Top PDF Genetic association of the KLK4 locus with risk of prostate cancer.

Study subjects have been described elsewhere [24,25]. Briefly, from 2004 onwards, 1349 histopathologically-confirmed prostate cancer cases were recruited through private and public urologists in Queensland, Australia via three prostate cancer studies or resources: the Retrospective Queensland Study (N = 154; [26]), the Prostate Cancer Supportive Care and Patient Outcomes Project (ProsCan, N = 857; [25]) and from the Australian Prostate Cancer BioResource (APCB, N = 338; http://www.apccbioresource.org.au/index.html). Men presented to urologists with lower urinary tract symptoms and/or abnormal serum Prostate Specific Antigen (PSA), and 72% of cases possessed prostate tumours of Gleason score 7 or above. Cases ranged in age at diagnosis from 40–88 years (median 63 years). Male controls (N = 1405) with no self-reported personal history of prostate cancer were randomly selected from the Australian Electoral Roll and age-matched (in 5 year groups) and post-code matched to cases (N = 569), or recruited through the Australian Red Cross Blood Services in Brisbane (N = 836). Controls were not screened for PSA levels and analyses excluded 50 controls with age at interview ,40 years (the age of the youngest case); included controls ranged in age at interview from 40–89 years of age (median 62 years). All participants had self-reported European ethnicity and gave written informed consent. The study protocol was approved by the Human Research Ethics Committees of the Queensland University of Technology, Queensland Institute of Medical Research, the Mater Hospital (for Brisbane Private Hospital), the Royal Brisbane Hospital, Princess Alexandra Hospital and the Cancer Council Queensland.

In our data example, we obtained confirmatory evidence of the association of the HOXB13 G84E mutation with prostate cancer, and provided age-specific risks for developing prostate cancer for mutation carriers in a large, prospective cohort. We also provided evidence that the G84E mutation exhibits a pleiotropic effect on numerous other cancers, though sample sizes made it difficult to determine precisely which cancers are involved. Consistent with the hypothe- sis of pleiotropy, we also provided suggestive evidence that the mutation exhibits a stronger asso- ciation in individuals with multiple cancers, both involving prostate cancer and independent of prostate cancer. Multiple cancers in the same individual will most often arise independently and may reflect pleiotropic events, though in some cases may be due to metastasis. A shared genetic basis among cancers may be supported by HOXB13’s role in embryonic development and body patterning [20,43,44]. HOXB13 is particularly expressed in the prostate [20], where it physically interacts with the androgen receptor, which is important for growth and regulation of differentia- tion in normal cell biology. Thus, HOXB13 may impact the carcinogenic process via its action on growth and development. More work is needed to examine the biological mechanisms and effects that the mutation has on the function of the HOXB13 gene. Two key factors made this investiga- tion possible: a very large genotyped cohort with information on multiple cancers and our ability to impute the G84E mutation using a custom reference panel.

Moreover, hK2 is expressed at higher level in poorly differentiated cancers and is a likely candidate for prostate carcinogenesis [16]. All of these observations strongly implicate KLK2 as a plausible candidate gene involved in PCa susceptibility. During this decade, a number of studies have assessed the association between polymorphism rs198977 in KLK2 and risk of PCa in different populations; however, the results are inconsistent and inconclusive [17] [18]. Different methodologies have been used, and in particular, samples are collected from all over the world. Therefore, it is not surprising that there has been a lack of replication in different studies. By using all the available published data to increase the statistical power, it was hypothesized that a meta-analysis might allow plausible candidate genes to be excluded and causative genes to be identified with reliability. To confirm whether the polymorphism rs198977 in KLK2 is associated with susceptibility of PCa, we have taken a meta- analysis in which all the published case-control studies are processed.

Eeles, R.A., Kote-Jarai, Z., Giles, G.G., Olama, A.A., Guy, M., Jugurnauth, S.K., Mulholland, S., Leongamornlert, D.A., Edwards, S.M., Morrison, J., Field, H.I., Southey, M.C., Severi, G., Donovan, J.L., Hamdy, F.C., Dearnaley, D.P., Muir, K.R., Smith, C., Bagnato, M., Ardern-Jones, A.T., Hall, A.L., O’Brien, L.T., Gehr-Swain, B.N., Wilkinson, R.A., Cox, A., Lewis, S., Brown, P.M., Jhavar, S.G., Tym- rakiewicz, M., Lophatananon, A., Bryant, S.L.; UK Genetic Prostate Cancer Study Collaborators; British Association of Urological Surgeons’ Section of Oncology; UK ProtecT Study Collaborators, Horwich, A., Huddart, R.A., Khoo, V.S., Parker, C.C., Woodhouse, C.J., Thompson, A., Christmas, T., Ogden, C., Fisher, C., Jamieson, C., Cooper, C.S., English, D.R., Hopper, J.L., Neal, D.E., and D.F. Easton (2008). Mul- tiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 40, 316–321.

Acute infections are often accompanied by inflammatory reactions including fever, which is a cytokine-mediated rise in core temperature, and other immunologic, endocrinologic, neu- rologic, and physiologic changes [1,30]. A fever can establish a cascade of host defense mechanisms by inducing the proliferation and differentiation of leucocytes and the secretion of interferons (IFNs), tumor necrosis factor (TNF)-a, antibodies, and neutrophil migration [11,12]. It has also been shown both in vitro and in vivo that dendritic cells (DC, key antigen-presenting cells in the immune system) treated with fever-like heat (41uC) were signifi- cantly superior compared to non-heat-treated DC in stimulating T cells and activating NF-kB (a transcription factor that regulates various immunological genes and plays an important role in human tumor suppression) [5,15]. Moreover, tumor cells are more vulnerable to heat than normal cells and undergo necrosis to a larger extent [31,32] and hyperthermia has become an auxiliary approach in cancer therapy [14,33–36]. In addition, several epidemiological studies have consistently found an inverse association between febrile acute infections and cancer risk [1,3,5–7,37–39], especially for malignant melanoma, which have been shown a link to breast cancer in epidemiologic and genetic studies [40–42]. Therefore, our finding of an inverse association between fever frequency and breast cancer risk is in agreement with the results of previous studies.

In this cohort of men subjected to prostate biopsy due to abnormal clinical and/or PSA findings where an extensive biopsy scheme was used, we showed that by adding a genetic score based on 7 SNPs significantly improved the discriminative ability of an established parsimonious model with only PSA and age. The AUC increased significantly from 0.65 to 0.68 for all prostate cancer and from 0.68 to 0.71 in high grade prostate cancer, when the genetic variants were added to the model. Furthermore, the improved predictive value of the score for prostate cancer risk persisted with a four SNPs risk score (excluding SNPs deviated from Hardy- Weinberg equilibrium). Although we present the largest effort to date to study the association between adipokine genetic risk score and risk of prostate cancer, our results should be interpreted in the context of several potential limitations. We took a focused candidate gene approach to evaluate key SNPs in adipokine pathways but our SNP panel could be incomplete. Likewise, several newly reported prostate cancer risk-associated SNPs from genome-wide association studies were not included in the risk prediction model. Had we been able to include them, the overall risk prediction might have improved. We also estimated risk associations in this study population with an exploratory intent, without having the opportunity to validate our findings in a separate sample of patients undergoing prostate cancer screening. Therefore, further studies in independent populations are required. Finally, despite our relatively large sample size, we had limited statistical power to examine genetic variants in relation to high-metastasis risk prostate cancer, because of the small number of cases in this group. However, our study has several strengths: i) it was prospective and large enough for key outcomes of interest, ii) most of the genes and SNPs selected were based on biological evidence of functional importance; iii) study design and statistical analyses accounted for relevant risk factors such as ethnicity and age [50], and although we did not have data on heredity information in a large set of subjects, only 2.2% were actually younger than 55 years of age, suggesting that hereditary prostate cancers were rare in our sample; iv) we used statistical strategies to

59 observed was probably not due to cis-regulatory SNPs altering the binding affinity of transcription factors. Therefore, we searched for evidence of cis-regulatory variants acting in different ways, for example, altering miRNA binding. This analysis showed predictions that 17 SNPs (including rs12302714) could alter miRNA binding affinity. Normally, miRNAs are associated to gene silencing through post-transcriptional binding to their target site (frequently in the 3’UTR of mRNA sequence), affecting the translation and the mRNA stability (Liu et al. 2012; Humphreys et al. 2005). There are studies that showed that the presence of SNPs in miRNA target site may regulate gene expression in an allele-specific manner (Wynendaele et al. 2010). Thus, miRNA regulation may be the mechanism causing DAE in the AACS gene. The preferential binding predicted for miRNA hsa-miR-4506 to the T allele of the candidate rSNP rs12302714, may suggest the association of the A allele of this SNP with gene expression regulation, since hypothetically, the mRNA containing the T allele in the 3’UTR will be silenced. More functional analysis is needed to validate the miRNA results, such as, microRNA functional analysis, in order to confirm the difference in binding affinity between the alleles of the 17 SNPs, and further test exactly how it affects the AACS gene expression.

The human GNMT gene is located at chromosome 6p12 and we previously reported that it has 3 polymorphic sites in the promoter region that may affect transcriptional activity: short tandem repeat 1 (STRP1), a (GA)n dinucleotide repeat polymor- phism, INS/DEL with insertion or deletion of a GAGT tetranucleotide, and rs10948059 [9,11,18]. A recent study in Italians by Ianni et al. showed that the GNMT rs9462856 T allele, which is also located in the promoter region upstream of rs10948059, was associated with increased prostate cancer risk [19]. Using the publicly available HapMap version 3, release R2 database, strong linkage disequilibrium was found between Ianni et al.’s rs9462856 and rs10948059 (D 9 = 1.000 and r 2 = 0.760 in Utah residents with Northern and Western European ancestry from the CEPH collection and D 9 = 0.946 and r 2 = 0.737 in Han Chinese in Beijing, China). In this study, we tried to determine the association of the GNMT polymorphisms STRP1, INS/DEL and rs10948059 and prostate cancer risk in Americans of European ancestry.

lop cancer than those without HGPIN (36.3% vs. 25%) (17). The clinical importance of recognizing HGPIN is based on its strong association with PCa, so its identification in biopsy specimens warrants further search for concurrent invasive carcinoma. Follow-up biopsy is suggested at 3 to 6 months for 2 years, and thereafter at 12 month intervals for life (18). Nevertheless, no factors seem to be useful in identifying which patients with HGPIN are at risk of PCa progression. Currently, routine treatment is not available for patients who have HGPIN. Prophylactic radical prostatectomy, radia- tion, and androgen deprivation are not acceptable treatments for patients who have HGPIN only (19). The development and identification of acceptable agents to treat HGPIN would fill a therapeutic void. In a meta-analysis of 9186 men with diabetes and PCa, Stopsack et al. showed that metformin decre- ased biochemical recurrence and improved overall

The genetic population based studies are mainly aimed at identifying groups at a higher risk of developing a cancer or at a higher risk of having a cancer with a worse prognosis. The case control popu- lation based researches are often biased by not con- trollable factors especially when the sample size is limited. Moreover, the results of genetic studies are complicated by the wide heterogeneity between dif- ferent ethnic groups. To draw any conclusion from genetic statistics we need wide sample sizes, from different regions to compare the results of different ethnic groups.

To date, no meta analysis has evaluated the relationship between polymorphisms in Gemin3 or Gemin4 and cancer risk. Our study selected seven articles, with a pooled total of 2,588 cases and 2,549 controls, relevant to the relationship between the rs7813 SNP and cancer risk, and we found a significant increase in cancer risk for TT relative to TC + CC (TT vs. TC + CC, OR = 1.18, 95% CI [1.05–1.32]. In addition, this association was significant in the Caucasian subgroup (OR = 1.20, 95% CI [1.03–1.39]). The results regarding the Gemin4 rs2740348 SNP were controversial. For this analysis, 6 articles were included, and the pooled OR was a critical value (GG vs. GC + CC, OR = 95% CI [1.00–1.43]). However, we did not conclude that this SNP may increase the incidence of cancer. Had we collected more related studies and a larger sample size, our data would have been more convincing. The P-values and Z -scores of meta-analyses are widely used to evaluate low-frequency and rare variants. In our study, the P-values for rs7813 (P = 0.006)

Interferon Regulatory Factor 1 (IRF-1) is a member of the IRF family of transcription factors, which have key and diverse roles in the gene-regulatory networks of the immune system. IRF-1 has been described as a critical mediator of IFN-gamma signalling and as the major player in driving TH1 type responses. It is therefore likely to be crucial in both innate and adaptive responses against intracellular pathogens such as Plasmodium falciparum. Polymorphisms at the human IRF1 locus have been previously found to be associated with the ability to control P. falciparum infection in populations naturally exposed to malaria. In order to test whether genetic variation at the IRF1 locus also affects the risk of developing severe malaria, we performed a family-based test of association for 18 Single Nucleotide Polymorphisms (SNPs) across the gene in three African populations, using genotype data from 961 trios consisting of one affected child and his/her two parents (555 from The Gambia, 204 from Kenya and 202 from Malawi). No significant association with severe malaria or severe malaria subphenotypes (cerebral malaria and severe malaria anaemia) was observed for any of the SNPs/haplotypes tested in any of the study populations. Our results offer no evidence that the molecular pathways regulated by the transcription factor IRF-1 are involved in the immune-based pathogenesis of severe malaria.

In contrast, several studies have found that HPV DNA is not preferentially associated with either BPH or prostate cancer. Tachezy et al. (2012) found no association between the persistence of HPV infection and the risk of developing prostate cancer, reporting the same prevalence of HPV DNA (2%) in 210 samples of tissues from 95 pa- tients with BPH and in 90 samples of 51 patients with pros- tatic cancer. Other studies have detected HPV DNA sequences in approximately 12–65% of malignant and in 5–48% of benign prostatic samples, and no statistically sig- nificant difference was shown (Carozzi et al., 2004; Aghakhani et al., 2011; Chen et al., 2011; Ghasemian et al., 2013). Based on these findings, it can be concluded that the prostate gland is a potential reservoir for transmission of HPV types with oncogenic potential. However, the HPV DNA findings in prostate tissue do not necessarily reflect active infection, or that the prostatic disease was caused by HPV; they could very well represent transient infections. Thus, while the prostate may act as a site for HPV replica- tion, it is unlikely that HPV is directly involved in the trans- formation of prostatic cells (Dodd et al., 1993; Aghakhani et al., 2011). On the other hand, the presence of high-risk HPV DNA in subsets of prostate cancers shows that at least

Table S1 Combined Effects of H. pylori Infection and Smoking on the Association between IL10 Genetic Variants and the Risk of Advanced Atrophy and Intestinal Metaplasia in the Antrum and Body of the Stomach. We evaluated the associations between either intestinal metaplasia or atrophy [advanced stage (grade 2 + grade 3) vs. early stage (grade 0 + grade 1)] and IL10 SNPs, and the combined effect of H. pylori infection and smoking on these associations. The Figure 1. Effects of Environmental Factors on the Association between IL10 Polymorphisms and the Risk of Noncardia Gastric Cancer. H. pylori (Hp) infection and smoking (S) were selected as environmental risk factors, and IL10 promoter genetic variants (-1082/-819/-592) were investigated. Since IL10-819 and -592 were found to be in complete linkage disequilibrium, we presented the data for IL10-1082 (A) and -592 (B). Noncardia gastric cancer was stratified by histological type. Multiple logistic regression was adjusted for age, sex, alcohol consumption, education, and income. The significance of the interactions between genetic variants and environmental risk factors was assessed with a likelihood ratio test, which compared a model that included the interaction term with one that only contained the main effects.

restrictions were placed on language, time period, sample size, type of study and population. All eligible articles were retrieved and their references were checked for other relevant studies. The inclusion criteria were: (1) studies which evaluated associations between GSTM1, GSTT1, GSTP1 polymorphisms and PCa risk; (2) control population did not contain malignant tumor patients. The exclusion reasons of studies were: (1) insufficient original data for the calculation of odds ratios (ORs) with corresponding 95% confidence intervals (95%CIs); (2) when multiple reports were available for the same study population, we included only the most recent or the largest report. Two investigators independently reviewed the titles, abstracts to determine if an individual study was eligible for the inclusion and exclusion criteria and all disagreements were resolved during a consensus meeting among all reviewers.

Though the most of the associations between genetic variants and cancer risk that were assessed in this study do not replicate between ethnic groups, this does not establish that there is no consistency of association for these variants across ethnic groups. Indeed, a survey of the odds ratios and confidence intervals in the studied loci suggests that the effect on cancer risk associated with the studied alleles may often be consistent across ethnic boundaries (Fig. 2, lung, gastric, liver, and prostate cancer; Fig. S1, breast cancer; Fig. S2, colorectal carcinoma). Though considerable variation is apparent among the ethnic groups, the direction of the association is often conserved. To more rigorously evaluate this, the differences of the odds ratio between ethnic groups was assessed using the Breslow-Day test with Tarone’s adjustment [30] to determine whether there was significant heterogeneity among ethnic groups. The Breslow-Day test assesses the homogeneity of the odds ratio across contingency tables and has an approximate chi-squared distribution. Loci were excluded if incomplete case and control numbers for each ethnic group were not reported. Only a minority of loci showed significant heterogeneity among ethnic groups (25%, 15/60 SNPs, Table 2). There were some differences between the cancer types, with two out of the four tested loci in gastric cancer showing significant heterogeneity, but the number of loci is too small to statistically determine if there is a meaningful difference in heterogeneity between the different cancers. Excluding gastric cancer, loci exhibiting significant heterogeneity were in the minority, ranging from 8% (colon cancer) to 40% (prostate cancer). If the analysis is restricted to only include data from populations where a significant result was found or the study was well powered, similar results are found, with 67% (28/42) of loci showing non-significant heterogeneity among ethnic groups (data not shown). As discoveries of significant risk associations in small populations could skew the results, the analysis was also performed excluding discovery populations whose number of total participants were less than the 10 th percentile of this entire study (N,548). The results were not

The evolutionary forces of mutation, natural selection, genetic drift, and recombination have shaped the pattern of variation in the human genome. Natural selection, which acts on functionally important genetic variations that result in alteration of fitness, such as adaptation to local environment and disease susceptibility, may leave specific signatures on affected loci [18], and analysis of genetic variation in populations is becoming central to understanding the function of genes [19,20]. Screening for signatures of natural selection may help uncover novel functional elements. Therefore, we used this approach to determine whether evidence of selection could be detected within the 30 kb FHIT intronic region. We conducted a re-sequencing survey and analyzed linkage disequilibrium (LD) and haplotype structure in sequences from intron 5 of FHIT in European American, Yoruban, and Japanese populations, and several non- human primates. Based on these data, we refined the region associated with prostate cancer risk to a 15 Kb LD block and revealed strong signatures of selection in multiple human popula- tions and, possibly, other primate species.

The work was aimed to determine the influence of aluminium in the amount from about 0.6% to about 2.8% on the structure of cast iron treated with cerium mischmetal and subjected to graphitizing modification with 75% ferrosilicon. Four experimental melts were held during the investigation. The charge was composed of the specially prepared grey iron, containing the basic elements within the presumed limits. While determining the desirable quantity of carbon in the charge cast iron, two contradicting conditions were taken into account, i.e. that the purpose is to achieve the nodular cast iron (which means that the relatively large carbon amount would be demanded) and that introducing aluminium to the melt results in the decreased solubility of carbon in cast steel. Taking this into account, it was stated that the quantity of carbon in the charge cast iron should be maintained within the range of 3.2÷3.4%. It has been assumed that the silicon content in the charge material should fall within 0.7÷1.0%, as it was during the former investigations. Manganese content was restricted to 0.1% maximally in order to achieve the desired structure with ferrite fraction as high as possible. It has been also assumed that the content of both sulphur and phosphor should be at the possible lowest level.

hormones, also known as the back door pathway, allows them to proliferate by binding to the androgen response element in the genome to trigger various signal transduction pathways; indings that have changed the understanding of castration resistance. Non-genomic signalling, via MAP kinases/ERK and PI3K pathways, results in the direct stimulation of prostate cancer cells; the complexity of this signalling cross talk, in addition to the thousands of genes that are regulated by the androgen receptor, allows for potential therapeutic intervention at various stages.

Phosphorus, which can be introduced to metal bath in free form, as a master alloy or a salt, belong to well-known modifiers of hypereutectic silumins. It has been confirmed [2] that in such case the aluminum phosphide, AlP, becomes the nucleus of the crystallization. In the studies [11-12] is presented a new view on interaction of phosphorus in process of modification of hypereutectic silumins, which is an effect of local overcooling in micro-areas caused by evaporation and expansion of bubbles of phosphorus vapours. Indispensable quantity of phosphorus in the alloy was determined as interval of 0,01 ÷ 0,05 % [1-3].