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Objective: A functional polymorphism at codon 16 (Alanine-to-Valine) of manganese superoxide dismutase (MnSOD) has been hypothesized to increase the risk of breast cancer and to modify the effects of oxidative stress. However, study findings have been inconsistent and sample sizes often small., Methods: We used a large population-based age-matched case-control study in German Caucasian women up to age 50 to assess breast cancer risk associated with this polymorphism and to investigate interaction with other known risk factors related to oxidative stress, including alcohol intake, cigarette smoking, and diet. Data on a total of 614 cases and 1,080 controls were evaluated using multivariate conditional logistic models., Results: No main effect between genotype and breast cancer was observed. However, risk was significantly increased for Ala carriers who consumed > or =19 g of alcohol per day, compared to women homozygous for the Val allele who did not drink (OR 2.1, 95% CI 1.1-3.9; p = 0.13 for interaction). No significant effect modification was observed for smoking or diet., Conclusions: The MnSOD Ala-9Val polymorphism may contribute to an increase in breast cancer risk in the context of high alcohol consumption, however the polymorphism is not an overall risk factor for breast cancer in this primarily premenopausal population.

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, although 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).

A functional polymorphism at codon 33 (leucine-to-proline, Leu33Pro)/nucleotide 1565 (T-to-C, T1565C) of the integrin beta3 has been hypothesized to increase the risk of breast cancer and its metastasis. Three studies have been conducted up to date and the results were contradictory. We used a large population-based age-matched case-control study in German Caucasian women by the age of 50 years to assess breast cancer risk associated with this polymorphism, taking into consideration of possible interaction with other risk factors, and to examine if it affects clinical presentation. Overall, the odds ratios (OR) for breast cancer were not increased in women carrying either allele. However, we observed a differential effect of the Leu33Pro polymorphism by age group when patients were stratified by 45 years of age (p=0.055). Being a carrier of the 33proline allele was found to be associated with a 32% increased risk (95% Cl=1.0-1.8) for breast cancer compared to the wild-type leucine homozygotes among women age 45 or younger but not in older women. Furthermore, we observed significant dose effect of the 33proline allele (p=0.04), with 30% risk increase per allele (95% Cl=1.0-1.7). Significant evidence was also found for a positive association between 33proline carrier status and increasing axillary node involvement (p=0.048) but neither size nor grading of tumor in this study. Our data suggest that inheritance of the integrin beta3 Leu33Pro polymorphism may increase the breast cancer risk by age 45 in the German population.

MaeIII Restriction Fragment Length Polymorphism in exon 3 of the alcohol dehydrogenase II was assessed in serum from 467 randomly selected German women and 278 women with invasive breast cancer to evaluate the interaction between a polymorphism of the alcohol dehydrogenase II gene, alcohol consumption and risk for breast cancer. In both groups, usual consumption of different alcoholic beverages was asked for using semiquantitative food frequency questionnaires. We used multivariable logistic regression to separately estimate the association between alcohol consumption and alcohol dehydrogenase II polymorphism in the population sample and women with breast cancer. The alcohol dehydrogenase II polymorphism was detected in 14 women from the population sample (3.0%) and in 27 women with invasive breast cancer (9.7%). Frequency of alcohol consumption was independent of the genotype in the population sample. In women with breast cancer, there was a significant inverse association between the alcohol dehydrogenase II polymorphism and frequency of alcohol consumption (adjusted case-only odds ratio over increasing frequency of alcohol consumption=0.5; P for interaction=0.02). We observed a gene-environment interaction between the alcohol dehydrogenase II polymorphism, alcohol consumption, and risk for breast cancer. Breast cancer risk associated with alcohol consumption may vary according to the alcohol dehydrogenase II polymorphism, probably due to differences in alcohol metabolism.

We used a large population-based case-control study to determine whether three known p53 polymorphisms, intron 3 16 bp duplication, codon 72(Arg/Pro) and intron 6 MspI restriction fragment length polymorphism, alter the risk for breast cancer in German women. For all three polymorphisms, the odds ratios (ORs) for breast cancer were increased in women carrying the rare allele; however, this was statistically significant only for the 16 bp duplication polymorphism. Compared with the 16 bp duplication wild-type A1/A1 genotype, ORs for A1/A2 genotype and A2/A2 genotype were 1.3 [95% confidence interval (CI) 1.0-1.7] and 1.7 (95% CI 0.8-3.4), suggesting an allele dosage effect (trend test, P = 0.03). Significant evidence was found for a differential effect by family history of breast cancer (P = 0.03 for interaction), with the OR being 5.3 among women with a first degree family history. Our data suggest that inheritance of an intronic polymorphism in the p53 gene increases breast cancer risk appreciably in women by the age of 50 years with a family history of breast cancer in the German population.

Three germline p53 polymorphisms, a 16 bp duplication in intron 3, a Bst UI RFLP in exon 4 and Msp I RFLP in intron 6 have previously been tested for a association with Swedish breast cancer patients. The rare Bst UI allele was found to be associated with breast cancer in the Swedish patients (OR 1.47, 95% CI, 1.08-2.00). In our hospital-based case-control study leukocyte DNA of 107 breast cancer patients and 305 control women was analyzed. Individuals heterozygous at all 3 polymorphic sites (27/107) were over-represented in the breast cancer group with an age-adjusted OR of 2.01 (95% CI, 1.02-3.94). Haplotype analysis identified the 16 bp A2 allele (with 16 bp duplication) and Msp I A1 allele (loss of Msp I restriction site) as risk alleles. The results of this study suggest that the rare alleles 16 bp A 2 and Msp I A1 of the p53 locus may modify the risk of breast cancer in German women.