Background and Purpose - The vitamin K-dependent protein Z (PZ) has been shown to possess anticoagulant as well as procoagulant properties. Plasma levels of PZ show a broad interindividual variation, but it is unknown to which extent this variation is under genetic control. Recent clinical studies revealed contradictory results on the association of PZ plasma levels and the risk of ischemic stroke. Methods - We performed a case-control study including 200 patients with cerebral ischemia aged less than or equal to50 years and 199 control subjects from the same South German region. We investigated a possible association of 2 common single nucleotide mutations in the PZ gene with the risk of cerebral ischemia. Furthermore, enzyme-linked immunosorbent assay measurements were done in control subjects without vascular disease to detect a potential association of different genotypes with PZ plasma ( antigen) levels. Results - In patients, the frequency of the A allele of the intron F polymorphism G79A was significantly lower than in controls (15.7% versus 24.4%; odds ratio, 0.58; 95% CI, 0.39 to 0.86; P = 0.007; adjusted for age, sex, and conventional risk factors). The G allele of the promoter polymorphism A-13G tended to be less common in patients (4.2% versus 7.0%; adjusted odds ratio, 0.56; 95% CI, 0.28 to 1.13; P = 0.105). In 42 control subjects, the A allele of the intron F polymorphism was associated with lower PZ antigen levels ( P = 0.0032; Spearman correlation coefficient r(s) = -0.48). Conclusions - The A allele of an intron F polymorphism of the PZ gene appears to be a novel protective genetic marker for the risk of cerebral ischemia in young adults. In the context of juvenile stroke, high PZ plasma levels may represent a prothrombotic condition.

Breast-conserving surgery followed by radiotherapy is effective in reducing recurrence; however, telangiectasia and fibrosis can occur as late skin side effects. As radiotherapy acts through producing DNA damage, we investigated whether genetic variation in DNA repair and damage response confers increased susceptibility to develop late normal skin complications. Breast cancer patients who received radiotherapy after breast-conserving surgery were examined for late complications of radiotherapy after a median follow-up time of 51 months. Polymorphisms in genes involved in DNA repair (APEX1, XRCC1, XRCC2, XRCC3, XPD) and damage response (TP53, P21) were determined. Associations between telangiectasia and genotypes were assessed among 409 patients, using multivariate logistic regression. A total of 131 patients presented with telangiectasia and 28 patients with fibrosis. Patients with variant TP53 genotypes either for the Arg72Pro or the PIN3 polymorphism were at increased risk of telangiectasia. The odds ratios (OR) were 1.66 (95% confidence interval (CI): 1.02–2.72) for 72Pro carriers and 1.95 (95% CI: 1.13–3.35) for PIN3 A2 allele carriers compared with non-carriers. The TP53 haplotype containing both variant alleles was associated with almost a two-fold increase in risk (OR 1.97, 95% CI: 1.11–3.52) for telangiectasia. Variants in the TP53 gene may therefore modify the risk of late skin toxicity after radiotherapy.

Genetic polymorphisms of cytochrome p450 (CYP1A1) and glutathione S-transferase M1 (GSTM1) genes are thought to have significant effects on the metabolism of environmental carcinogens and thus on cancer risk, but the reported results are not always consistent. In this meta-analysis, we assessed reported studies of associations between polymorphisms of these two genes and risk of lung cancer in Chinese populations. Through a systematic literature search for publications between 1989 and 2006, we summarized the data from 46 studies on polymorphisms of MspI and exon7-Val of CYP1A1 and GSTM1 and lung cancer risk in Chinese populations, and found that compared with the wild-type homozygous genotype (type A), lung cancer risk for the combined variant genotypes (types B and C) was 1.34-fold (95% confidence interval [CI] = 1.08–1.67) (Z = 2.64, P = 0.008); the risk for the combined variant genotypes (Ile/Val and Val/Val) of CYP1A1 exon7 was 1.61-fold (95% CI = 1.24–2.08) (Z = 3.62, P < 0.001), compared with the Ile/Ile genotype; and that the risk for the GSTM1 null genotype was 1.54-fold (95% CI = 1.31–1.80) (Z = 5.32, P < 0.001), compared with the GSTM1 present genotype. Therefore, in 46 published studies in Chinese populations, we found evidence of an association between the CYP1A1 variant and GSTM1 null genotypes and increased risk of lung cancer.

Vitamin D pathway gene polymorphisms may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D. The association between polymorphisms in the vitamin D binding protein (Gc) and postmenopausal breast cancer risk, with additional focus on the influence of serum 25-hydroxyvitamin D [25(OH)D], the biomarker for vitamin D status in humans, has not been examined thus far. We assessed the combined effects of two known functional polymorphisms in the Gc gene (rs4588 and rs7041), composing the phenotypic alleles Gc1s, Gc1f (combined: Gc1), and Gc2, on postmenopausal breast cancer risk and potential effect modification by 25(OH)D status in a population-based case-control study including 1,402 cases and 2,608 matched controls. Odds ratios (OR) for breast cancer risk adjusted for potential confounders were calculated for Gc genotypes. ANOVA was used to compare geometric means of serum 25(OH)D across Gc genotypes. Serum 25(OH)D concentrations in the control group significantly differed by Gc genotype, being lowest in Gc2 allele carriers. The geometric means of 25(OH)D were 53.0, 47.8, and 40.4 nmol/L for Gc1-1, Gc2-1, and Gc2-2 genotypes, respectively (P(trend) < 0.0001). Gc2-2 genotype was associated with a significantly decreased risk of postmenopausal breast cancer with an odds ratio (95% confidence interval) of 0.72 (0.54-0.96), compared with homozygote Gc1s allele carriers. No interaction between 25(OH)D status and Gc genotype was observed, nor did the association change considerably after adjustment for 25(OH)D status. Our results provide evidence for a serum 25(OH)D-independent effect of Gc2 allele carrier status in postmenopausal breast cancer.

Myeloperoxidase (MPO) is a metabolic/oxidative enzyme found in neutrophils and monocytes that contributes to pulmonary carcinogenesis through activation of specific procarcinogens including benzo[a]pyrene intermediates, 4-aminobiphenyl and the arylamines. There is a G→A polymorphism located in the 5′ untranslated region of the MPO gene that may be responsible for reduced transcriptional activity due to the decreased binding affinity for the SP1 transcription factor. Individuals with one or two copies of the A-allele may be afforded protection due to decreased transcriptional activity of MPO and subsequent decreased metabolic activation of procarcinogens. Previous studies have reported a range of protective effects in different ethnic populations. We employed a restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) assay to identify the MPO genotypes in 375 lung cancer cases and 378 healthy controls, all of whom were Caucasian. Our results demonstrate a reduced risk of lung cancer when the A-allele genotypes (G/A+A/A) were combined (odds ratio (OR)=0.66; 95% confidence interval (CI) 0.49–0.90). We also noted a protective effect (OR=0.63; 95% CI 0.45–0.87) in ever smokers with the A-allele genotypes which was not evident in never smokers (OR=1.14; 95% CI 0.42–3.11). We observed an incremental decrease in the protective effects as cigarette pack-years increased. Thus, lightest smokers were provided the greatest protection. When the data were stratified by gender, there was a statistically significant reduced risk of lung cancer among men (OR=0.55; 95% CI 0.36–0.84), but not among women (OR=0.81; 95% CI 0.55–1.26) for the A-allele genotypes. Lastly, an age effect was evident only in men but not women. The protective effects of the A-allele genotypes decreased with increasing age. This report provides further support for the hypothesis that a single nucleotide polymorphism in the MPO gene is a protective factor in lung cancer carcinogenesis.

Objective: In a population-based case-control study examining the effects of postmenopausal hormone therapy (HT) on breast cancer risk, the authors conducted a validation study comparing prescription data from gynecologists with self-reports.Study Design and Setting: The study was conducted in the Rhein-Neckar and Hamburg regions of Germany from 2002 to 2005. A total of 224 cases and 225 controls, stratified by region, age, and hormone use were randomly selected for the validation study.Results: For ever/never use 88.2% agreement was seen, and agreement for ever/never use by type of HT was 80.6%, 80.3%, and 90.5% for mono-estrogen, cyclical combined, and continuous combined therapy, respectively. The intraclass correlation coefficient (ICC) for duration of use was high, 0.82 (95% confidence interval [CI]: 0.77, 0.85), as were the ICCs for age at first and last use, 0.88 (95% CI: 0.85, 0.91) and 0.98 (95% CI: 0.97, 0.98). Despite the exceptionally high number of different HT prescriptions available in Germany, comparison of exact brand name resulted in perfect agreement for 50.2% of participants, partial agreement for 29.3%, and no agreement for 20.7%. In general, agreement was not differential by disease status.Conclusion: Overall, the self-reported HT of the study participants corresponded well with physicians' reports. (C) 2007 Elsevier Inc. All rights reserved.

Clinical sensitivity to ionizing radiation varies considerably among patients, and radiation-induced adverse effects developing in normal tissue can be therapy limiting in >10% of patients ([1][1]). Ionizing radiation induces both DNA single-strand breaks and double-strand breaks (DSB), with the

In a population-based study of 613 cases and 1082 controls, alcohol dehydrogenase 1B ( ADH1B ) genotype was not an independent risk factor for breast cancer, athough the possibility was raised that it modifies risk associated with high levels of alcohol consumption (OR 1.1, 95% confidence interval (CI) 0.8–1.6 for ADH1B*1/*1 genotype vs 0.2, 95% CI 0.1–1.0 for ADH1B*2 carriers).

Insulin-like growth factors (IGF) play an important role in the proliferation and apoptosis of several cell types and may therefore be associated with the risk of malignant transformation (1). IGF binding protein-3 (IGFBP-3) is the most common binding protein for IGF-I in serum. High levels of IGFBP-3 are associated with reduced IGF-I levels and thereby influence cell proliferation by modulating access of IGFs to the IGF receptors. In healthy women, alcohol consumption was found to suppress IGF-I and IGFBP-3 levels, and the use of oral contraceptives reduced IGF-I levels and increased IGFBP-3 levels (2). There is increasing evidence from prospective cohort as well as case-control studies that increased serum IGF-I levels are associated with an increased breast cancer risk among premenopausal women (3). Serum IGFBP-3 levels have not consistently been found to be related to breast cancer risk.Recently, an A → C polymorphism in the IGFBP-3 promoter region was identified that is related to circulating IGFBP-3 levels (4). The AA genotype was associated with higher circulating IGFBP-3 levels than the AC or CC genotype in men and in premenopausal women (4, 2). The genotype-phenotype correlation was modified by body mass index and height (4). Further, it has been shown in in vitro tests that the A allele has higher promoter activity than the C allele (4).Hypothesis. We hypothesized that the C allele of IGFBP-3 polymorphism leading to decreased serum IGFBP-3 levels and thereby increased serum IGF-I levels would be associated with increased breast cancer risk. We used a case-control study to examine this IGFBP-3 polymorphism as a potential risk factor for breast cancer risk in premenopausal Caucasian women. We also investigated whether other factors, such as alcohol consumption, use of oral contraceptives, and body size, modify the association.The population-based breast cancer case-control study in Germany (1992-1995) enrolled 603 breast cancer patients and 1,068 age-matched controls. All patients were ages <51 years at the time of diagnosis of incident in situ or invasive breast cancer. A group of 476 cases and 866 controls were premenopausal, and 34 cases and 65 controls were postmenopausal. The women who had undergone hysterectomy but not bilateral ovariectomy were considered to be of unknown menopausal status (93 cases and 137 controls; for details, see ref. 5). All participants provided a blood sample and completed a self-administered questionnaire eliciting information on known and suspected risk factors for breast cancer.We compared the IGFBP-3 promoter polymorphism sequence referred previously to ref. 4 (accession no. M 35878) with sequences available from genome databases (AC 091524 and AX 323409) and three sequences from our own samples (DNA I-III, sequences obtained from GENterprise, Mainz, Germany). The multiple sequence alignment showed differences between the IGFBP-3 sequences: (a) At positions 40,449 and 40,448 of AC 091524 as well as on the same sections of DNA I to III, we found two cytosine bases missing on M 35878 and AX 323409. (b) At positions 40,344 and 40,239 of AC 091524 as well as on the equivalent positions of DNA I to III, we found one cytosine base each, which was not present on M 35878 and AX 323409. (c) At positions 40,253 and 40,252 of AC 091524, we found one guanine base followed by one cytosine base and the same was true for DNA I to III, whereas on M 35878 and AX 323409, the order was inverse (i.e., CG). The IGFBP-3 polymorphism analyzed is therefore in position −204 (not −202 as described in ref. 4) relative to the CAP site and at position −336 relative to the ATG start codon). Genotyping was done based on PCR followed by RFLP (4).We used the χ2 test to assess departures of the genotype distribution from Hardy-Weinberg equilibrium. For the assessment of IGFBP-3 genotypes in association with breast cancer risk, we used multivariate logistic regression (SAS Institute, Cary, NC) to calculate odds ratios and 95% confidence intervals (95%CI). Women with AA genotype were taken as reference group. The analyses were stratified by age in 5-year intervals and adjusted for family history of breast cancer in first-degree relatives (yes, no), duration of breast-feeding (continuous), number of full-term pregnancies (1-2, >3), daily amount of alcohol (1-5, 6-11, 12-18, >19 g), use of oral contraceptives (yes, no), and menopausal status (premenopausal, postmenopausal, unknown).The A allele frequency was 0.48 in cases and 0.47 in controls, and the C allele was 0.52 in cases and 0.53 in controls. AC genotype was the most frequent genotype, being 49.0% in both cases and controls (Table 1). The genotype frequencies were in Hardy-Weinberg equilibrium. There were no significant differences between cases and controls in the frequencies of the IGFBP-3 polymorphism alleles A and C and the genotypes AA, AC, and CC. Compared with the AA genotype, the adjusted odds ratio (95% CI) was 0.99 (0.77-1.27) and 0.97 (0.73-1.29) associated with the AC and CC genotypes, respectively. Further adjustment for established risk factors did not alter these estimates. Point estimates differed somewhat by menopausal status; however, 95% CIs were wide. We also failed to detect any association between IGFBP-3 polymorphism and breast cancer risk in subgroups of women differentiated by alcohol consumption, use of oral contraceptives, and body mass index.Using a population-based, case-control study of breast cancer by age 50 years, we were not able to find an association between IGFBP-3 promoter polymorphism and breast cancer risk. Our study confirms the recent results of Schernhammer et al. (6), indicating that the A−336C IGFBP-3 polymorphism alone does not play an important role in the etiology of breast cancer.Further work should consider that the circulating IGFBP-3 levels might be strongly influenced by exogenous factors (environmental factors or hormones) other than the genotype. Simultaneous consideration of variability at several polymorphic sites in both IGFBP-3 and IGF-I (2, 7) may also be necessary to gain more information about the associations of the IGF systems with breast cancer.

PURPOSE:Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility. We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), APE1 (Asp148Glu), and XPD (Lys751Gln and Asp312Asn), with the risk of acute skin reactions following radiotherapy.DESIGN:We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose.RESULTS:Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of the APE1 148Glu and the XRCC1 399Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1 148Glu and XRCC1 399Gln alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; Pinteraction = 0.009).CONCLUSION:The XRCC1 399Gln or APE1 148Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight.

Important aspects of the recognized inverse relation between physical activity and breast cancer risk are still under discussion. Data on physical activity from sports, occupational activity, household tasks, walking, and cycling by reported frequency, duration, and intensity during adolescence and young adulthood were collected in 1999-2000 from 360 premenopausal breast cancer cases and 886 controls who had previously participated in a German population-based case-control study. In multivariate conditional logistic regression, no association between total physical activity and premenopausal breast cancer was found in two age periods. For women who were active during both periods, the adjusted odds ratio was 0.83 (95% confidence interval: 0.60, 1.14). When both age periods were combined, higher quartiles of total physical activity compared with the lowest quartile showed adjusted odds ratios of 0.97, 0.68, and 0.94. Only the effect of moderately high physical activity was statistically significant. Analyses by type of activity revealed significant protective effects for women who reported the highest levels of cycling activities (adjusted odds ratio = 0.66, 95% confidence interval: 0.45, 0.97). These data do not suggest an inverse monotonic association between total physical activity and breast cancer risk in premenopausal women. The study prevalence of cycling and walking for transportation demonstrated that national habits need consideration in the exposure assessment.

BACKGROUND Polymorphisms in the N-acetyltransferase 2 (NAT2) gene influence the rate of metabolism of aromatic and heterocyclic amines present in tobacco smoke. Because the physicochemical composition of mainstream and sidestream smoke differ, we conducted a case-control study to assess a possible differential effect of NAT2 genotype on the relationship between active/passive smoke exposure and breast cancer risk. METHODS Breast cancer patients diagnosed by 50 years of age and population-sampled controls were interviewed to obtain detailed lifetime active and passive smoking history. NAT2 genotype was determined in 422 breast cancer patients and 887 controls. Multivariate logistic regression analysis was performed to estimate breast cancer risk in relation to smoking history by acetylator status and interaction effects. RESULTS Compared with women never regularly exposed to tobacco smoke, odds ratios (ORs) for current smoking and ex-smoking were 1.7 [95% confidence interval (CI): 1.0-2.9] and 1.2 (95% CI, 0.7-2.0) in slow acetylators, and not increased in rapid acetylators. Active smoking variables, such as pack-years, duration of smoking, and time since cessation, showed significant dose-response relationships with breast cancer risk among slow acetylators but not rapid acetylators. In contrast, passive smoking was associated with higher risk in rapid than in slow acetylators, with ORs of 2.0 (95% CI, 1.0-4.1) and 1.2 (95% CI, 0.7-2.0), respectively. CONCLUSIONS Our results suggest that the NAT2 status has a differential effect on the association of active and passive smoking with breast cancer and demonstrate the need to consider possible different mechanisms associated with exposure to main- and sidestream tobacco smoke.

Recent studies suggest that both active and passive smokers have an increased risk of breast cancer compared with women who have never been either actively or passively exposed. Data on lifetime active and passive smoking were collected in 1999-2000 from 468 predominantly premenopausal breast cancer patients diagnosed by age 50 years and 1,093 controls who had previously participated in a German case-control study conducted in 1992-1995. Compared with never active/passive smokers, former smokers and current smokers had odds ratios of 1.2 (95% confidence interval (CI): 0.8, 1.7) and 1.5 (95% CI: 1.0, 2.2), respectively, and ever active smokers had an odds ratio of 1.3 (95% CI: 0.9, 1.9). The risk increased with duration of smoking and decreased after cessation of smoking. Among never active smokers, ever passive smoking was associated with an odds ratio of 1.6 (95% CI: 1.1, 2.4). Exposure to environmental tobacco smoke during childhood or before the first pregnancy did not appear to increase breast cancer risk. At greatest risk were women who had a high level of exposure to both passive and active smoking (odds ratio = 1.8, 95% CI: 1.2, 2.7). This study strengthens the hypothesis of a causal relation between active and passive smoke exposures and breast cancer risk.

Studies of the association between alcohol drinking and breast cancer show a tendency towards an increase in risk for high consumption levels but yield less consistent results for low-to-moderate levels, particularly among premenopausal women. In a population-based case-control study in Germany, the authors determined the effect of alcohol consumption at low-to-moderate levels on breast cancer risk among women up to age 50 years. The study included 706 case women whose breast cancer had been newly diagnosed in 1992-1995 and 1,381 residence- and age-matched controls. In multivariate conditional logistic regression analysis, the adjusted odds ratios for breast cancer were 0.71 (95% confidence interval (CI): 0.54, 0.91) for average ethanol intake of 1-5 g/day, 0.67 (95% CI: 0.50, 0.91) for intake of 6-11 g/day, 0.73 (95% CI: 0.51, 1.05) for 12-18 g/day, 1.10 (95% CI: 0.73, 1.65) for 19-30 g/day, and 1.94 (95% CI: 1.18, 3.20) for > or = 31 g/day. The association with high daily ethanol intake of > or = 19 g was modified by educational level, such that odds ratios were 3.7, 1.6, and 0.7 for women with low, moderate, and high levels of education, respectively. These data suggest that low-level consumption of alcohol does not increase breast cancer risk in premenopausal women.