SwePub - search: WFRF:(Mucci Lorelei A.)

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1.	Wang, Anqi, et al. (author) Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants 2023 In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074 Journal article (peer-reviewed)abstract The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
2.	Conti, David, V, et al. (author) Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction 2021 In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75 Journal article (peer-reviewed)abstract Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
3.	Law, Philip J., et al. (author) Association analyses identify 31 new risk loci for colorectal cancer susceptibility 2019 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10 Journal article (peer-reviewed)abstract Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
4.	Watts, Eleanor L., et al. (author) Observational and genetic associations between cardiorespiratory fitness and cancer : a UK Biobank and international consortia study 2024 In: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 130, s. 114-124 Journal article (peer-reviewed)abstract Background: The association of fitness with cancer risk is not clear.Methods: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method.Results: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min−1⋅kg−1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73–0.89), colorectal (0.94, 0.90–0.99), and breast cancer (0.96, 0.92–0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min−1⋅kg−1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86–0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated.Discussion: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.
5.	Adams, Charleen, et al. (author) Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study 2019 In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:1, s. 208-216 Journal article (peer-reviewed)abstract BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
6.	Brandão, Andreia, et al. (author) The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor 2020 In: Cancers. - : MDPI AG. - 2072-6694. ; 12:11 Journal article (peer-reviewed)abstract The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
7.	Matejcic, Marco, et al. (author) Germline variation at 8q24 and prostate cancer risk in men of European ancestry 2018 In: Nature Communications. - : Springer Nature. - 2041-1723. ; 9 Journal article (peer-reviewed)abstract Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 x 10(-15)), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95% CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for similar to 25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.
8.	Watts, Eleanor L., et al. (author) Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer : a collaborative analysis of 20 prospective studies and Mendelian randomization analysis 2023 In: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 52:1, s. 71-86 Journal article (peer-reviewed)abstract Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer.Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium.Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I.Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.
9.	Watts, Eleanor L., et al. (author) The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 in a pooled analysis of 16,024 men from 22 studies 2019 In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 145:12, s. 3244-3256 Journal article (peer-reviewed)abstract Insulin‐like growth factors (IGFs) and insulin‐like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross‐sectional associations of these exposures with circulating concentrations of IGFs (IGF‐I and IGF‐II) and IGFBPs (IGFBP‐1, IGFBP‐2 and IGFBP‐3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22–89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGF‐I, IGF‐II and IGFBP‐3. Higher body mass index was associated with lower concentrations of IGFBP‐1 and IGFBP‐2. Taller height was associated with higher concentrations of IGF‐I and IGFBP‐3 and lower concentrations of IGFBP‐1. Smokers had higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGFBP‐3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF‐II and lower concentrations of IGF‐I and IGFBP‐2. African Americans had lower concentrations of IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 and Hispanics had lower IGF‐I, IGF‐II and IGFBP‐3 than non‐Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.
10.	Watts, Eleanor L., et al. (author) Circulating free testosterone and risk of aggressive prostate cancer : Prospective and Mendelian randomisation analyses in international consortia 2022 In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 151:7, s. 1033-1046 Journal article (peer-reviewed)abstract Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet =.0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.
11.	Wu, Lang, et al. (author) Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk : A Transcriptome-Wide Association Study in over 140,000 European Descendants 2019 In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 79:13, s. 3192-3204 Journal article (peer-reviewed)abstract Genome-wide association study-identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 x 10(-6), a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 x 10(-6) after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. Significance: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.
12.	Andrén, Ove, 1963-, et al. (author) MUC-1 gene is associated with prostate cancer death : a 20-year follow-up of a population-based study in Sweden 2007 In: British Journal of Cancer. - London : Harcourt Publishers. - 0007-0920 .- 1532-1827. ; 97:6, s. 730-734 Journal article (peer-reviewed)abstract Anti-adhesion mucins have proven to play an important part in the biology of several types of cancer. Therefore, we test the hypothesis that altered expression of MUC-1 is associated with prostate cancer progression. We retrieved archival tumour tissue from a population-based cohort of 195 men with localised prostate cancer (T1a-b, Nx, M0) that has been followed for up to 20 years with watchful waiting. Semi-automated, quantitative immunohistochemistry was undertaken to evaluate MUC-1 expression. We modelled prostate cancer-specific death as a function of MUC-1 levels accounting for age, Gleason grade and tumour extent, and calculated age-adjusted and multivariate adjusted hazard ratios (HR). Men that had tumours with an MUC-intensity lower or higher than normal tissue had a higher risk of dying in prostate cancer, independent of tumour extent and Gleason score (HR 5.1 and 4.5, respectively). Adjustment for Gleason grade and tumour stage did not alter the results. Men with a Gleason score >=7 and MUC-1 deviating from the normal had a 17 (RR=17.1 95% confidence interval=2.3–128) times higher risk to die in prostate cancer compared with men with Gleason score <7 and normal MUC-1 intensity. In summary, our data show that MUC-1 is an independent prognostic marker for prostate cancer death.
13.	Dickerman, Barbra A., et al. (author) Midlife metabolic factors and prostate cancer risk in later life 2018 In: International Journal of Cancer. - Hoboken, USA : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 142:6, s. 1166-1173 Journal article (peer-reviewed)abstract Metabolic syndrome is associated with several cancers, but evidence for aggressive prostate cancer is sparse. We prospectively investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a cohort of Icelandic men. Men in the Reykjavik Study (n = 9,097, enrolled 1967-1987) were followed for incident (n = 1,084 total; n = 378 advanced; n = 148 high-grade) and fatal (n = 340) prostate cancer until 2014. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for (1) measured metabolic factors at cohort entry (body mass index (BMI), blood pressure, triglycerides, fasting blood glucose) and (2) a metabolic syndrome score (range 0-4) combining the risk factors: BMI ≥30 kg/m2 ; systolic blood pressure (SBP) ≥130 or diastolic blood pressure (DBP) ≥85 mm Hg or taking antihypertensives; triglycerides ≥150 mg/dl; fasting blood glucose ≥100 mg/dl or self-reported type 2 diabetes. Hypertension and type 2 diabetes were associated with a higher risk of total, advanced, high-grade, and fatal prostate cancer, independent of BMI. Neither BMI nor triglycerides were associated with prostate cancer risk. Higher metabolic syndrome score (3-4 vs 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p trend = 0.08), although this finding was not statistically significant. Our findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer.
14.	Setlur, Sunita R., et al. (author) Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer 2008 In: Journal of the National Cancer Institute. - Oxford : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:11, s. 815-825 Journal article (peer-reviewed)abstract BACKGROUND: The majority of prostate cancers harbor gene fusions of the 5'-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion. METHODS: We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians(') Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided. RESULTS: We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P < .001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERbeta agonist (ERbeta agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERbeta agonist treatment (fold change over internal control, ERbeta agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95% CI = 0.29- to 0.57-fold) and increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34- to 4.92-fold). CONCLUSIONS: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.
15.	Sigurdardottir, Lara G., et al. (author) Pineal Gland Volume Assessed by MRI and Its Correlation with 6-Sulfatoxymelatonin Levels among Older Men 2016 In: Journal of Biological Rhythms. - Thousand Oaks, USA : Sage Publications. - 0748-7304 .- 1552-4531. ; 31:5, s. 461-469 Journal article (peer-reviewed)abstract The pineal gland produces the hormone melatonin, and its volume may influence melatonin levels. We describe an innovative method for estimating pineal volume in humans and present the association of pineal parenchyma volume with levels of the primary melatonin metabolite, 6-sulfatoxymelatonin. We selected a random sample of 122 older Icelandic men nested within the AGES-Reykjavik cohort and measured their total pineal volume, their parenchyma volume, and the extent of calcification and cysts. For volume estimations we used manual segmentation of magnetic resonance images in the axial plane with simultaneous side-by-side view of the sagittal and coronal plane. We used multivariable adjusted linear regression models to estimate the association of pineal parenchyma volume and baseline characteristics, including 6-sulfatoxymelatonin levels. We used logistic regression to test for differences in first morning urinary 6-sulfatoxymelatonin levels among men with or without cystic or calcified glands. The pineal glands varied in volume, shape, and composition. Cysts were present in 59% of the glands and calcifications in 21%. The mean total pineal volume measured 207 mm(3) (range 65-536 mm(3)) and parenchyma volume 178 mm(3) (range 65-503 mm(3)). In multivariable-adjusted models, pineal parenchyma volume was positively correlated with 6-sulfatoxymelatonin levels (β = 0.52, p < 0.001). Levels of 6-sulfatoxymelatonin did not differ significantly by presence of cysts or calcification. By using an innovative method for pineal assessment, we found pineal parenchyma volume to be positively correlated with 6-sulfatoxymelatonin levels, in line with other recent studies.
16.	Sigurdardottir, Lara G., et al. (author) Sleep disruption among older men and risk of prostate cancer 2013 In: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 22:5, s. 872-879 Journal article (peer-reviewed)abstract Background: Although positive associations have consistently been reported between sleep disruption and breast cancer, less is known about its potential role in prostate cancer.Methods: Within the prospective AGES-Reykjavik cohort study, we followed 2,102 men recruited in 20022006 until the end of 2009. Participants answered questions on sleep disruption. Information on the occurrence of prostate cancer was obtained through record linkages across the Icelandic Cancer Registry. We used Cox regression models with 95% confidence intervals (CI) to estimate HRs of prostate cancer by symptoms of sleep disruption.Results: During follow-up, 135 men (6.4%) were diagnosed with prostate cancer. Compared with men without sleep disruption, those with problems falling and staying asleep were at significantly increased risk of prostate cancer [HR, 1.7 (95% CI, 1.0-2.9) and 2.1 (95% CI, 1.2-3.7)], respectively, with increasing sleep disruption severity. When restricted to advanced prostate cancer (>= stage T3 or lethal disease), these associations became even stronger [HR 2.1 (95% CI, 0.7-6.2) and 3.2 (95% CI, 1.1-9.7)]. The results did not change after excluding from the analyses men who woke up during the night, indicative of nocturia, suggesting limited risk of reverse association.Conclusions: Our data suggest that certain aspects of sleep disruption may confer an increased risk of prostate cancer and call for additional, larger studies with longer follow-up times.Impact: Prostate cancer is one of the leading public health concerns in men; if confirmed in future studies, the association between sleep disruption and prostate cancer risk may open new avenues for prevention.
17.	Sigurdardottir, Lara G., et al. (author) Urinary melatonin levels, sleep disruption, and risk of prostate cancer in elderly men 2015 In: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 67:2, s. 191-194 Journal article (peer-reviewed)abstract Melatonin has anticarcinogenic properties in experimental models. We undertook a case-cohort study of 928 Icelandic men without prostate cancer (PCa) nested within the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort to investigate the prospective association between first morning-void urinary 6-sulfatoxymelatonin (aMT6s) levels and the subsequent risk for PCa, under the hypothesis that men with lower aMT6s levels have an increased risk for advanced PCa. We used weighted Cox proportional hazards models to assess the association between first morning-void aMT6s levels and PCa risk, adjusting for potential confounders. A total of 111 men were diagnosed with incident PCa, including 24 with advanced disease. Men who reported sleep problems at baseline had lower morning aMT6s levels compared with those who reported no sleep problems. Men with morning aMT6s levels below the median had a fourfold statistically significant increased risk for advanced disease compared with men with levels above the median (hazard ratio: 4.04; 95% confidence interval, 1.26-12.98). These results require replication in larger prospective studies with longer follow-up.Patient summary: In this report, we evaluated the prospective association between urinary aMT6s levels and risk of PCa in an Icelandic population. We found that lower levels of aMT6s were associated with an increased risk for advanced PCa.
18.	Stopsack, Konrad H., et al. (author) Cholesterol Metabolism and Prostate Cancer Lethality 2016 In: Cancer Research. - : American Association for Cancer Research Inc.. - 0008-5472 .- 1538-7445. ; 76:16, s. 4785-4790 Journal article (peer-reviewed)abstract Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease.
19.	Lu, Donghao, et al. (author) Stress-Related Signaling Pathways in Lethal and Nonlethal Prostate Cancer 2016 In: Clinical cancer research : an official journal of the American Association for Cancer Research. - Philadelphia, USA : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 22:3, s. 765-772 Journal article (peer-reviewed)abstract Purpose: Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and nonlethal disease.Experimental design: We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n = 150; n = 82 with normal) and the Health Professionals Follow-Up Study (n = 254; n = 120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome and to biomarkers as secondary outcomes.Results: Differential mRNA expression of genes within the adrenergic (P = 0.001), glucocorticoid (P < 0.0001), serotoninergic (P = 0.0019), and muscarinic (P = 0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (P = 0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and nonlethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion.Conclusions: Our study suggests that stress-related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies.
20.	Markt, Sarah C, et al. (author) Insufficient Sleep and Risk of Prostate Cancer in a Large Swedish Cohort 2015 In: Sleep. - : American Academy of Sleep Medicine. - 0161-8105 .- 1550-9109. ; 38:9, s. 1405-1410 Journal article (peer-reviewed)abstract Study Objective: There are some data to suggest that insufficient sleep, including short sleep duration and sleep disruption, may be associated with an increased risk of cancer. We investigated the association between sleep duration and sleep disruption and risk of prostate cancer. Design: Prospective cohort study. Setting: Sweden. Participants: A total of 14,041 men in the Swedish National March Cohort. Interventions: None. Measurements and Results: Habitual sleep duration and sleep disruption were self-reported in 1997. Prostate cancer diagnoses, including lethal (metastases at diagnosis or death from prostate cancer) and advanced (stage T4, N1, or M1 at diagnosis or death from prostate cancer), were determined from linkage to nationwide cancer registries through 2010. We conducted Cox proportional hazards regression adjusted for potential confounding variables. During 13 years of follow-up, we identified 785 cases of incident prostate cancer, including 118 lethal and 127 advanced cases. Four percent of men reported sleeping 5 h or less a night, and 2% reported sleeping 9 h or more per night. We found no association between sleep duration and risk of prostate cancer overall or for advanced/lethal disease. We also did not find an association between prostate cancer and sleep disruption, as defined by difficulty falling asleep, difficulty maintaining sleep, sleep quality, and restorative power of sleep. Conclusions: In this large prospective study from Sweden, we found no association between habitual sleep duration or sleep disruption and risk of prostate cancer.
21.	Martin, Neil E., et al. (author) Measuring PI3K Activation : Clinicopathologic, Immunohistochemical, and RNA Expression Analysis in Prostate Cancer 2015 In: Molecular Cancer Research. - : American Association for Cancer Research. - 1541-7786 .- 1557-3125. ; 13:10, s. 1431-1440 Journal article (peer-reviewed)abstract Assessing the extent of PI3K pathway activity in cancer is vital to predicting sensitivity to PI3K-targeting drugs, but the best biomarker of PI3K pathway activity in archival tumor specimens is unclear. Here, PI3K pathway activation was assessed, in clinical tissue from 1,021 men with prostate cancers, using multiple pathway nodes that include PTEN, phosphorylated AKT (pAKT), phosphorylated ribosomal protein S6 (pS6), and stathmin. Based on these markers, a 9-point score of PI3K activation was created using the combined intensity of the 4-markers and analyzed its association with proliferation (Ki67), apoptosis (TUNEL), and androgen receptor (AR) status, as well as pathologic features and cancer-specific outcomes. In addition, the PI3K activation score was compared with mRNA expression profiling data for a large subset of men. Interestingly, those tumors with higher PI3K activation scores also had higher Gleason grade (P = 0.006), increased AR (r = 0.37; P < 0.001) and Ki67 (r = 0.24; P < 0.001), and decreased TUNEL (r = -0.12; P = 0.003). Although the PI3K activation score was not associated with an increased risk of lethal outcome, a significant interaction between lethal outcome, Gleason and high PI3K score (P = 0.03) was observed. Finally, enrichment of PI3K-specific pathways was found in the mRNA expression patterns differentiating the low and high PI3K activation scores; thus, the 4-marker IHC score of PI3K pathway activity correlates with features of PI3K activation.
22.	Mucci, Lorelei A., et al. (author) Circadian dysrhythm and advanced prostate cancer 2014 In: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 32:4 Journal article (other academic/artistic)abstract Background: The circadian rhythm regulates diverse biologic pathways including tumor oncogenes, metabolism, and cell proliferation. Dysregulation of the circadian rhythm arises from faulty input signals such as exposure to light at night, variability in core circadian rhythm genes, and variation in outputs that regulate circadian behavior including melatonin. There is compelling biologic rationale, but little human data, on circadian dysrhythm and advanced prostate cancer.Methods: We undertook an integrative molecular epidemiology study of circadian dysrhythm and advanced prostate cancer among men in the Icelandic AGES-Reykjavik cohort and the U.S. Health Professionals Follow-up Study, which allowed integration of questionnaire data, biorepositories, and long-term follow-up. We characterized circadian dysrhythm using complimentary approaches: information on sleep problems from questionnaires, prediagnostic melatonin (6-sulfatoxymelatonin) measured on first morning void urine samples, and genetic variation across twelve circadian clock genes. We used multivariable regression models to estimate relative risks (RR) and 95% confidence intervals (CI) of associations with advanced prostate cancer, adjusted for potential confounders.Results: Twenty percent of men reported sleep problems. Men who had trouble falling asleep (RR = 2.1; 95% CI 0.7-6.2) and staying asleep (RR=3.2, 95% CI 1.1-9.7) had an increased risk of developing advanced prostate cancer. Men with sleep problems had significantly lower melatonin levels compared to those without. Low melatonin levels were associated with a statistically significant 4-fold higher risk of advanced prostate cancer compared to those with high levels (95% CI: 1.25-10.0). Variant alleles in two SNPs in cryptochrome (CRY1), involved in generating and maintaining circadian rhythms, were significantly associated with risk of advanced prostate cancer in both cohorts, with a gene-level p-value<0.01.Conclusions: Our results suggest there are multiple nodes in the circadian rhythm that are associated with an increased risk of advanced prostate cancer. As such, there is the potential for complimentary strategies to target circadian disruption and reduce the risk of advanced prostate cancer.
23.	Mucci, Lorelei A., et al. (author) Nine-gene molecular signature is not associated with prostate cancer death in a watchful waiting cohort 2008 In: Cancer Epidemiology, Biomarkers and Prevention. - Baltimore : Waverly Press. - 1055-9965 .- 1538-7755. ; 17:1, s. 249-251 Journal article (peer-reviewed)abstract Tumor molecular markers hold promise to distinguish potentially lethal from indolent prostate cancer and to guide treatment choices. A previous study identified a nine-gene molecular signature in tumors associated with prostate-specific antigen relapse after prostatectomy. We examined this molecular model in relation to prostate cancer death among 172 men with initially localized disease. We quantified protein expression of the nine genes in tumors to classify progression risk. Accounting for clinical prognostic factors, the nine-gene model did not provide discrimination to predict lethal and indolent prostate cancer.
24.	Mucci, Lorelei A., et al. (author) Testing a multigene signature of prostate cancer death in the Swedish Watchful Waiting Cohort 2008 In: Cancer Epidemiology, Biomarkers and Prevention. - Philadelphia : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 17:7, s. 1682-1688 Journal article (peer-reviewed)abstract Although prostate cancer is a leading cause of cancer death, most men die with and not from their disease, underscoring the urgency to distinguish potentially lethal from indolent prostate cancer. We tested the prognostic value of a previously identified multigene signature of prostate cancer progression to predict cancer-specific death. The Örebro Watchful Waiting Cohort included 172 men with localized prostate cancer of whom 40 died of prostate cancer. We quantified protein expression of the markers in tumor tissue by immunohistochemistry and stratified the cohort by quintiles according to risk classification. We accounted for clinical variables (age, Gleason, nuclear grade, and tumor volume) using Cox regression and calculated receiver operator curves to compare discriminatory ability. The hazard ratio of prostate cancer death increased with increasing risk classification by the multigene model, with a 16-fold greater risk comparing highest-risk versus lowest-risk strata, and predicted outcome independent of clinical factors (P = 0.002). The best discrimination came from combining information from the multigene markers and clinical data, which perfectly classified the lowest-risk stratum where no one developed lethal disease; using the two lowest-risk groups as reference, the hazard ratio (95% confidence interval) was 11.3 (4.0-32.8) for the highest-risk group and difference in mortality at 15 years was 60% (50-70%). The combined model provided greater discriminatory ability (area under the curve = 0.78) than the clinical model alone (area under the curve = 0.71; P = 0.04). Molecular tumor markers can add to clinical variables to help distinguish lethal and indolent prostate cancer and hold promise to guide treatment decisions.
25.	Preston, Mark A., et al. (author) Baseline Prostate-specific Antigen Level in Midlife and Aggressive Prostate Cancer in Black Men 2019 In: European Urology. - : Elsevier BV. - 0302-2838. ; 75:3, s. 399-407 Journal article (peer-reviewed)abstract Background: Prostate-specific antigen (PSA) measurement in midlife predicts long-term prostate cancer (PCa) mortality among white men. Objective: To determine whether baseline PSA level during midlife predicts risk of aggressive PCa in black men. Design, setting, and participants: Nested case-control study among black men in the Southern Community Cohort Study recruited between 2002 and 2009. A prospective cohort in the southeastern USA with recruitment from community health centers. A total of 197 incident PCa patients aged 40–64 yr at study entry and 569 controls matched on age, date of blood draw, and site of enrollment. Total PSA was measured in blood collected and stored at enrollment. Outcome measurements and statistical analysis: Total and aggressive PCa (91 aggressive: Gleason ≥7, American Joint Committee on Cancer stage III/IV, or PCa-specific death). Exact conditional logistic regression estimated odds ratios (ORs) with 95% confidence intervals (CIs) for PCa by category of baseline PSA. Results and limitations: Median PSA among controls was 0.72, 0.80, 0.94, and 1.03 ng/ml for age groups 40–49, 50–54, 55–59, and 60–64 yr, respectively; 90th percentile levels were 1.68, 1.85, 2.73, and 3.33 ng/ml. Furthermore, 95% of total and 97% of aggressive cases had baseline PSA above the age-specific median. Median follow-up was 9 yr. The OR for total PCa comparing PSA >90th percentile versus ≤median was 83.6 (95% CI, 21.2–539) for 40–54 yr and 71.7 (95% CI, 23.3–288) for 55–64 yr. For aggressive cancer, ORs were 174 (95% CI, 32.3–infinity) for 40–54 yr and 51.8 (95% CI, 11.0–519) for 55–64 yr. A composite endpoint of aggressive PCa based on stage, grade, and mortality was used and is a limitation. Conclusions: PSA levels in midlife strongly predicted total and aggressive PCa among black men. PSA levels among controls were similar to those among white controls in prior studies. Patient summary: Prostate-specific antigen (PSA) level during midlife strongly predicted future development of aggressive prostate cancer among black men. Targeted screening based on a midlife PSA might identify men at high risk while minimizing screening in those men at low risk. Prostate-specific antigen (PSA) level during midlife strongly predicted total and aggressive prostate cancer among black men. Risk-stratified screening based on midlife PSA might retain the benefits of screening while reducing harms.

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