Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk.

Copy number variants (CNVs) are a recently recognized class of human germ line polymorphisms and are associated with a variety of human diseases, including cancer. Because of the strong genetic influence on prostate cancer, we sought to identify functionally active CNVs associated with susceptibility of this cancer type. We queried low-frequency biallelic CNVs from 1,903 men of Caucasian origin enrolled in the Tyrol Prostate Specific Antigen Screening Cohort and discovered two CNVs strongly associated with prostate cancer risk. The first risk locus (P = 7.7 × 10(-4), odds ratio = 2.78) maps to 15q21.3 and overlaps a noncoding enhancer element that contains multiple activator protein 1 (AP-1) transcription factor binding sites. Chromosome conformation capture (Hi-C) data suggested direct cis-interactions with distant genes. The second risk locus (P = 2.6 × 10(-3), odds ratio = 4.8) maps to the α-1,3-mannosyl-glycoprotein 4-ß-N-acetylglucosaminyltransferase C (MGAT4C) gene on 12q21.31. In vitro cell-line assays found this gene to significantly modulate cell proliferation and migration in both benign and cancer prostate cells. Furthermore, MGAT4C was significantly overexpressed in metastatic versus localized prostate cancer. These two risk associations were replicated in an independent PSA-screened cohort of 800 men (15q21.3, combined P = 0.006; 12q21.31, combined P = 0.026). These findings establish noncoding and coding germ line CNVs as significant risk factors for prostate cancer susceptibility and implicate their role in disease development and progression.

Stoichiometry of natural bacterial assemblages from lakes located across an elevational gradient.

Heterotrophic bacteria are thought to be phosphorus-rich organisms with relatively homeostatic stoichiometry, but the elemental composition of natural bacterial communities has rarely been assessed. Here we tested whether bacterial stoichiometry changes with the trophic status of lakes by assessing the elemental composition of the bacterial-dominated (hereafter microbial) fraction together with that of the dissolved and seston fractions in 11 lakes situated along an elevational gradient. The stoichiometry of these three size-fractions was analyzed during the thermal stratification and mixing periods in composite water samples and in the water layer of the deep chlorophyll-a maximum. In addition, we analyzed the relative abundance of the most common bacterial groups in the lakes. Our results show that the microbial fraction was always enriched in phosphorus compared to the dissolved fraction, irrespectively of the lake trophic status. Further, they indicate that the elemental composition of bacteria in mountain lakes is at least seasonally very dynamic, resulting not only from changes in the nutrient ratios of the resource itself, but probably from changes in the composition of the dominant bacterial taxa too, though at the taxonomic level analyzed, we did not find evidence for this.

Daphnia as a refuge for an antibiotic resistance gene in an experimental freshwater community.

Mechanisms that enable the maintenance of antibiotic resistance genes in the environment are still greatly unknown. Here we show that the tetracycline resistance gene tet(A) is largely removed from the pelagic aquatic bacterial community through filter feeding by Daphnia obtusa while it becomes detectable within the microbiome of the daphniids themselves, where it was not present prior to the experiment. We moreover show that a multitude of Daphnia-associated bacterial taxa are potential carriers of tet(A) and postulated that the biofilm-like structures, where bacteria grow in, may enable horizontal transfer of such genes. This experiment highlights the need to take ecological interactions and a broad range of niches into consideration when studying and discussing the fate of antibiotic resistance genes in nature.

Clinically insignificant improvement of prostate cancer prediction by addition of sex steroid hormones and SHBG serum levels to serum PSA, fPSA%, and age in a screening setting.

Abstract Various findings implicate sex hormones in prostate growth and development and also in prostate carcinogenesis. We investigated if addition of sex steroid hormone and sex hormone binding globulin (SHBG) serum levels to standard risk assessment parameters [prostate-specific antigen (PSA), free PSA percentage (fPSA%), and age] improves prostate cancer prediction in a PSA screening setting. Steroid hormones testosterone (T), free testosterone (fT), and estradiol (E2), and binding protein SHBG levels were measured in 762 men undergoing prostate biopsy due to suspect PSA serum levels. Prostate cancer was diagnosed in 286 (37.5%) of these men. Our data confirmed that PSA (mean BE=5.09; mean CA=6.05; p=1.24×10-5), fPSA% (mean BE=22.08; mean CA=18.67; p=1.97×10-7), and age (mean BE=60.64; mean CA=64.5; p=7.05×10-10) differentiate men with cancer (CA) and men with benign disease (BE), such as benign prostate hyperplasia. In addition, SHBG (mean BE=50.3; mean CA=54.9; p=0.008) also differed statistically significantly between these two groups. All hormones except E2 and tumor markers correlated significantly with age (T: ρ=-0.09; fT: ρ=-0.27; SHBG: ρ=0.21; PSA: ρ=0.32; and fPSA%: ρ=0.22). Furthermore, we found that PSA correlates with E2 (ρ=0.08), and fPSA% with SHBG (ρ=0.1) and fT (ρ=-0.09). Addition of hormones and SHBG to a baseline marker model including PSA, fPSA%, and age improved cancer prediction in three multivariate classification methods; however, the improvement was minimal. The best improvement by 0.8% was obtained in the logistic regression model with the addition of T and SHBG or of E2 and SHBG, or in the support vector machine model with the addition of SHBG and all steroid hormones to the combination of standard markers PSA, fPSA%, and age; however, this additional gain of accuracy is too small to justify the additional efforts and costs.

Genetic variation of genes involved in dihydrotestosterone metabolism and the risk of prostate cancer.

PURPOSE: Dihydrotestosterone (DHT) is an important factor in prostate cancer (PCA) genesis and disease progression. Given PCA's strong genetic component, we evaluated the possibility that variation in genes involved in DHT metabolism influence PCA risk. EXPERIMENTAL DESIGN: We investigated copy number variants (CNV) and single nucleotide polymorphisms (SNP). We explored associations between CNV of uridine diphospho-glucuronosyltransferase (UGT) genes from the 2B subclass, given their prostate specificity and/or involvement in steroid metabolism and PCA risk. We also investigated associations between SNPs in genes (HSD3B1, SRD5A1/2, and AKR1C2) involved in the conversion of testosterone to DHT, and in DHT metabolism and PCA risk. The population consisted of 426 men (205 controls and 221 cases) who underwent prostate-specific antigen screening as part of a PCA early detection program in Tyrol, Austria. RESULTS: No association between CNV in UGT2B17 and UGT2B28 and PCA risk was identified. Men carrying the AA genotype at SNP rs6428830 (HSD3B1) had an odds ratio (OR) of 2.0 [95% confidence intervals (95% CI), 1.1-4.1] compared with men with GG, and men with AG or GG versus AA in rs1691053 (SRD5A1) had an OR of 1.8 (95% CI, 1.04-3.13). Individuals carrying both risk alleles had an OR of 3.1 (95% CI, 1.4-6.7) when compared with men carrying neither (P = 0.005). Controls with the AA genotype on rs7594951 (SRD5A2) tended toward higher serum DHT levels (P = 0.03). CONCLUSIONS: This is the first study to implicate the 5alpha-reductase isoform 1 (SRD5A1) and PCA risk, supporting the rationale of blocking enzymatic activity of both isoforms of 5alpha-reductase for PCA chemoprevention.