| 111. |
- Wiklund, Fredrik, 1963-
(författare)
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Genetic epidemiology of prostate cancer
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer is a major health burden throughout the world, yet the etiology of prostate cancer is poorly understood. Evidence has accumulated supporting the existence of a hereditary form of this disease. Improved understanding of the genetic mechanisms underlying the development and progression of prostate cancer would be a major advance for improved prevention, detection and treatment strategies. This thesis evaluates different aspects of the genetic epidemiology of prostate cancer. In a genomic scan two chromosomal regions with evidence for linkage was observed. The strongest support was found on chromosome 19p with an allele sharing LOD score of 2.91 (genome-wide P = 0.032). The second region, showing suggestive evidence of linkage, was observed in the centromeric region of chromosome 5. Linkage analyses of densely spaced markers on chromosome 8p22-23 confirmed (P = 0.03) previously reported linkage to this region. A systematic evaluation of the possible impact that the RNASEL gene have on prostate cancer was performed. Overall, limited evidence for association with prostate cancer risk was found. The results provide strong evidence against a role of RNASEL in prostate cancer etiology in Sweden. In a comprehensive evaluation of occurrence of other malignancies in HPC families, previously reported association between gastric and prostate carcinoma was confirmed. The increased risk was of the same magnitude in early and late onset HPC families and confined to only male relatives. A genome-wide linkage analysis, stratified by occurrence of gastric carcinoma, identified a novel susceptibility locus on chromosome Xp21. In summary, chromosome 5q and 19p represents the regions most likely to harbor susceptibility genes predisposing to prostate cancer in the Swedish population. A common genetic basis for both gastric and prostate cancer has been confirmed and a novel susceptibility locus on chromosome Xp21 has been identified.
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| 112. |
- Wiklund, Fredrik, et al.
(författare)
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Lifetime total physical activity and prostate cancer risk : a population-based case-control study in Sweden
- 2008
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Ingår i: European Journal of Epidemiology. - Berlin : Springer. - 0393-2990 .- 1573-7284. ; 23:11, s. 739-746
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Tidskriftsartikel (refereegranskat)abstract
- The etiologic role of physical activity in prostate cancer development is unclear. We assessed the association between lifetime total physical activity and prostate cancer risk in a Swedish population-based case–control study comprising 1,449 incident prostate cancer cases and 1,118 unaffected population controls. Information regarding physical activity was obtained via a self-administered questionnaire assessing occupational, household, and recreational activity separately at various ages throughout an individual’s lifetime. Clinical data (TNM-classification, Gleason sum and PSA) was obtained from linkage to the National Prostate Cancer Registry. Overall, we observed no association between lifetime total physical activity and prostate cancer risk (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 0.77–1.41 for ≥49.7 vs. <41.9 metabolic equivalent-hours per day). There was a significantly increased risk of prostate cancer in the most active men compared with the least active men in household (OR = 1.44, 95% CI = 1.08–1.92) and recreational physical activity (OR = 1.56, 95% CI = 1.16–2.10). Comparing the most active with the least active men, total physical activity was not associated with either localized disease (OR = 0.95, 95% CI = 0.67–1.34) or advanced disease (OR = 1.19, 95% CI = 0.83–1.71). These findings do not support the hypothesis that physical activity uniformly protects against prostate cancer development.
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| 113. |
- Xu, Jianfeng, et al.
(författare)
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Estimation of absolute risk for prostate cancer using genetic markers and family history
- 2009
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 69:14, s. 1565-1572
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Multiple DNA sequence variants in the form of single-nucleotide polymorphisms (SNPs) have been found to be reproducibly associated with prostate cancer (PCa) risk. METHODS: Absolute risk for PCa among men with various numbers of inherited risk alleles and family history of PCa was estimated in a population-based case-control study in Sweden (2,893 cases and 1,781 controls), and a nested case-control study from the Prostate, Lung, Colon and Ovarian (PLCO) Cancer Screening Trial in the U.S. (1,172 cases and 1,157 controls). RESULTS: Increased number of risk alleles and positive family history were independently associated with PCa risk. Considering men with 11 risk alleles (mode) and negative family history as having baseline risk, men who had >or=14 risk alleles and positive family history had an odds ratio (OR) of 4.92 [95% confidence interval (CI): 3.64-6.64] in the Swedish study. These associations were confirmed in the U.S. population. Once a man's SNP genotypes and family history are known, his absolute risk for PCa can be readily calculated and easily interpreted. For example, 55-year-old men with a family history and >or=14 risk alleles have a 52% and 41% risk of being diagnosed with PCa in the next 20 years in the Swedish and U.S. populations, respectively. In comparison, without knowledge of genotype and family history, these men had an average population absolute risk of 13%. CONCLUSION: This risk prediction model may be used to identify men at considerably elevated PCa risk who may be selected for chemoprevention.
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| 114. |
- Xu, Jianfeng, et al.
(författare)
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Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.
- 2010
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 107:5, s. 2136-40
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Tidskriftsartikel (refereegranskat)abstract
- Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 x 10(-8) under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non-organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.
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| 115. |
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| 116. |
- Zheng, S. Lilly, et al.
(författare)
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Genetic variants and family history predict prostate cancer similar to prostate-specific antigen
- 2009
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 15:3, s. 1105-1111
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Although prostate-specific antigen (PSA) is the best biomarker for predicting prostate cancer, its predictive performance needs to be improved. Results from the Prostate Cancer Prevention Trial revealed the overall performance measured by the areas under curve of the receiver operating characteristic at 0.68. The goal of the present study is to assess the ability of genetic variants as a PSA-independent method to predict prostate cancer risk. EXPERIMENTAL DESIGN: We systematically evaluated all prostate cancer risk variants that were identified from genome-wide association studies during the past year in a large population-based prostate cancer case-control study population in Sweden, including 2,893 prostate cancer patients and 1,781 men without prostate cancer. RESULTS: Twelve single nucleotide polymorphisms were independently associated with prostate cancer risk in this Swedish study population. Using a cutoff of any 11 risk alleles or family history, the sensitivity and specificity for predicting prostate cancer were 0.25 and 0.86, respectively. The overall predictive performance of prostate cancer using genetic variants, family history, and age, measured by areas under curve was 0.65 (95% confidence interval, 0.63-0.66), significantly improved over that of family history and age (0.61%; 95% confidence interval, 0.59-0.62; P = 2.3 x 10(-10)). CONCLUSION: The predictive performance for prostate cancer using genetic variants and family history is similar to that of PSA. The utility of genetic testing, alone and in combination with PSA levels, should be evaluated in large studies such as the European Randomized Study for Prostate Cancer trial and Prostate Cancer Prevention Trial.
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| 117. |
- Zheng, S. Lilly, et al.
(författare)
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Two independent prostate cancer risk-associated Loci at 11q13
- 2009
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 18:6, s. 1815-1820
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Tidskriftsartikel (refereegranskat)abstract
- Single nucleotide polymorphisms (SNP) at 11q13 were recently implicated in prostate cancer risk by two genome-wide association studies and were consistently replicated in multiple study populations. To explore prostate cancer association in the regions flanking these SNPs, we genotyped 31 tagging SNPs in a approximately 110 kb region at 11q13 in a Swedish case-control study (Cancer of the Prostate in Sweden), including 2,899 cases and 1,722 controls. We found evidence of prostate cancer association for the previously implicated SNPs including rs10896449, which we termed locus 1. In addition, multiple SNPs on the centromeric side of the region, including rs12418451, were also significantly associated with prostate cancer risk (termed locus 2). The two groups of SNPs were separated by a recombination hotspot. We then evaluated these two representative SNPs in an additional approximately 4,000 cases and approximately 3,000 controls from three study populations and confirmed both loci at 11q13. In the combined allelic test of all four populations, P = 4.0 x 10(-11) for rs10896449 at locus 1 and P = 1.2 x 10(-6) for rs12418451 at locus 2, and both remained significant after adjusting for the other locus and study population. The prostate cancer association at these two 11q13 loci was unlikely confounded by prostate-specific antigen (PSA) detection bias because neither SNP was associated with PSA levels in controls. Unlike locus 1, in which no known gene is located, several putative mRNAs are in close proximity to locus 2. Additional confirmation studies at locus 2 and functional studies for both loci are needed to advance our knowledge on the etiology of prostate cancer.
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| 118. |
- Åström, Lennart
(författare)
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Dose Escalation with High Dose Rate Brachytherapy or Protons in Curative Radiotherapy of Prostate Cancer
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the thesis was to study the outcome and side effects after dose-escalated radiotherapy with high dose rate brachytherapy (HDR-BT) or proton beam therapy (PBT) boost in prostate cancer.The first cohorts of men in Sweden treated with either HDR-BT or PBT in combination with conventional photon beam therapy (2 Gray (Gy) fractions to 50 Gy) were analysed. The HDR-BT was given with two 10 Gy fractions, and the PBT with four fractions of 5 Gy. The analyses included 823 men in two HDR-BT cohorts, and 265 men in the PBT cohort. A large proportion of the cohorts, from 38% to 53%, were classified as high risk. After a follow-up between four and eleven years, both combinations showed low risks for relapse. The overall 5-year risk for PSA relapse was 0% for men with low risk. After PBT, the 5-year PSA relapse risk for intermediate and high risk were 5% and 26% respectively. After HDR-BT the 10-year risks for PSA relapse were 0%, 21% and 33% for low, intermediate, and high risk, respectively.The risk for early and late toxicity was low. Genitourinary (GU) toxicity was more frequent than gastrointestinal (GI) toxicity. GU toxicity may have a late onset and progress slowly with time after HDR-BT. The 5- and 10-year actuarial incidences of urethral stricture were 6% and 10% respectively after HDR-BT. With applied dose constraints to the urethra the 10-year risk was 5%. The actuarial prevalence of GI toxicity declined slowly with time after HDR-BT as well as after PBT.A PSA bounce after HDR-BT was seen in 26% of the patients, more frequent with younger age and lower Gleason score, and followed by a low risk for relapse.For dose-escalated radiotherapy with HDR-BT or PBT:long-term tumour control was achieved, not only for low- and intermediate risk, but also for the majority of high risk patients,a PSA bounce after HDR-BT was folled by a good prognosis,levels of late toxicity were low,genitourinary toxicity was more frequent than gastrointestinal toxicity,dose constraints to risk organs must be applied to minimise risks for late toxicity.
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