| 1. |
- Arndt, D. S., et al.
(författare)
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STATE OF THE CLIMATE IN 2017
- 2018
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
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Forskningsöversikt (refereegranskat)
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| 2. |
- Klein, Robert J, et al.
(författare)
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Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms : kallikreins and prostate cancer
- 2010
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Ingår i: Cancer Prevention Research. - : American Association for Cancer Research. - 1940-6207 .- 1940-6215. ; 3:5, s. 611-619
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Tidskriftsartikel (refereegranskat)abstract
- Polymorphisms associated with prostate cancer include those in three genes encoding major secretory products of the prostate: KLK2 (encoding kallikrein-related peptidase 2; hK2), KLK3 (encoding prostate-specific antigen; PSA), and MSMB (encoding beta-microseminoprotein). PSA and hK2, members of the kallikrein family, are elevated in sera of men with prostate cancer. In a comprehensive analysis that included sequencing of all coding, flanking, and 2 kb of putative promoter regions of all 15 kallikrein (KLK) genes spanning approximately 280 kb on chromosome 19q, we identified novel single-nucleotide polymorphisms (SNP) and genotyped 104 SNPs in 1,419 cancer cases and 736 controls in Cancer Prostate in Sweden 1, with independent replication in 1,267 cases and 901 controls in Cancer Prostate in Sweden 2. This verified prior associations of SNPs in KLK2 and in MSMB (but not in KLK3) with prostate cancer. Twelve SNPs in KLK2 and KLK3 were associated with levels of PSA forms or hK2 in plasma of control subjects. Based on our comprehensive approach, this is likely to represent all common KLK variants associated with these phenotypes. A T allele at rs198977 in KLK2 was associated with increased cancer risk and a striking decrease of hK2 levels in blood. We also found a strong interaction between rs198977 genotype and hK2 levels in blood in predicting cancer risk. Based on this strong association, we developed a model for predicting prostate cancer risk from standard biomarkers, rs198977 genotype, and rs198977 x hK2 interaction; this model had greater accuracy than did biomarkers alone (area under the receiver operating characteristic curve, 0.874 versus 0.866), providing proof in principle to clinical application for our findings.
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| 3. |
- Assel, Melissa, et al.
(författare)
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Association Between Lead Time and Prostate Cancer Grade : Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening
- 2018
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 73:6, s. 961-967
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lead time (LT) is of key importance in early detection of cancer, but cannot be directly measured. We have previously provided LT estimates for prostate cancer (PCa) using archived blood samples from cohorts followed for many years without screening. Objective: To determine the association between LT and PCa grade at diagnosis to provide an insight into whether grade progresses or is stable over time. Design, setting, and participants: The setting was three long-term epidemiologic studies in Sweden including men not subject to prostate-specific antigen (PSA) screening. The cohort included 1041 men with PSA of 3–10 ng/ml at blood draw and subsequently diagnosed with PCa with grade data available. Outcome measurements and statistical analysis: Multivariable logistic regression was used to predict high-grade (Gleason grade group ≥2 or World Health Organization grade 3) versus low-grade PCa at diagnosis in terms of LT, defined as the time between the date of elevated PSA and the date of PCa diagnosis with adjustment for cohort and age. Results and limitations: The probability that PCa would be high grade at diagnosis increased with LT. Among all men combined, the risk of high-grade disease increased with LT (odds ratio 1.13, 95% confidence interval [CI] 1.10–1.16; p < 0.0001), with no evidence of differences in effect by age group or cohort. Higher PSA predicted shorter LT by 0.46 yr (95% CI 0.28–0.64; p < 0.0001) per 1 ng/ml increase in PSA. However, there was no interaction between PSA and grade, suggesting that the longer LT for high-grade tumors is not simply related to age. Limitations include the assumption that men with elevated PSA and subsequently diagnosed with PCa would have had biopsy-detectable PCa at the time of PSA elevation. Conclusions: Our data support grade progression, whereby following a prostate over time would reveal transitions from benign to low-grade and then high-grade PCa. Patient summary: Men with a longer lead time between elevated prostate-specific antigen and subsequent prostate cancer diagnosis were more likely to have high-grade cancers at diagnosis. The probability that a cancer will be of high grade at diagnosis increases with the lead time. Our findings provide evidence of grade progression, whereby a prostate followed over time would exhibit transitions from benign to low-grade to high-grade prostate cancer.
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| 4. |
- Klein, Robert J., et al.
(författare)
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Prostate cancer polygenic risk score and prediction of lethal prostate cancer
- 2022
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Ingår i: npj Precision Oncology. - : Nature Publishing Group. - 2397-768X. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) for prostate cancer incidence have been proposed to optimize prostate cancer screening. Prediction of lethal prostate cancer is key to any stratified screening program to avoid excessive overdiagnosis. Herein, PRS for incident prostate cancer was evaluated in two population-based cohorts of unscreened middle-aged men linked to cancer and death registries: the Västerbotten Intervention Project (VIP) and the Malmö Diet and Cancer study (MDC). SNP genotypes were measured by genome-wide SNP genotyping by array followed by imputation or genotyping of selected SNPs using mass spectrometry. The ability of PRS to predict lethal prostate cancer was compared to PSA and a commercialized pre-specified model based on four kallikrein markers. The PRS was associated with incident prostate cancer, replicating previously reported relative risks, and was also associated with prostate cancer death. However, unlike PSA, the PRS did not show stronger association with lethal disease: the hazard ratio for prostate cancer incidence vs. prostate cancer metastasis and death was 1.69 vs. 1.65 in VIP and 1.25 vs. 1.25 in MDC. PSA was a much stronger predictor of prostate cancer metastasis or death with an area-under-the-curve of 0.78 versus 0.63 for the PRS. Importantly, addition of PRS to PSA did not contribute additional risk stratification for lethal prostate cancer. We have shown that a PRS that predicts prostate cancer incidence does not have utility above and beyond that of PSA measured at baseline when applied to the clinically relevant endpoint of prostate cancer death. These findings have implications for public health policies for delivery of prostate cancer screening. Focusing polygenic risk scores on clinically significant endpoints such as prostate cancer metastasis or death would likely improve clinical utility.
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| 5. |
- Stattin, Pär, et al.
(författare)
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Improving the Specificity of Screening for Lethal Prostate Cancer Using Prostate-specific Antigen and a Panel of Kallikrein Markers : a Nested Case-Control Study
- 2015
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Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 68:2, s. 207-213
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Tidskriftsartikel (refereegranskat)abstract
- Background: A disadvantage of prostate-specific antigen (PSA) for the early detection of prostate cancer (PCa) is that many men must be screened, biopsied, and diagnosed to prevent one death. Objective: To increase the specificity of screening for lethal PCa at an early stage. Design, setting, and participants: We conducted a case-control study nested within a population-based cohort. PSA and three additional kallikreins were measured in cryopreserved blood from a population-based cohort in Vasterbotten, Sweden. Of 40 379 men providing blood at ages 40, 50, and 60 yr from 1986 to 2009, 12 542 men were followed for > 15 yr. From this cohort, the Swedish Cancer Registry identified 1423 incident PCa cases, 235 with distant metastasis. Outcome measurements and statistical analysis: Risk of distant metastasis for different PSA levels and a prespecified statistical model based on the four kallikrein markers. Results and limitations: Mostmetastatic cases occurred in men with PSA in the top quartile at age 50 yr (69%) or 60 yr (74%), whereas 20-yr risk of metastasis for men with PSA below median was low (<= 0.6%). Among men with PSA > 2 ng/ml, a prespecified model based on four kallikrein markers significantly enhanced the prediction of metastasis compared with PSA alone. About half of all men with PSA > 2 ng/ml were defined as low risk by this model and had a <= 1% 15-yr risk of metastasis. Conclusions: Screening at ages 50-60 yr should focus on men with PSA in the top quartile. A marker panel can aid biopsy decision making. Patient summary: For men in their fifties, screening should focus on those in the top 10% to 25% of PSA values because the majority of subsequent cases of distant metastasis are found among these men. Testing of four kallikrein markers in men with an elevated PSA could aid biopsy decision making.
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| 6. |
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| 7. |
- Vertosick, Emily A, et al.
(författare)
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Prespecified Four Kallikrein Marker Model (4Kscore) at Age 50 or 60 for Early Detection of Lethal Prostate Cancer in a Large Population-Based Cohort of Asymptomatic Men Followed for 20 Years.
- 2020
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Ingår i: Journal of Urology. - : Lippincott Williams & Wilkins. - 0022-5347 .- 1527-3792. ; 204:2, s. 281-288
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: A prespecified statistical model based on 4 kallikrein markers in blood, commercially available as the 4Kscore®, has been shown to accurately detect high grade (greater than Grade Group 2) prostate cancer in men with moderately elevated prostate specific antigen. We assessed whether the model predicted prostate cancer metastasis or death in men not subject to prostate specific antigen screening.Materials and Methods: The cohort includes 43,692 unscreened prostate cancer-free men from a Swedish population based cohort with low rates of prostate specific antigen screening (Västerbotten Intervention Project). Using cryopreserved blood collected at ages 50 and 60 years from men in this cohort we analyzed the association between prostate specific antigen and other kallikrein marker levels in blood and risk of prostate cancer metastasis or death.Results: There were 308 with metastases and 172 prostate cancer deaths. Baseline prostate specific antigen was strongly associated with 20-year risk of prostate cancer death (c-index at age 50, 0.859, 95% CI 0.799–0.916; age 60, 0.840, 95% CI 0.799–0.878). Men 60 years old with prostate specific antigen below median (less than 1.2 ng/ml) had 0.4% risk of prostate cancer death at 20 years. Among men with moderately elevated prostate specific antigen (2.0 ng/ml or greater) the 4Kscore markedly improved discrimination (c-index 0.767 vs 0.828 and 0.774 vs 0.862 in men age 50 and 60, respectively). Long-term risk of prostate cancer death or metastasis in men with low 4Kscores was very low.Conclusions: Screening should focus on men in top prostate specific antigen quartile at age 60 years. Men with elevated prostate specific antigen but a low 4Kscore can safely be monitored with repeated blood markers in place of immediate biopsy.
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