Genetic variation: effect on prostate cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Sissung TM
PROVIDER: S-EPMC4260983 | biostudies-literature | 2014 Dec
REPOSITORIES: biostudies-literature
Publications
Genetic variation: effect on prostate cancer.
Sissung Tristan M TM Price Douglas K DK Del Re Marzia M Ley Ariel M AM Giovannetti Elisa E Figg William D WD Danesi Romano R
Biochimica et biophysica acta 20140906 2
The crucial role of androgens in the development of prostate cancer is well established. The aim of this review is to examine the role of constitutional (germline) and tumor-specific (somatic) polymorphisms within important regulatory genes of prostate cancer. These include genes encoding enzymes of the androgen biosynthetic pathway, the androgen receptor gene, genes that encode proteins of the signal transduction pathways that may have a role in disease progression and survival, and genes invol ...[more]
Similar Datasets
Project description:BACKGROUND:Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls. METHODS:We undertook a genome-wide association study (GWAS) of screen-detected prostate cancer (ProtecT: 1,146 cases and 1,804 controls); meta-analyzed the results with those from the previously published UK Genetic Prostate Cancer Study (1,854 cases and 1,437 controls); investigated associations of SNPs with prostate cancer using either "low" (PSA < 0.5 ng/mL) or "high" (PSA ? 3 ng/mL, biopsy negative) PSA controls; and investigated associations of SNPs with PSA. RESULTS:The ProtecT GWAS confirmed previously reported associations of prostate cancer at three loci: 10q11.23, 17q24.3, and 19q13.33. The meta-analysis confirmed associations of prostate cancer with SNPs near four previously identified loci (8q24.21,10q11.23, 17q24.3, and 19q13.33). When comparing prostate cancer cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849, and rs2735839 were associated with an increased risk of prostate cancer, but the effect-estimates were attenuated to the null when using high PSA controls (Pheterogeneity in effect-estimates < 0.04). We found a novel inverse association of rs9311171-T with circulating PSA. CONCLUSIONS:Differences in effect-estimates for prostate cancer observed when comparing low versus high PSA controls may be explained by associations of these SNPs with PSA. IMPACT:These findings highlight the need for inferences from genetic studies of prostate cancer risk to carefully consider the influence of control selection criteria.
| S-EPMC4082405 | biostudies-literature
Project description:Collective evidence suggests that cyclooxygenase 2 (COX2) plays a role in prostate cancer risk. Cyclooxygenase 2 is the major enzyme that converts arachidonic acid to prostaglandins, which are potent mediators of inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic activity of COX2 and long-term use of NSAIDs appears to modestly lower the risk of prostate cancer. We investigated whether common genetic variation in COX2 influences the risk of advanced prostate cancer. Nine single-nucleotide polymorphisms (SNPs) in COX2 were genotyped among 1012 men in our case-control study of advanced prostate cancer. Gene-environment interactions between COX2 polymorphisms and NSAID use were also evaluated. Information on NSAID use was obtained by questionnaire. Three SNPs demonstrated nominally statistically significant associations with prostate cancer risk, with the most compelling polymorphism (rs2745557) associated with a lower risk of disease (odds ratio (OR) GC vs GG=0.64; 95% confidence interval (CI): 0.49-0.84; P=0.002). We estimated through permutation analysis that a similarly strong result would occur by chance 2.7% of the time. Nonsteroidal anti-inflammatory drug use was associated with a lower risk of disease in comparison to no use (OR=0.67; 95% CI: 0.52-0.87). No significant statistical interaction between NSAID use and rs2745557 was observed (P=0.12). Our findings suggest that variation in COX2 is associated with prostate cancer risk.
| S-EPMC2360347 | biostudies-literature
Project description:A considerable fraction of prostate cancers harbor a gene fusion between the androgen-regulated TMPRSS2 and ERG, one of the most frequently over-expressed proto-oncogenes in prostate cancer. Here, we investigated if inherited genetic variation upstream of ERG alters prostate cancer risk and survival.We genotyped 21 haplotype tagging SNPs (htSNPs) covering 123 kb of 5'UTR DNA including exon 3 of ERG in 2,760 incident prostate cancer cases and 1,647 controls from a population-based Swedish case-control study (CAPS). Individual SNPs and haplotypes were tested for association with prostate cancer risk and survival.One haplotype-'CTCGTATG' located 100 kb upstream of ERG-was associated with lethal prostate cancer (HR, 1.36; 95% CI, 1.2-1.9, p = 0.006). Carriers of the variant 'T' allele of rs2836626 were diagnosed with higher TNM-stage (p = 0.009) and had an increased risk of prostate cancer-specific death (HR = 1.3; 95% CI, 1.1-1.7, p = 0.009). However, this association did not remain statistically significant after adjusting for multiple testing. We found overall no association between ERG variation and prostate cancer risk.Genetic variation upstream of ERG may alter prostate cancer stage and ultimately prostate cancer-specific death but it is unlikely that it plays a role in prostate cancer development.
| S-EPMC3755494 | biostudies-literature
Project description:Inflammation has been hypothesized to play an important etiological role in the initiation or progression of prostate cancer. Circulating levels of the systemic inflammation marker C-reactive protein (CRP) have been associated with increased risk of prostate cancer. We investigated the role of genetic variation in CRP and prostate cancer, under the hypothesis that variants may alter risk of disease.We undertook a case-control study nested within the prospective Physicians' Health Study among 1,286 men with incident prostate cancer and 1,264 controls. Four single-nucleotide polymorphisms (SNPs) were selected to capture the common genetic variation across CRP (r(2) ?>?0.8). We used unconditional logistic regression to assess the association between each SNP and risk of prostate cancer. Linear regression models explored associations between each genotype and plasma CRP levels.None of the CRP SNPs were associated with prostate cancer overall. Individuals with one copy of the minor allele (C) in rs1800947 had an increased risk of high-grade prostate cancer (OR: 1.7; 95% CI: 1.1-2.8), and significantly lower mean CRP levels (P-value <0.001), however, we found no significant association with lethal disease. Mean CRP levels were significantly elevated in men with one or two copies of the minor allele in rs3093075 and rs1417939, but these were unrelated to prostate cancer risk.Our findings suggest that SNPs in the CRP gene are not associated with risk of overall or lethal prostate cancer. Polymorphisms in CRP rs1800947 may be associated with higher grade disease, but our results require replication in other cohorts.
| S-EPMC4063346 | biostudies-literature
Project description:Variation in genes contributing to the host immune response may mediate the relationship between inflammation and prostate carcinogenesis. RNASEL at chromosome 1q25 encodes ribonuclease L, part of the interferon-mediated immune response to viral infection. We therefore investigated the association between variation in RNASEL and prostate cancer risk and progression in a study of 1286 cases and 1264 controls nested within the prospective Physicians' Health Study. Eleven single-nucleotide polymorphisms (SNPs) were selected using the web-based 'Tagger' in the HapMap CEPH panel (Utah residents of Northern and Western European Ancestry). Unconditional logistic regression models assessed the relationship between each SNP and incident advanced stage (T(3)/T(4), T(0)-T(4)/M(1) and lethal disease) and high Gleason grade (>/=7) prostate cancer. Further analyses were stratified by calendar year of diagnosis. Cox proportional hazards models examined the relationship between genotype and prostate cancer-specific survival. We also explored associations between genotype and serum inflammatory biomarkers interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-alpha receptor 2 using linear regression. Individuals homozygous for the variant allele of rs12757998 had an increased risk of prostate cancer [AA versus GG; odds ratio (OR): 1.63, 95% confidence interval (CI): 1.18-2.25), and more specifically, high-grade tumors (OR: 1.90, 95% CI: 1.25-2.89). The same genotype was associated with increased CRP (P = 0.02) and IL-6 (P = 0.05) levels. Missense mutations R462Q and D541E were associated with an increased risk of advanced stage disease only in the pre-prostate-specific antigen era. There were no significant associations with survival. The results of this study support a link between RNASEL and prostate cancer and suggest that the association may be mediated through inflammation. These novel findings warrant replication in future studies.
| S-EPMC2930803 | biostudies-literature
Project description:Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17beta-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Delta5-androsterone-3beta,17beta-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.
| S-EPMC1287955 | biostudies-literature
Project description:The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648?kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC?=?0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.
| S-EPMC7089954 | biostudies-literature
Project description:Antioxidants may reduce risk of aggressive prostate cancer, and single-nucleotide polymorphisms (SNP) in antioxidant genes may modify this association.We used Cox proportional hazards regression to examine circulating prediagnostic ?-tocopherol, ?-tocopherol, and lycopene; SNPs in SOD2 (n = 5), CAT (n = 6), GPX1 (n = 2), GPX4, (n = 3); and their interactions and risk of lethal prostate cancer among 2,439 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study and Physicians' Health Study.We observed 223 events over a median follow-up of 10 years. Higher ?-tocopherol levels were associated with lower risk of lethal prostate cancer [HR 3rd versus 1st quartile (Q): 0.51; 95% confidence interval (CI), 0.30-0.89; HR 4th versus 1st Q: 0.68; 95% CI, 0.41-1.13; P trend: 0.02]. Men homozygous for the less common allele (G) at rs3746165 in GPX4 had a 35% lower risk of lethal prostate cancer compared with men homozygous for the more common allele (A; HR, 0.65; 95% CI, 0.43-0.99). Among men homozygous for the less common allele in rs3746165, high ?-tocopherol levels were associated with a 3.5-fold increased risk of lethal prostate cancer (95% CI, 1.27-9.72; P value, 0.02; interaction P value, 0.01).Among men with nonmetastatic prostate cancer, higher circulating prediagnostic ?-tocopherol may be associated with lower risk of developing lethal disease. Variants in GPX4 may be associated with risk of lethal prostate cancer, and may modify the relation between ?-tocopherol and prostate cancer survival.Circulating tocopherol levels and variants in GPX4 may affect prostate cancer progression. Cancer Epidemiol Biomarkers Prev; 23(6); 1037-46. ©2014 AACR.
| S-EPMC4047147 | biostudies-literature
Project description:Bony metastases cause substantial morbidity and mortality from prostate cancer (PCa). The calcium-sensing receptor (CaSR) is expressed on prostate tumors and may participate in bone metastases development. We assessed whether (i) common genetic variation in CaSR was associated with PCa risk and (ii) these associations varied by calcium intake or plasma 25-hydroxyvitamin D [25(OH)D] levels.We included 1,193 PCa cases and 1,244 controls nested in the prospective Health Professionals Follow-up Study (1993-2004). We genotyped 18 CaSR single-nucleotide polymorphism (SNPs) to capture common variation. The main outcome was risk of lethal PCa (n = 113); secondary outcomes were overall (n = 1,193) and high-grade PCa (n = 225). We used the kernel machine approach to conduct a gene-level multimarker analysis and unconditional logistic regression to compute per-allele ORs and 95% confidence intervals (CI) for individual SNPs.The joint association of SNPs in CaSR was significant for lethal PCa (P = 0.04); this association was stronger in those with low 25(OH)D (P = 0.009). No individual SNPs were associated after considering multiple testing; three SNPs were nominally associated (P < 0.05) with lethal PCa with ORs (95% CI) of 0.65(0.42-0.99): rs6438705; 0.65(0.47-0.89): rs13083990; and 1.55(1.09-2.20): rs2270916. The three nonsynonymous SNPs (rs1801725, rs1042636, and rs1801726) were not significantly associated; however, the association for rs1801725 was stronger in men with low 25(OH)D [OR(95%CI): 0.54(0.31-0.95)]. There were no significant associations with overall or high-grade PCa.Our findings indicate that CaSR may be involved in PCa progression.Further studies investigating potential mechanisms for CaSR and PCa, including bone remodeling and metastases are warranted.
| S-EPMC3538912 | biostudies-literature
Project description:Dietary intake of long-chain omega-3 (LC n-3) polyunsaturated fatty acids may reduce inflammation and in turn decrease risk of prostate cancer development and progression. This potential effect may be modified by genetic variation in cyclooxygenase-2 (COX-2), a key enzyme in fatty acid metabolism and inflammation.We used a case-control study of 466 men diagnosed with aggressive prostate cancer and 478 age- and ethnicity-matched controls. Diet was assessed with a semiquantitative food frequency questionnaire, and nine COX-2 tag single nucleotide polymorphisms (SNP) were genotyped. We used logistic regression models to estimate odds ratios (OR) for association and interaction.Increasing intake of LC n-3 was strongly associated with a decreased risk of aggressive prostate cancer (P(trend) <or= 0.0001). The OR (95% confidence interval) for prostate cancer comparing the highest with the lowest quartile of n-3 intake was of 0.37 (0.25-0.54). The LC n-3 association was modified by SNP rs4648310 (+8897 A/G), flanking the 3' region of COX-2 (P(interaction) = 0.02). In particular, the inverse association was even stronger among men with this variant SNP. This reflected the observation that men with low LC n-3 intake and the variant rs4648310 SNP had an increased risk of disease (OR, 5.49; 95% confidence interval, 1.80-16.7), which was reversed by increasing intake of LC n-3.Dietary LC n-3 polyunsaturated fatty acids appear protective for aggressive prostate cancer, and this effect is modified by the COX-2 SNP rs4648310. Our findings support the hypothesis that LC n-3 may impact prostate inflammation and carcinogenesis through the COX-2 enzymatic pathway.
| S-EPMC2749066 | biostudies-literature