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Sökning: WFRF:(Kibel Adam S)

  • Resultat 11-16 av 16
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  • Matejcic, Marco, et al. (författare)
  • Germline variation at 8q24 and prostate cancer risk in men of European ancestry
  • 2018
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 9
  • Tidskriftsartikel (refereegranskat)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.
  • Szulkin, Robert, et al. (författare)
  • Prediction of individual genetic risk to prostate cancer using a polygenic score.
  • 2015
  • Ingår i: The Prostate. - 0270-4137 .- 1097-0045. ; 75:13, s. 1467-74
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction.METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls.RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk.CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
  • Preston, Mark A, et al. (författare)
  • Baseline Prostate-Specific Antigen Levels in Midlife Predict Lethal Prostate Cancer
  • 2016
  • Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 34:23, s. 2705-11
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostate-specific antigen (PSA) level in midlife predicted future prostate cancer (PCa) mortality in an unscreened Swedish population. Our purpose was to determine if a baseline PSA level during midlife predicts lethal PCa in a US population with opportunistic screening.We conducted a nested case-control study among men age 40 to 59 years who gave blood before random assignment in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and β-carotene among 22,071 US male physicians initiated in 1982 and then transitioned into a prospective cohort with 30 years of follow-up. Baseline PSA levels were available for 234 patients with PCa and 711 age-matched controls. Seventy-one participants who developed lethal PCa were rematched to 213 controls. Conditional logistic regression was used to estimate odds ratios and the area under the receiver operating characteristic curve, with 95% CIs, of the association between baseline PSA and risk of lethal PCa.Median PSA among controls was 0.68, 0.88, and 0.96 ng/mL for men age 40 to 49, 50 to 54, and 55 to 59 years, respectively. Risk of lethal PCa was strongly associated with baseline PSA in midlife: odds ratios (95% CIs) comparing PSA in the > 90th percentile versus less than or equal to median were 8.7 (1.0 to 78.2) at 40 to 49 years, 12.6 (1.4 to 110.4) at 50 to 54 years, and 6.9 (2.5 to 19.1) at 55 to 59 years. A total of 82%, 71%, and 86% of lethal cases occurred in men with PSA above the median at ages 40 to 49, 50 to 54, and 55 to 59 years, respectively.PSA levels in midlife strongly predict future lethal PCa in a US cohort subject to opportunistic screening. Risk-stratified screening on the basis of midlife PSA should be considered in men age 45 to 59 years.
  • Preston, Mark A., et al. (författare)
  • Baseline Prostate-specific Antigen Level in Midlife and Aggressive Prostate Cancer in Black Men
  • 2019
  • Ingår i: European Urology. - : Elsevier. - 0302-2838. ; 75:3, s. 399-407
  • Tidskriftsartikel (refereegranskat)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.
  • Shui, Irene M., et al. (författare)
  • Prostate Cancer (PCa) Risk Variants and Risk of Fatal PCa in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium
  • 2014
  • Ingår i: European Urology. - 0302-2838 .- 1873-7560. ; 65:6, s. 1069-1075
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM). Objective: To examine the association of 47 established PCa risk single-nucleotide polymorphisms (SNPs) with PCSM. Design, setting, and participants: We included 10 487 men who had PCa and 11 024 controls, with a median follow-up of 8.3 yr, during which 1053 PCa deaths occurred. Outcome measurements and statistical analysis: The main outcome was PCSM. The risk allele was defined as the allele associated with an increased risk for PCa in the literature. We used Cox proportional hazards regression to calculate the hazard ratios of each SNP with time to progression to PCSM after diagnosis. We also used logistic regression to calculate odds ratios for each risk SNP, comparing fatal PCa cases to controls. Results and limitations: Among the cases, we found that 8 of the 47 SNPs were significantly associated (p < 0.05) with time to PCSM. The risk allele of rs11672691 (intergenic) was associated with an increased risk for PCSM, while 7 SNPs had risk alleles inversely associated (rs13385191 [C2orf43], rs17021918 [PDLIM5], rs10486567 [JAZF1], rs6465657 [LMTK2], rs7127900 (intergenic), rs2735839 [KLK3], rs10993994 [MSMB], rs13385191 [C2orf43]). In the case-control analysis, 22 SNPs were associated (p < 0.05) with the risk of fatal PCa, but most did not differentiate between fatal and nonfatal PCa. Rs11672691 and rs10993994 were associated with both fatal and nonfatal PCa, while rs6465657, rs7127900, rs2735839, and rs13385191 were associated with nonfatal PCa only. Conclusions: Eight established risk loci were associated with progression to PCSM after diagnosis. Twenty-two SNPs were associated with fatal PCa incidence, but most did not differentiate between fatal and nonfatal PCa. The relatively small magnitudes of the associations do not translate well into risk prediction, but these findings merit further follow-up, because they may yield important clues about the complex biology of fatal PCa. Patient summary: In this report, we assessed whether established PCa risk variants could predict PCSM. We found eight risk variants associated with PCSM: One predicted an increased risk of PCSM, while seven were associated with decreased risk. Larger studies that focus on fatal PCa are needed to identify more markers that could aid prediction. (C) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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