Polymorphic catechol-O-methyltransferase gene and breast cancer risk.

We examined 483 Finnish breast cancer cases and 482 population controls to determine the potential effect of catechol-O-methyltransferase (COMT) genotype in individual susceptibility to breast cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression after adjustment for known or suspected risk factors for breast cancer. When studied separately by menopausal status, the COMT-L allele-containing genotypes were inversely associated with premenopausal breast cancer, especially with advanced stage of the disease (OR, 0.44; 95% CI, 0.22-0.87). Among postmenopausal women a similar decreased risk was seen for local carcinoma associated with the COMT-LL genotype (OR, 0.55; 95% CI, 0.31-0.98). The lowest breast cancer risk was seen in the postmenopausal women with the COMT-LL genotype and low body-mass index (30 months) use of estrogen (OR, 4.02; 95% CI, 1.13-14.3), or with the COMT-L allele-containing genotypes and early age (

Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk.

Superoxide dismutases play a key role in the detoxification of superoxide radicals and thus protect cells from damage induced by free radicals. Within mitochondria manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species. Polymorphism in the mitochondrial targeting sequence of MnSOD has recently been associated with risk of breast cancer. We examined this in a study population consisting of 483 breast cancer cases and 482 controls, all of Finnish Caucasian origin. Odds ratios (OR) and 95% confidence intervals (95% CIs) were estimated by unconditional logistic regression. MnSOD genotypes containing the variant A allele were found to be associated with a 1.5-fold (95% CI 1.1-2.0) increased risk of breast cancer compared with those with the homozygous wild-type genotype (MnSOD VV). This finding supports the proposal that MnSOD genotypes may modify individual breast cancer risk.

Glutathione S-transferase M1, M3, P1, and T1 genetic polymorphisms and susceptibility to breast cancer.

This study was undertaken to examine if glutathione S-transferase (GST) M1, M3, P1, and T1 genotypes affected breast cancer risk in Finnish women. The study population consisted of 483 incident breast cancer cases and 482 healthy population controls. Genotyping analyses were performed by PCR-based methods, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for known or suspected risk factors for breast cancer. When the genes were studied separately, the only significant finding was between GSTM1 null genotype and postmenopausal breast cancer risk (OR, 1.49; 95% CI, 1.03-2.15). Conversely, when the potential combined effects of the at-risk genotypes were examined, significant associations were observed only among premenopausal women. Although only a moderate risk of breast cancer was seen for premenopausal women concurrently carrying the GSTM3*B allele containing genotypes and the GSTP1 Ile/ Ile genotype (OR, 2.07; 95% CI, 1.02-4.18), the risk rose steeply if they simultaneously lacked the GSTT1 gene (OR, 9.93, 95% CI, 1.10-90.0). A borderline significant increase in the risk of breast cancer was also seen for premenopausal women with the combination of GSTM1 null, GSTP1 Ile/Ile, and GSTT1 null genotypes (OR, 3.96; 95% CI, 0.99-15.8). Our findings support the view that GST genotypes contribute to the individual breast cancer risk, especially in certain combinations.

High-activity microsomal epoxide hydrolase genotypes and the risk of oral, pharynx, and larynx cancers.

Human microsomal epoxide hydrolase (mEH), encoded by the EPHX1 gene, is involved in the metabolism of tobacco carcinogens. We investigated the effect of exon 3 and 4 polymorphisms of the EPHX1 gene in 121 patients with cancers of the oral cavity/pharynx, 129 patients with cancer of the larynx, and 172 non-cancer controls, all Caucasian regular smokers. The potential modifying role of previously analyzed GSTM1, GSTM3, and GSTP1 genotypes was also examined. Compared with the putative low-activity genotypes, odds ratios (ORs) associated with predicted intermediate and high mEH activity genotypes were significantly increased for oropharyngeal cancers [OR = 1.8; 95% confidence interval (CI) = 1.0-3.3; and OR = 2.1; 95% CI = 1.0-4.5, respectively; P(trend) = 0.03] and laryngeal cancers (OR = 1.7; 95% CI = 1.0-3.1; and OR = 2.4; 95% CI = 1.1-5.1, respectively; P(trend) = 0.02). Moreover, a positive interaction was found between mEH activity and GSTM3 genotype for laryngeal cancer. The combined EPHX1 high activity-associated genotype and GSTM3 (AB or BB) genotype conferred a 13.1-fold risk (95% CI = 3.5-48.4) compared with the concurrent presence of the EPHX1 low activity-associated genotype and the GSTM3 AA genotype. Thus, EPHX1 polymorphisms may be one of the factors of importance in susceptibility to smoking-related cancers of the upper aerodigestive tract.

Steroid metabolism gene CYP17 polymorphism and the development of breast cancer.

The potential role of the polymorphism in the CYP17 gene was evaluated in a case-control study with 483 incident breast cancer patients and 482 population controls, all of homogenous Finnish origin. Our data disagree with the earlier suggestions that the minor A2 variant of CYP17 would pose an increased risk for developing advanced breast cancer. In contrast, a tendency of inverse association was found for premenopausal women carrying the A2 allele containing genotypes with a multivariate adjusted odds ratio of 0.58 approaching statistical significance (95% CI, 0.31-1.07). Agreeing with previous observations, the protective effect of later age at menarche (> or =13 years) was mainly limited to women with A1/A1 genotype, although this could only be seen in premenopausal women (odds ratio, 0.34; 95% CI, 0.15-0.76). Similarly, we found a remarkably lower risk for premenopausal women with at least one child (odds ratio, 0.22; 95% CI, 0.07-0.62) to be mainly attributable to the A1/A1 genotype. CYP17 genotypes may thus modify individual breast cancer proneness in certain subpopulations, although they appear not to have any major modifying role in the risk of this malignancy overall. Because these findings are based on relatively small numbers in stratified analysis, they should, however, be interpreted with caution before being confirmed in future studies.

N-acetyltransferase NAT1 and NAT2 genotypes and lung cancer risk.

Acetyltransferases, encoded by the NAT1 and NAT2 genes, are involved in the activation/inactivation reactions of numerous xenobiotics, including tobacco-derived aromatic amine carcinogens. Several allelic variants of NAT1 and NAT2, which cause variations in acetylation capacity, have been detected. The NAT2 slow acetylator phenotype/genotype has been inconsistently associated with lung cancer and, to date, the role of NAT1 polymorphism in lung cancer has not been reported. The effect of NAT1 and NAT2 genetic polymorphisms on individual lung cancer risk was evaluated among 150 lung cancer patients and 172 control individuals, all French Caucasian smokers. The NAT1 alleles (*3, *4, *10, *11, *14, and *15) and the NAT2 alleles (*4, *5, *6, *7) were differentiated by polymerase chain reaction-based restriction fragment length polymorphism methods using DNA extracted from peripheral white blood cells. Genotypes were classified according to current knowledge of the functional activity of the variant alleles. The NAT1*10 and NAT1*11 alleles were considered as rapid alleles, the NAT1*4 and the NAT1*3 as normal alleles and NAT1*14 and NAT1*15 as slow-acetylation alleles. Logistic regression analyses were performed taking into account the age, sex, smoking and occupational exposures. A significant association was observed between lung cancer and NAT1 genotypes (P(homogeneity) < 0.02) with a gene dose effect (P(trend) < 0.01); compared with homozygous rapid acetylators, the lung cancer risk was 4.0 (95% confidence interval 0.8-19.6) for heterozygous rapid acetylators, 6.4 (95% confidence interval 1.4-30.5) for homozygous normal acetylators and 11.7 (95% confidence interval 1.3-106.5) for heterozygous slow acetylators. None of the individuals were homozygous slow acetylators. Similar results were obtained whatever the adjustment considered. No significant association was found between NAT2 genotype and lung cancer. The NAT1 polymorphism may thus be an important modifier of individual susceptibility to smoking-induced lung cancer.

One-step all-in-one dry reagent immunoassays with fluorescent europium chelate label and time-resolved fluorometry.

The availability of an intrinsically fluorescent, inert, and stable Eu chelate label made it feasible to design one-step all-in-one immunoassays with time-resolved fluorometry for detection. Both competitive and noncompetitive immunoassays are performed in microtitration wells containing all assay-specific components in a stable dry form. Only the sample and one assay buffer common for all analytes need to be added. Model assays for human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), and progesterone all reached equilibrium in 15 min or less without compromising the performance characteristics of the measurements, all of which perform at least equivalent to state-of-the-art assays. The detection limits for hCG, AFP, and progesterone were 0.3 IU/L, 0.1 microgram/L, and 0.5 nmol/L, respectively. The assay ranges for hCG and AFP were linear to 5000 IU/L and 1200 micrograms/L, respectively. The immunoassay format can be readily implemented in a fully automated random-access immunoassay system with optimal performance characteristics and no handling of analyte-specific assay components.

Dual-label one-step immunoassay for simultaneous measurement of free and total prostate-specific antigen concentrations and ratios in serum.

We developed a simple one-step dual-label immunoassay for simultaneous measurement of the free, noncomplexed form of prostate-specific antigen (PSA) and total PSA. The assay is based on time-resolved fluorescence and includes a stable fluorescent chelate of Eu to label a monoclonal antibody (mAb) that detects only free PSA, whereas a second mAb labeled with a fluorescent chelate of Tb provides equimolar detection of both free PSA and PSA complexed to alpha 1-antichymotrypsin. A third mAb on a solid phase captures the free and complexed forms of PSA in an equimolar fashion. The simultaneous measurement of the free-to-total PSA ratio (F/T) with the one-step dual assay is not sensitive to variations in the sample volume. The discrimination between benign prostatic hyperplasia and prostate cancer patients, i.e., the area under the receiver-operating characteristic curve, increased from 0.64 (total PSA assay) to 0.78 and 0.81 when the F/T ratio was measured with single and dual assays, respectively.