcinogenesis through an unbalanced generation of reactive oxygen species that leads to genetic instability. The aim of this study is to assess the influence of common single nucleotide polymorphisms (SNPs) in candidate genes related to oxidative stress on postmenopausal breast cancer risk. We genotyped 109 polymorphisms (mainly tagging SNPs) in 22 candidate genes in 1,639 postmenopausal breast cancer cases and 1,967 controls (set 1) from the German population-based case-control study "MARIE". SNPs showing association in set 1 were tested in further 863 cases and 2,863 controls from MARIE (set 2) using a joint analysis strategy. Six polymorphisms evaluated in the combined set showed significantly modified breast cancer risk per allele in the joint analysis, including SNPs in CYBA (encoding a subunit of the NADPH oxidase: rs3794624), MT2A (metallothionein 2A: rs1580833), TXN (thioredoxin: rs2301241), and in TXN2 (thioredoxin 2: rs2267337, rs2281082, rs4821494). Associations with the CYBA rs3794624 (OR per allele: 0.93, 95% CI 0.87-0.99) and TXN rs2301241 variants (OR per allele: 1.05, 95% CI 1.00-1.10) were confirmed in the summary risk estimate analysis using up to three additional studies. We found some evidence for association of polymorphisms in genes of the thioredoxin system, CYBA, and MT2A with postmenopausal breast cancer risk. Summary evidence including independent datasets indicated moderate effects in CYBA and TXN that warrant confirmation in large independent studies.


Assuntos
Neoplasias da Mama/genética , Estresse Oxidativo/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Medição de Risco
14.
Genet Epidemiol ; 33 Suppl 1: S24-8, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19924718

RESUMO

In this summary article, we describe the contributions included in the haplotype-based analysis group (Group 4) at the Genetic Analysis Workshop 16, which was held in September 17-20, 2008. Our group applied a large number of haplotype-based methods in the context of genome-wide association studies. Two general approaches were applied: a two-stage approach that selected significant single-nucleotide polymorphisms (SNPs) in the first stage and then created haplotypes in the second stage and genome-wide analysis of smaller sets of SNPs selected by sliding windows or estimating haplotype blocks. Genome-wide haplotype analyses performed in these ways were feasible. The presence of the very strong chromosome 6 association in the North American Rheumatoid Arthritis Consortium data was detected by every method, and additional analyses attempted to control for this strong result to allow detection of additional haplotype associations.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Cromossomos Humanos Par 6/genética , Antígenos HLA/genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Epidemiologia Molecular , Polimorfismo de Nucleotídeo Único
15.
Hum Hered ; 68(4): 252-67, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19622892

RESUMO

OBJECTIVE: We compared four haplotype-based approaches for the analysis of gene-environment interactions when haplotype-phase is ambiguous. The methods employ different versions of the expectation maximization algorithm and differ in the choice of the reference group and in the way the risk of disease is modeled (retrospective versus prospective). Furthermore, the methods are based on distinct assumptions (such as Hardy Weinberg equilibrium). The haplotype-based methods were also compared to single-marker logistic regression (LR). METHODS: We simulated case-control scenarios where the risk variant was directly genotyped (direct scenario) or in linkage disequilibrium with the genotyped markers (indirect scenario). RESULTS: The retrospective methods tended to be more powerful for detecting interactions than the prospective methods. In the indirect scenarios, the power of all methods was decreased. However, the power of the retrospectives methods was high in some scenarios and the interactions may only be detectable when using these approaches. Furthermore, we observed that the precision of one prospective method was clearly lower than the precision of the retrospective methods. CONCLUSION: For the analysis of gene-environment (GxE) interactions in case-control data, the investigated retrospective methods can be an attractive alternative to haplotype-based methods which do not account for the retrospective sampling design.


Assuntos
Meio Ambiente , Genes , Predisposição Genética para Doença , Técnicas Genéticas , Haplótipos/genética , Estudos de Casos e Controles , Simulação por Computador , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Análise de Regressão
16.
J Thorac Oncol ; 14(4): 606-616, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30605727

RESUMO

INTRODUCTION: Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes. METHODS: Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients. RESULTS: We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. CONCLUSION: KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação
17.
Eur J Hum Genet ; 16(10): 1164-72, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18523454

RESUMO

Genetic and environmental risk factors and their interactions contribute to the development of complex diseases. In this review, we discuss methodological issues involved in investigating gene-environment (G x E) interactions in genetic-epidemiological studies of complex diseases and their potential relevance for clinical application. Although there are some important examples of interactions and applications, the widespread use of the knowledge about G x E interaction for targeted intervention or personalized treatment (pharmacogenetics) is still beyond current means. This is due to the fact that convincing evidence and high predictive or discriminative power are necessary conditions for usefulness in clinical practice. We attempt to clarify conceptual differences of the term 'interaction' in the statistical and biological sciences, since precise definitions are important for the interpretation of results. We argue that the investigation of G x E interactions is more rewarding for the detailed characterization of identified disease genes (ie at advanced stages of genetic research) and the stratified analysis of environmental effects by genotype or vice versa. Advantages and disadvantages of different epidemiological study designs are given and sample size requirements are exemplified. These issues as well as a critical appraisal of common methodological concerns are finally discussed.


Assuntos
Meio Ambiente , Genes , Técnicas Genéticas , Característica Quantitativa Herdável , Humanos , Saúde Pública , Tamanho da Amostra
18.
J Pain Symptom Manage ; 52(5): 617-625, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27693898

RESUMO

CONTEXT: Episodic breathlessness is a frequent and burdensome symptom in cancer patients but pharmacological treatment is limited. OBJECTIVES: To determine time to onset, efficacy, feasibility, and safety of transmucosal fentanyl in comparison to immediate-release morphine for the relief of episodic breathlessness. METHODS: Phase II, investigator-initiated, multicenter, open-label, randomized, morphine-controlled, crossover trial with open-label titration of fentanyl buccal tablet (FBT) in inpatients with incurable cancer. The primary outcome was time to onset of meaningful breathlessness relief. Secondary outcomes were efficacy (breathlessness intensity difference at 10 and 30 minutes; sum of breathlessness intensity difference at 15 and 60 minutes), feasibility, and safety. Study was approved by local ethics committees. RESULTS: Twenty-five of 1341 patients were eligible, 10 patients agreed to participate (four female, mean age 58 ± 11, mean Karnofsky score 67 ± 11). Two patients died before final visits and two patients dropped-out because of disease progression leaving six patients for analysis with 61 episodes of breathlessness. Mean time to onset was for FBT 12.7 ± 10.0 and for immediate-release morphine 23.6 ± 15.1 minutes with a mean difference of -10.9 minutes (95% CI = -24.5 to 2.7, P = 0.094). Efficacy measures were predominately in favor for FBT. Both interventions were safe. Feasibility failed because of too much study demands for a very ill patient group. CONCLUSION: The description of a faster and greater relief of episodic breathlessness by transmucosal fentanyl versus morphine justifies further evaluation by a full-powered trial.


Assuntos
Analgésicos Opioides/administração & dosagem , Dispneia/tratamento farmacológico , Fentanila/administração & dosagem , Neoplasias/complicações , Administração Bucal , Analgésicos Opioides/efeitos adversos , Estudos Cross-Over , Progressão da Doença , Dispneia/etiologia , Estudos de Viabilidade , Feminino , Fentanila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Pacientes Desistentes do Tratamento , Projetos Piloto , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
19.
J Thorac Oncol ; 11(1): 122-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26762747

RESUMO

INTRODUCTION: Rearrangements of RET are rare oncogenic events in patients with non-small cell lung cancer (NSCLC). While the characterization of Asian patients suggests a predominance of nonsmokers of young age in this genetically defined lung cancer subgroup, little is known about the characteristics of non-Asian patients. We present the results of an analysis of a European cohort of patients with RET rearranged NSCLC. METHODS: Nine hundred ninety-seven patients with KRAS/EGFR/ALK wildtype lung adenocarcinomas were analyzed using fluorescence in situ hybridization for RET fusions. Tumor specimens were molecularly profiled and clinicopathological characteristics of the patients were collected. RESULTS: Rearrangements of RET were identified in 22 patients, with a prevalence of 2.2% in the KRAS/EGFR/ALK wildtype subgroup. Co-occurring genetic aberrations were detected in 10 patients, and the majority had mutations in TP53. The median age at diagnosis was 62 years (range, 39-80 years; mean ± SD, 61 ± 11.7 years) with a higher proportion of men (59% versus 41%). There was only a slight predominance of nonsmokers (54.5%) compared to current or former smokers (45.5%). CONCLUSIONS: Patients with RET rearranged adenocarcinomas represent a rare and heterogeneous NSCLC subgroup. In some contrast to published data, we see a high prevalence of current and former smokers in our white RET cohort. The significance of co-occurring aberrations, so far, is unclear.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Rearranjo Gênico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-ret/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Europa (Continente) , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas de Fusão Oncogênica/genética , Prognóstico , Estudos Retrospectivos
20.
PLoS One ; 9(11): e109973, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25390939

RESUMO

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Sítios de Ligação , Estudos de Casos e Controles , Mapeamento Cromossômico , Biologia Computacional , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Receptores de Estrogênio/metabolismo
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