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Biomedical subjects

Ulla Vogel

Publications and source records attributed to Ulla Vogel.

At least 19 recordsLinked to original sources
PubMed2007

Polymorphisms in the genes ERCC2, XRCC3 and CD3EAP influence treatment outcome in multiple myeloma patients undergoing autologous bone marrow transplantation.

Individual variations in the ability to cope with DNA damage by DNA repair may be essential for the response to chemotherapy, since cancer cells from patients with an effective DNA repair may survive treatment. We have studied the effect on time to treatment failure (TTF) and overall survival (OS) of polymorphism in the DNA repair genes ERCC1, ERCC2 and XRCC3, and in the apoptotic genes PPP1R13L and CD3EAP in 348 patients with multiple myeloma undergoing autologous bone marrow transplantation. Carriers of the variant C-allele of ERCC2 K751Q, the variant T-allele of XRCC3 T241M and the variant A-allele of CD3EAP G-21A had a 1.3-fold, 1.8-fold and 1.9-fold longer TTF, respectively, than homozygous wild type carriers (p = 0.006, p = 0.004, p < 0.001). The polymorphism CD3EAP G-21A also had significant effect on OS (p < 0.045). The polymorphism ERCC2 K751Q may to be related to sex, since the prolonged TTF was only seen in women (p = 0.001). Carriers of the combination of variant alleles of ERCC2 K751Q and XRCC3 T241M had 2.8-fold longer TTF (p = 0.0002). This indicates that suboptimal repair of both DNA mechanisms favors prolonged TTF and that polymorphism in ERCC2, XRCC3 and CD3EAP predicts the outcome for patients treated with autologous stem cell transplantation.

Aged↗
PubMed2006

Peroxisome proliferator-activated [corrected] receptor-gamma2 [corrected] Pro12Ala, interaction with alcohol intake and NSAID use, in relation to risk of breast cancer in a prospective study of Danes.

Use of non-steroid anti-inflammatory drugs (NSAIDs) has been associated with decreased risk of breast cancer in epidemiological studies. Thus, a high-inflammatory response may be associated with increased breast cancer risk. It is thus possible that genetic variations leading to a modified inflammatory response will influence breast cancer risk. The purpose of this study was to determine if polymorphisms associated with an altered inflammatory response are associated with breast cancer risk, and to investigate the possible interaction with lifestyle factors such as alcohol use, smoking and NSAID use. We matched 361 female breast cancer cases with 361 controls, nested within the prospective 'Diet, Cancer and Health' study. Carriers of the variant Ala-allele of PPARgamma2 Pro12Ala were at lower risk of breast cancer (IRR=0.67, 95% CI=0.46-0.97). This was primarily due to an interaction with alcohol consumption. Alcohol consumption was associated with a 1.21-fold increased risk of breast cancer per 10 g alcohol/day (95% CI=1.06-1.35) among homozygous wild-type carriers, whereas alcohol was not associated with breast cancer risk among variant allele carriers (P for interaction=0.005). Non-users of NSAID, who were carriers of the variant allele of PPARgamma2 Pro12Ala, were at lower risk of breast cancer (IRR=0.44; 95% CI=0.26-0.73) compared with non-users carrying wild-type alleles (P for interaction=0.03). No effects were found for IL6 G-174C, IL8 T-251A and COX2 T8473C. Our results suggest that PPARgamma2 Pro12Ala is an important determinant in alcohol mediated breast carcinogenesis. We also observe interaction between NSAID, alcohol consumption and PPARgamma2 Pro12Ala genotype in relation to breast cancer risk.

Alanine↗
PubMed2006

Increased mRNA expression levels of ERCC1, OGG1 and RAI in colorectal adenomas and carcinomas.

BACKGROUND: The majority of colorectal cancer (CRC) cases develop through the adenoma-carcinoma pathway. If an increase in DNA repair expression is detected in both early adenomas and carcinomas it may indicate that low repair capacity in the normal mucosa is a risk factor for adenoma formation. METHODS: We have examined mRNA expression of two DNA repair genes, ERCC1 and OGG1 as well as the putative apoptosis controlling gene RAI, in normal tissues and lesions from 36 cases with adenomas (mild/moderat n = 21 and severe n = 15, dysplasia) and 9 with carcinomas. RESULTS: Comparing expression levels of ERCC1, OGG1 and RAI between normal tissue and all lesions combined yielded higher expression levels in lesions, 3.3-fold higher (P = 0.005), 5.6-fold higher (P < 3.10-5) and 7.7-fold higher (P = 0.0005), respectively. The levels of ERCC1, OGG1 and RAI expressions when comparing lesions, did not differ between adenomas and CRC cases, P = 0.836, P = 0.341 and P = 0.909, respectively. When comparing expression levels in normal tissue, the levels for OGG1 and RAI from CRC cases were significantly lower compared to the cases with adenomas, P = 0.012 and P = 0.011, respectively. CONCLUSION: Our results suggest that increased expression of defense genes is an early event in the progression of colorectal adenomas to carcinomas.

Adenoma↗
PubMed2006

The ratio of Matriptase/HAI-1 mRNA is higher in colorectal cancer adenomas and carcinomas than corresponding tissue from control individuals.

BACKGROUND: It has recently been shown that overexpression of the serine protease, matriptase, in transgenic mice causes a dramatically increased frequency of carcinoma formation. Overexpression of HAI-1 and matriptase together changed the frequency of carcinoma formation to normal. This suggests that the ratio of matriptase to HAI-1 influences the malignant progression. The aim of this study has been to determine the ratio of matriptase to HAI-1 mRNA expression in affected and normal tissue from individuals with colorectal cancer adenomas and carcinomas as well as in healthy individuals, in order to determine at which stages a dysregulated ratio of matriptase/HAI-1 mRNA is present during carcinogenesis. METHODS: Using quantitative RT-PCR, we have determined the mRNA levels for matriptase and HAI-1 in colorectal cancer tissue (n = 9), severe dysplasia (n = 15), mild/moderate dysplasia (n = 21) and in normal tissue from the same individuals. In addition, corresponding tissue was examined from healthy volunteers (n = 10). Matriptase and HAI-1 mRNA levels were normalized to beta-actin. RESULTS: Matriptase mRNA level was lower in carcinomas compared to normal tissue from healthy individuals (p < 0.01). In accordance with this, the matriptase mRNA level was also lower in adenomas/carcinomas combined as compared to their adjacent normal tissue (p < 0.01). HAI-1 mRNA levels in both normal and affected tissue from individuals with severe dysplasia or carcinomas and in affected tissue with mild/moderate dysplasia were all significantly lower than mRNA levels observed in corresponding tissue from healthy control individuals. HAI-1 mRNA was lower in carcinomas as compared to normal tissue from healthy individuals (p < 0.001). HAI-1 mRNA levels were significantly lower in tissue displaying mild/moderate (p < 0.001) and severe (p < 0.01) dysplasia compared to normal tissue from the same patients. Both adenomas and carcinomas displayed a significantly different matriptase/HAI-1 mRNA ratio than corresponding normal tissue from healthy control individuals (p < 0.05). In addition statistically significant difference (p < 0.001) could be observed between mild/moderate and severe adenomas and their adjacent normal tissue. CONCLUSION: Our results show that dysregulation of the matriptase/HAI-1 mRNA ratio occurs early during carcinogenesis. Future studies are required to clarify whether the dysregulated matriptase/HAI-1 ratio was causing the malignant progression or is a consequence of the same.

Adenoma↗
PubMed2006

Effects of polymorphisms in ERCC1, ASE-1 and RAI on the risk of colorectal carcinomas and adenomas: a case control study.

BACKGROUND: The risk of sporadic colorectal cancer is mainly associated with lifestyle factors and may be modulated by several genetic factors of low penetrance. Genetic variants represented by single nucleotide polymorphisms in genes encoding key players in the adenoma carcinoma sequence may contribute to variation in susceptibility to colorectal cancer. In this study, we aimed to evaluate whether the recently identified haplotype encompassing genes of DNA repair and apoptosis, is associated with increased risk of colorectal adenomas and carcinomas. METHODS: We used a case-control study design (156 carcinomas, 981 adenomas and 399 controls) to test the association between polymorphisms in the chromosomal region 19q13.2-3, encompassing the genes ERCC1, ASE-1 and RAI, and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR) and 95% confidence interval (CI) were estimated by binary logistic regression model adjusting for age and gender. RESULTS: The ASE-1 polymorphism was associated with an increased risk of adenomas, OR of 1.39 (95% CI 1.06-1.81), which upon stratification was apparent among women only, OR of 1.66 (95% CI 1.15-2.39). The RAI polymorphism showed a trend towards risk reduction for both adenomas (OR of 0.70, 95% CI 0.49-1.01) and carcinomas (OR of 0.49, 95% CI 0.21-1.13) among women, although not significant. Women who were homozygous carriers of the high risk haplotype had an increased risk of colorectal cancer, OR of 2.19 (95% CI 0.95-5.04) compared to all non-carriers although the estimate was not statistically significant. CONCLUSION: We found no evidence that the studied polymorphisms were associated with risk of adenomas or colorectal cancer among men, but we found weak indications that the chromosomal region may influence risk of colorectal cancer and adenoma development in women.

Adenoma↗
PubMed2006

GPX1 Pro198Leu polymorphism, interactions with smoking and alcohol consumption, and risk for lung cancer.

We genotyped blood samples from 432 lung cancer cases and 798 persons in a comparison group and examined the role of the GPX1 (Pro198Leu, rs1050450) polymorphism and interactions with external exposures in the development of lung cancer. The incidence rate ratio for lung cancer was 0.60 (95% confidence interval: 0.35-1.05) when homozygous carriers of the variant allele were compared with the homozygous carriers of the wild type, and the risk for lung cancer was significantly lower among participants carrying more variant alleles (p-trend=0.03). We found stronger associations between several smoking variables and alcohol intake and lung cancer risk among GPX1(TT) carriers than among GPX1(CC) and GPX1(CT) carriers.

Alcohol Drinking↗
PubMed2006

Gene-environment interactions between smoking and a haplotype of RAI, ASE-1 and ERCC1 polymorphisms among women in relation to risk of lung cancer in a population-based study.

Homozygous carriers of a haplotype consisting of ERCC1 Asn118Asn(A), ASE-1 G-21A(G), RAI IVS1 A4364G(A) are at increased risk of lung cancer especially among women. Here, we analyse for gene-environment interactions with the predefined haplotype in a case cohort study including 428 lung cancer cases and a comparison group of 800 persons, all from the prospective Diet, Cancer and Health cohort of 57,000 Danes. At high smoking intensity (>20g tobacco/day), there was only additional risk of smoking intensity among women who were homozygous carriers of the haplotype (IRR=2.03; 95% CI: 1.10-3.73 per 5 additional g tobacco/day).

Adult↗
PubMed2006

Bulky DNA adducts as risk indicator of lung cancer in a Danish case-cohort study.

Little is known of the predictive value of the levels of DNA adducts in terms of cancer risk. We examined the association between bulky DNA adducts and risk of lung cancer in a population-based cohort, comprising of 25,717 men and 27,972 women aged 50-64 years at entry. We included 245 cases (137 men and 108 women) with lung cancer and a comparison group of 255 individuals (137 men and 118 women), matched on sex, age and smoking duration. Bulky adducts in white blood cells collected at enrollment and stored at -150 degrees C were analyzed by (32)P-postlabeling method, using the butanol enrichment procedure. The median level of bulky DNA adducts was 0.196 adduct/10(8) nucleotides (5-95 percentiles: 0.094-0.595) among current smokers who were later diagnosed with lung cancer and 0.163 adduct/10(8) nucleotides (5-95 percentiles: 0.091-0.455) among current smokers in the comparison group. The smoking adjusted incidence rate ratios (IRR) for lung cancer in relation to one log unit (natural logarithm) difference in adduct levels were 1.22 (95% CI 0.85-1.74), 1.33 (95% CI 0.89-1.98) and 0.76 (95% CI 0.39-1.47) among all, current and former smokers, respectively. Current smokers with bulky DNA adduct levels above the median had a significant higher lung cancer rate than those with adduct levels below the median (IRR = 1.61; 95% CI 1.04-2.49). The results are compatible with previous studies, suggesting a slightly higher risk of lung cancer with higher levels of adducts among smokers. Our results indicate that bulky DNA adducts may have a weak association with lung cancer risk.

Case-Control Studies↗
PubMed2006

Polymorphisms of the XRCC1, XRCC3 and XPD genes and risk of colorectal adenoma and carcinoma, in a Norwegian cohort: a case control study.

BACKGROUND: Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of developing cancer. For colorectal cancer the importance of mutations in mismatch repair genes has been extensively documented. Less is known about other DNA repair pathways in colorectal carcinogenesis. In this study we have focused on the XRCC1, XRCC3 and XPD genes, involved in base excision repair, homologous recombinational repair and nucleotide excision repair, respectively. METHODS: We used a case-control study design (157 carcinomas, 983 adenomas and 399 controls) to test the association between five polymorphisms in these DNA repair genes (XRCC1 Arg194Trp, Arg280His, Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln), and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression model adjusting for age, gender, cigarette smoking and alcohol consumption. RESULTS: The XRCC1 280His allele was associated with an increased risk of adenomas (OR 2.30, 95% CI 1.19-4.46). The XRCC1 399Gln allele was associated with a reduction of risk of high-risk adenomas (OR 0.62, 95% CI 0.41-0.96). Carriers of the variant XPD 751Gln allele had an increased risk of low-risk adenomas (OR 1.40, 95% CI 1.03-1.89), while no association was found with risk of carcinomas. CONCLUSION: Our results suggest an increased risk for advanced colorectal neoplasia in individuals with the XRCC1 Arg280His polymorphism and a reduced risk associated with the XRCC1 Arg399Gln polymorphism. Interestingly, individuals with the XPD Lys751Gln polymorphism had an increased risk of low-risk adenomas. This may suggest a role in regression of adenomas.

Adenoma↗
PubMed2006

Cytokine expression in mice exposed to diesel exhaust particles by inhalation. Role of tumor necrosis factor.

BACKGROUND: Particulate air pollution has been associated with lung and cardiovascular disease, for which lung inflammation may be a driving mechanism. The pro-inflammatory cytokine, tumor necrosis factor (TNF) has been suggested to have a key-role in particle-induced inflammation.We studied the time course of gene expression of inflammatory markers in the lungs of wild type mice and Tnf-/- mice after exposure to diesel exhaust particles (DEPs). Mice were exposed to either a single or multiple doses of DEP by inhalation. We measured the mRNA level of the cytokines Tnf and interleukin-6 (Il-6) and the chemokines, monocyte chemoattractant protein (Mcp-1), macrophage inflammatory protein-2 (Mip-2) and keratinocyte derived chemokine (Kc) in the lung tissue at different time points after exposure. RESULTS: Tnf mRNA expression levels increased late after DEP-inhalation, whereas the expression levels of Il-6, Mcp-1 and Kc increased early. The expression of Mip-2 was independent of TNF if the dose was above a certain level. The expression levels of the cytokines Kc, Mcp-1 and Il-6, were increased in the absence of TNF. CONCLUSION: Our data demonstrate that Tnf is not important in early DEP induced inflammation and rather exerts negative influence on Mcp-1 and Kc mRNA levels. This suggests that other signalling pathways are important, a candidate being one involving Mcp-1.

Journal Article↗
PubMed2006

Lack of association between DNA repair gene ERCC1 polymorphism and risk of lung cancer in a Chinese population.

The ERCC1 (Excision Repair Cross Complementation Group 1) gene is involved in the nucleotide excision repair pathway. This study was designed to examine whether ERCC1 Asn118Asn (G19007A) polymorphism, which has been associated with risk of some cancers among Caucasians, may be associated with risk of lung cancer in a Chinese population. ERCC1 Asn118Asn (G19007A) genotypes were determined in DNA samples from 151 cases and 143 controls. The distribution of genotypes between cases and controls was not associated with an increased risk of lung cancer (AA versus GG: adjusted OR (odds ratio) = 1.41, 95% CI (confidence interval) = 0.76-2.59; AG versus GG: adjusted OR = 0.78, 95% CI = 0.47-1.29; and AA + AG versus GG: adjusted OR = 0.93, 95% CI = 0.73-1.19). The frequency A (0.20) of the A-allele was significantly lower among these Chinese controls than in the Caucasian control populations (A = 0.54-0.65) (All P < 0.001). No statistically significant effects of age, histological subtype or smoking were found. These findings suggest that ERCC1 Asn118Asn (G19007A) polymorphism may play a limited role for lung cancer in this Chinese population.

Adult↗
PubMed2006

Polymorphism of the DNA repair gene ERCC2 Lys751Gln and risk of lung cancer in a northeastern Chinese population.

The ERCC2 gene (excision repair cross-complementing rodent repair deficiency, complementation group 2 [xeroderma pigmentosum D]) (previously XPD), encoding a DNA repair protein, is involved in nucleotide excision repair and basal transcription. To test the effect of the polymorphism ERCC2 Lys751Gln on the risk of lung cancer in a northeastern Chinese population, a hospital-based case-control study was designed consisting of 147 newly diagnosed and previously untreated subjects with lung cancer and 145 cancer-free control subjects matched on age (+/-3 years), gender, and ethnicity. Among the controls, the allele frequency of the C-allele of ERCC2 Lys751Gln was 0.02. The C-allele of ERCC2 Lys751Gln was significantly overrepresented among lung cancer cases (C versus A: adjusted odds ratio OR(adj) = 2.61, 95% CI = 1.12-6.05, P = 0.03). The carriers of AC genotype were at 2.78-fold (OR(adj) = 2.78, 95% CI = 1.12-6.93) higher risk of lung cancer than carriers of the AA genotype. Subdivided by tumor type, carriers of AC genotype had a 4.65-fold higher risk of squamous cell carcinoma of lung compared with carriers of AA genotype (OR(adj) = 4.65, 95% CI = 1.67-12.98, P = 0.003); similar, but not statistically significant estimates were found for adenocarcinoma of lung. In conclusion, our results suggest that ERCC2 Lys751Gln(C) allele is a potential risk marker for lung cancer in this northeastern Chinese population.

Adult↗
PubMed2006

Interactions between the OGG1 Ser326Cys polymorphism and intake of fruit and vegetables in relation to lung cancer.

The enzyme 8-oxoguanine glycosylase 1 (OGG1) repairs oxidatively damaged DNA and a polymorphism in the OGG1 gene (Ser326Cys) has been associated with lung cancer. We examined associations between the polymorphism and intake of fruits and vegetables and smoking in the development of lung cancer, by genotyping blood samples from 431 lung cancer cases and 796 comparison persons, which were identified within a prospective cohort on 57,000 cohort members. We found no overall association between the OGG1 polymorphism and lung cancer. There was a statistically significant interaction between the polymorphism and dietary intake of vegetables, with a 54% decrease in lung cancer risk per 50% increase in vegetable intake among homozygous Cys326Cys carriers and no decrease in risk among carriers of Ser326Ser or Ser326Cys. The same tendency was seen in relation to intake of fruit. There were no statistically significant interactions between the OGG1 polymorphism and smoking.

Cysteine↗
PubMed2005

Prospective study of 8-oxo-7,8-dihydro-2'-deoxyguanosine excretion and the risk of lung cancer.

Oxidative damage to DNA may be important in carcinogenesis and a possible risk factor for lung cancer. The urinary excretion of products of damaged nucleotides in cellular pools or in DNA may be important biomarkers of exposure to relevant carcinogens reflecting the rate of damage in steady state and may predict cancer risk. Oxidation of guanine in DNA or the nucleotide pool may give rise to 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) for urinary excretion. Oxoguanine glycosylase (OGG1) is the base excision enzyme repairing 8-oxodG in DNA by release of 8-oxoguanine. In a nested case-cohort design we examined associations between urinary excretion of 8-oxodG and risk of lung cancer as well as potential interaction with the OGG1 Ser326Cys polymorphism in a population-based cohort of 25 717 men and 27 972 women aged 50-64 years with 3-7 years follow-up. We included 260 cases with lung cancer and a sub-cohort of 263 individuals matched on sex, age and smoking duration for comparison. Urine collected at entry was analysed for 8-oxodG by HPLC with electrochemical detection. The excretion of 8-oxodG was higher in current smokers, whereas OGG1 genotype had no effect. Overall the incidence rate ratio (IRR) (95% confidence interval) of lung cancer was 0.99 (0.80-1.22) per doubling of 8-oxodG excretion and there was no interaction with OGG1 genotype. However, among never-smokers (eight cases and eight sub-cohort members) the IRR was 11.8 (1.21-115) per doubling of 8-oxodG excretion. The association between 8-oxodG excretion and lung cancer risk among never-smokers suggests that oxidative damage to DNA nucleotides is important in this group.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Associations between GPX1 Pro198Leu polymorphism, erythrocyte GPX activity, alcohol consumption and breast cancer risk in a prospective cohort study.

Breast cancer may be related to oxidative stress. Breast cancer patients have been reported to have lower antioxidant enzyme activity than healthy controls and the polymorphism GPX1 Pro198Leu has been associated with risk of lung and breast cancer. The purpose of the present nested case-control study was to determine whether GPX1 Pro198Leu and glutathione peroxidase (GPX) activity in prospectively collected blood samples are associated with breast cancer risk among postmenopausal women and whether GPX activity levels are associated with other known breast cancer risk factors. We matched 377 female breast cancer cases with 377 controls all nested within the prospective 'Diet, Cancer and Health' study of 57 000 Danes. Carriers of the variant T-allele of GPX1 Pro198Leu were at 1.43-fold higher risk of breast cancer compared with non-carriers (95% CI=1.07-1.92). Pre-diagnostic GPX activity tended to be lower in cases compared with controls. GPX activity was positively correlated with intake of alcohol (P<0.0001) and the catalytic activity was lowered 5% for each additional copy of the variant T-allele (P=0.0003). Alcohol intake was correlated with increased GPX activity for the C-allele but not for the T-allele. Results from this prospective study suggest that the GPX1 Pro198Leu-associated lowered GPX activity is associated with higher breast cancer risk among Danish women.

Alcohol Drinking↗
PubMed2005

GPX Pro198Leu and OGG1 Ser326Cys polymorphisms and risk of development of colorectal adenomas and colorectal cancer.

Little is known about genetic risk factors for colorectal cancer. We assessed the association between polymorphisms in two genes involved in DNA repair of oxidative stress, GPX and OGG1, and risk of colorectal carcinoma or adenomas. We studied 166 cases with adenocarcinoma, 974 with adenomas and 397 controls recruited from the Norwegian cohort NORCCAP. No associations were found between the polymorphism GPX Pro198Leu and risk of colorectal adenomas or carcinomas. Carriers of the variant allele OGG1 Ser326Cys polymorphism had a lowered risk of colorectal cancer, OR=0.56 (95% confidence interval 0.33-0.95), while no association were found with risk of adenomas. This indicates that a low repair capacity of oxidative DNA damage may not be a risk factor for development of colorectal adenomas or carcinoma.

Adenocarcinoma↗
PubMed2005

Polymorphisms in RAI and in genes of nucleotide and base excision repair are not associated with risk of testicular cancer.

Testicular cancer has been suggested to be primed in utero and there is familiar occurrence, particularly brothers and sons of men with testicular cancer have increased risk. Although no specific causative genotoxic agents have been identified, variations in DNA repair capacity could be associated with the risk of testicular cancer. A case-control study of 184 testicular cancer cases and 194 population-based controls living in the Copenhagen Greater Area in Denmark was performed. We found that neither polymorphisms in several DNA repair genes nor alleles of several polymorphisms in the chromosomal of region 19q13.2-3, encompassing the genes ASE, ERCC1, RAI and XPD, were associated with risk of testicular cancer in Danish patients. This is in contrast to other cancers, where we reported strong associations between polymorphisms in ERCC1, ASE and RAI and occurrence of basal cell carcinoma, breast cancer and lung. To our knowledge this is the first study of DNA repair gene polymorphisms and risk of testicular cancer.

Case-Control Studies↗