| 51. |
- Setlur, Sunita R., et al.
(författare)
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Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer
- 2008
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Ingår i: Journal of the National Cancer Institute. - Oxford : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:11, s. 815-825
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Tidskriftsartikel (refereegranskat)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.
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| 52. |
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| 53. |
- Smedby, Karin Ekström, et al.
(författare)
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Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype
- 2006
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 98:1, s. 51-60
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL). Because different NHL subtypes develop at different stages of lymphocyte differentiation, associations of autoimmune and inflammatory disorders with specific NHL subtypes could lead to a better understanding of lymphomagenic mechanisms. METHODS: In a population-based case-control study in Denmark and Sweden, 3055 NHL patients and 3187 matched control subjects were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity, and treatment. Logistic regression with adjustment for study matching factors was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for NHL overall and for NHL subtypes. RESULTS: Risks of all NHL were increased in association with rheumatoid arthritis (OR = 1.5, 95% CI = 1.1 to 1.9), primary Sjögren syndrome (OR = 6.1, 95% CI = 1.4 to 27), systemic lupus erythematosus (OR = 4.6, 95% CI = 1.0 to 22), and celiac disease (OR = 2.1, 95% CI = 1.0 to 4.8). All of these conditions were also associated with diffuse large B-cell lymphoma, and some were associated with marginal zone, lymphoplasmacytic, or T-cell lymphoma. Ever use of nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and selected immunosuppressants was associated with risk of NHL in rheumatoid arthritis patients but not in subjects without rheumatoid arthritis. Also, multivariable adjustment for treatment had little impact on risk estimates. Psoriasis, sarcoidosis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype. CONCLUSIONS: Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.
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| 54. |
- Smedby, Karin Ekström, et al.
(författare)
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Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma
- 2006
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 15:2, s. 258-265
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Tidskriftsartikel (refereegranskat)abstract
- The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.
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| 55. |
- Sun, Jielin, et al.
(författare)
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Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12
- 2008
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Ingår i: Nature Genetics. - London : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 40:10, s. 1153-1155
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 10-9 for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.
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| 56. |
- Wiklund, Fredrik E, et al.
(författare)
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Established prostate cancer susceptibility variants are not associated with disease outcome.
- 2009
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 18:5, s. 1659-62
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Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies have been successful in identifying common sequence variants associated with prostate cancer risk; however, their importance in prostate cancer prognosis remains unknown. To assess confirmed prostate cancer susceptibility variants with prostate cancer prognosis, we genotyped 16 established susceptibility variants in a Swedish cohort of 2,875 prostate cancer cases, ascertained between 2001 and 2003, with complete follow-up regarding vital status through January 2008. Cox regression models, adjusted for age, clinical stage, pathologic grade, nodal or distant metastases, and diagnostic serum levels of prostate-specific antigen level, were used to assess association between risk variants and prostate cancer-specific survival. During follow-up, 626 men died, and of those, 440 had prostate cancer classified as their underlying cause of death. We found no association between any of the explored sequence variants and prostate cancer-specific mortality, either in exploring individual variants or in assessing the cumulative effect of all variants. We conclude that hitherto established prostate cancer susceptibility variants are not associated with the lethal potential of prostate cancer.
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| 57. |
- 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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| 58. |
- Wiklund, Fredrik, et al.
(författare)
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Risk of bilateral renal cell cancer
- 2009
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Ingår i: Journal of Clinical Oncology. - Alexandria, USA : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 27:23, s. 3737-41
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The risk of developing bilateral kidney cancer has not been adequately defined in any large, population-based study with long-term follow-up to our knowledge.Patients and methods: We estimated the risk of metachronous bilateral renal cell cancer in patients diagnosed with unilateral kidney cancer, as recorded in the nationwide cancer registries of Norway and Sweden. Altogether 28,642 patients were followed for an average of 4.4 years. The standardized incidence ratio--the ratio of the observed number of bilateral cancers to the number expected on the basis of the incidence in the Norwegian and Swedish population at large--was used as a measure of relative risk. We used multivariate Poisson regression to separate the effects of the explanatory variables.Results: A synchronous bilateral renal cell cancer was reported in 86 patients. A total of 112 metachronous bilateral cancers were recorded during 126,493 person-years of follow-up compared with 35.8 expected, yielding an overall relative risk (RR) of 3.1 (95% CI, 2.6 to 3.8) and a cumulative incidence of 0.8% after 20 or more years of follow-up. In the multivariate analyses, risk increased monotonically with younger age at first diagnosis (P for trend < .001); compared with patients who were 60 years or older, those younger than 40 years were at a 17-fold higher risk (RR = 17.4; 95% CI, 10.1 to 29.8). We also found a modest but statistically significant decreasing trend with increasing duration of follow-up.Conclusion: The risk of metachronous bilateral renal cell cancer is drastically higher among patients first affected at a young age, suggesting a subset of early onset renal cell cancer with a strong genetic component.
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| 59. |
- Wilson, Kathryn M., et al.
(författare)
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Acrylamide exposure measured by food frequency questionnaire and hemoglobin adduct levels and prostate cancer risk in the Cancer of the Prostate in Sweden Study
- 2009
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Ingår i: International Journal of Cancer. - : WILEY-LISS. - 0020-7136 .- 1097-0215. ; 124:10, s. 2384-2390
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Tidskriftsartikel (refereegranskat)abstract
- Acrylamide, a probable human carcinogen, is formed during the cooking of many commonly consumed foods. Data are scant on whether dietary acrylamide represents an important cancer risk in humans. We studied the association between acrylamide and prostate cancer risk using 2 measures of acrylamide exposure: intake from a food frequency questionnaire (FFQ) and acrylamide adducts to hemoglobin. We also studied the correlation between these 2 exposure measures. We used data from the population-based case-control study Cancer of the Prostate in Sweden (CAPS). Dietary data was available for 1,499 cases and 1, 118 controls. Hemoglobin adducts of acrylamide were measured in blood samples from a subset of 170 cases and 161 controls. We calculated odds ratios (ORs) for the risk of prostate cancer in high versus low quantiles of acrylamide exposure using logistic regression. The correlation between FFQ acrylamide intake and acrylamide adducts in non-smokers was 0.25 (95% confidence interval: 0.14-0.35), adjusted for age, region, energy intake, and laboratory batch. Among controls the correlation was 0.35 (95% CI: 0.21-0.48); among cases it was 0.15 (95% CI: 0.00-0.30). The OR of prostate cancer for the highest versus lowest quartile of acrylamide adducts was 0.93 (95% CI: 0.47-1.85, p-value for trend = 0.98). For FFQ acrylamide, the OR of prostate cancer for the highest versus lowest quintile was 0.97 (95% CI: 0.75-1.27,p trend = 0.67). No significant associations were found between acrylamide exposure and risk of prostate cancer by stage, grade, or PSA level. Acrylamide adducts to hemoglobin and FFQ-measured acrylamide intake were moderately correlated. Neither measure of acrylamide exposure-hemoglobin adducts or FFQ-was associated with risk of prostate cancer. (C) 2008 Wiley-Liss. Inc.
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| 60. |
- Zheng, S. Lilly, et al.
(författare)
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A comprehensive association study for genes in inflammation pathway provides support for their roles in prostate cancer risk in the CAPS study
- 2006
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Ingår i: The Prostate. - Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. Karolinska Inst, Dept Med Epidemiol & Biotat, Stockholm, Sweden. Orebro Univ Hosp, Dept Urol & Clin Med, Orebro, Sweden. Translat Genom Res Inst, Phoenix, AZ USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. : WILEY-LISS. - 0270-4137 .- 1097-0045. ; 66:14, s. 1556-1564
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Recently identified associations of prostate cancer risk with several genes involved in innate immunity support a role of inflammation in the etiology of prostate cancer. Considering inflammation is regulated by a complex system of gene products, we hypothesize sequence variants in many other genes of this pathway are associated with prostate cancer. METHODS. We evaluated 9,275 SNPs; in 1,086 genes of the inflammation pathway using a MegAlleleTM genotyping system among 200 familial cases and 200 unaffected controls selected from a large Swedish case-control population (CAPS). RESULTS. We found that significantly more than the expected numbers of SNPs were significant at a nominal P-value of 0.01, 0.05, and 0.1, providing overall support for our hypothesis. The excess was largest when using a more liberal nominal P-value (0.1); we observed 992 significant SNPs compared with the 854 significant SNPs expected by chance, and this difference was significant based on a permutation test (P = 0.0025). We also began the effort of differentiating true associated SNPs by selecting a small subset of significant SNPs (N = 26) and genotyped these in an independent sample of similar to 1,900 CAPS1 subjects. We were able to confirm 3 of these 26 SNPs. It is expected that many more true associated SNPs will be confirmed among the 992 significant SNPs identified in our pathway screen. CONCLUSIONS. Our study provides the first objective support for an association between prostate cancer and multiple modest-effect genes in inflammatory pathways.
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