Prostate cancer risk prediction using a polygenic risk score.

Hereditary factors have a strong influence on prostate cancer (PC) risk and poorer outcomes, thus stratification by genetic factors addresses a critical need for targeted PC screening and risk-adapted follow-up. In this Finnish population-based retrospective study 2283 clinically diagnosed and 455 screen-detected patients from the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC), 2400 healthy individuals have been involved. Individual genetic risk through establishment of a polygenic risk score based on 55 PC risk SNPs identified through the Finnish subset of the Collaborative Oncological Gene-Environment Study was assessed. Men with PC had significantly higher median polygenic risk score compared to the controls (6.59 vs. 3.83, P < 0.0001). The polygenic risk score above the control median was a significant predictor of PC (OR 2.13, 95% CI 1.90-2.39). The polygenic risk score predicted the risk of PC with an AUC of 0.618 (95% CI 0.60-0.63). Men in the highest polygenic risk score quartile were 2.8-fold (95% CI 2.4-3.30) more likely to develop PC compared with men in the lowest quartile. In the FinRSPC cohort, a significantly higher percentage of men had a PSA level of ≥ 4 ng/mL in polygenic risk score quartile four compared to quartile one (18.7% vs 8.3%, P < 0.00001). Adding the PRS to a PSA-only model contributed additional information in predicting PC in the FinRSPC model. Results strongly suggest that use of the polygenic risk score would facilitate the identification of men at increased risk for PC.

A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer.

BACKGROUND: The European Randomized study of Screening for Prostate Cancer (ERSPC) has previously demonstrated that prostate-specific antigen (PSA) screening decreases prostate cancer (PCa) mortality. OBJECTIVE: To determine whether PSA screening decreases PCa mortality for up to 16yr and to assess results following adjustment for nonparticipation and the number of screening rounds attended. DESIGN, SETTING, AND PARTICIPANTS: This multicentre population-based randomised screening trial was conducted in eight European countries. Report includes 182160 men, followed up until 2014 (maximum of 16yr), with a predefined core age group of 162389 men (55-69yr), selected from population registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was PCa mortality, also assessed with adjustment for nonparticipation and the number of screening rounds attended. RESULTS AND LIMITATIONS: The rate ratio of PCa mortality was 0.80 (95% confidence interval [CI] 0.72-0.89, p<0.001) at 16yr. The difference in absolute PCa mortality increased from 0.14% at 13yr to 0.18% at 16yr. The number of men needed to be invited for screening to prevent one PCa death was 570 at 16yr compared with 742 at 13yr. The number needed to diagnose was reduced to 18 from 26 at 13yr. Men with PCa detected during the first round had a higher prevalence of PSA >20ng/ml (9.9% compared with 4.1% in the second round, p<0.001) and higher PCa mortality (hazard ratio=1.86, p<0.001) than those detected subsequently. CONCLUSIONS: Findings corroborate earlier results that PSA screening significantly reduces PCa mortality, showing larger absolute benefit with longer follow-up and a reduction in excess incidence. Repeated screening may be important to reduce PCa mortality on a population level. PATIENT SUMMARY: In this report, we looked at the outcomes from prostate cancer in a large European population. We found that repeated screening reduces the risk of dying from prostate cancer.

Synergistic Interaction of HOXB13 and CIP2A Predisposes to Aggressive Prostate Cancer.

PURPOSE: Distinguishing aggressive prostate cancer from indolent disease improves personalized treatment. Although only few genetic variants are known to predispose to aggressive prostate cancer, synergistic interactions of HOXB13 G84E high-risk prostate cancer susceptibility mutation with other genetic loci remain unknown. The purpose of this study was to examine the interplay of HOXB13 rs138213197 (G84E) and CIP2A rs2278911 (R229Q) germline variants on prostate cancer risk. EXPERIMENTAL DESIGN: Genotyping was done in Finnish discovery cohort (n = 2,738) and validated in Swedish (n = 3,132) and independent Finnish (n = 1,155) prostate cancer cohorts. Expression pattern analysis was followed by functional studies in prostate cancer cell models. RESULTS: Interplay of HOXB13 (G84E) and CIP2A (R229Q) variants results in highest observed inherited prostate cancer risk (OR, 21.1; P = 0.000024). In addition, this synergism indicates a significant association of HOXB13 T and CIP2A T dual carriers with elevated risk for high Gleason score (OR, 2.3; P = 0.025) and worse prostate cancer-specific life expectancy (HR, 3.9; P = 0.048), and it is linked with high PSA at diagnosis (OR, 3.30; P = 0.028). Furthermore, combined high expression of HOXB13-CIP2A correlates with earlier biochemical recurrence. Finally, functional experiments showed that ectopic expression of variants stimulates prostate cancer cell growth and migration. In addition, we observed strong chromatin binding of HOXB13 at CIP2A locus and revealed that HOXB13 functionally promotes CIP2A transcription. The study is limited to retrospective Nordic cohorts. CONCLUSIONS: Simultaneous presence of HOXB13 T and CIP2A T alleles confers for high prostate cancer risk and aggressiveness of disease, earlier biochemical relapse, and lower disease-specific life expectancy. HOXB13 protein binds to CIP2A gene and functionally promotes CIP2A transcription.

Socio-economic differences in self-reported insomnia and stress in Finland from 1979 to 2002: a population-based repeated cross-sectional survey.

BACKGROUND: Over the decades, global public health efforts have sought to reduce socio-economic health differences, including differences in mental health. Only a few studies have examined changes in socio-economic differences in psychological symptoms over time. The aim of this study was to assess trends in socio-economic differences in self-reported insomnia and stress over a 24-year time period in Finland. METHODS: The data source is a repeated cross-sectional survey "Health Behaviour and Health among the Finnish Adult Population" (AVTK), from the years 1979 to 2002, divided into five study periods. Indicators for socio-economic status included employment status from the survey, and educational level and household income from the Statistics Finland register data. We studied the age group of 25-64 years (N = 70115; average annual response rate 75%). Outcome measures were single questions of self-reported insomnia and stress. RESULTS: The overall prevalence of insomnia was 18-19% and that of stress 16-19%. Compared to the first study period, 1979-1982, the prevalence of stress increased until study period 1993-1997. The prevalence of insomnia increased during the last study period, 1998-2002. Respondents who were unemployed or had retired early reported more insomnia and stress over time among both men and women. Lower education was associated with more insomnia especially among men; and conversely, with less stress among both sexes. Compared to the highest household income level, those in the intermediate levels of income had less stress whereas those in the lowest income levels had more stress among both sexes. Income level differences in insomnia were less consistent. In general, socio-economic differences in self-reported insomnia and stress fluctuated some, but did not change substantially over the study period 1979-2002. CONCLUSIONS: Self-reported insomnia and stress were more common during later study periods. The socio-economic differences in insomnia and stress have remained fairly stable over a 24-year time period. However, some of the associations in socio-economic differences were curvilinear and converse. Future studies are needed to explore the complex socio-economic gradients, especially in stress.

The contribution of psychological distress to socio-economic differences in cause-specific mortality: a population-based follow-up of 28 years.

BACKGROUND: Psychological factors associated with low social status have been proposed as one possible explanation for the socio-economic gradient in health. The aim of this study is to explore whether different indicators of psychological distress contribute to socio-economic differences in cause-specific mortality. METHODS: The data source is a nationally representative, repeated cross-sectional survey, "Health Behaviour and Health among the Finnish Adult Population" (AVTK). The survey results were linked with socio-economic register data from Statistics Finland (from the years 1979-2002) and mortality follow-up data up to 2006 from the Finnish National Cause of Death Register. The data included 32,451 men and 35,420 women (response rate 73.5%). Self-reported measures of depression, insomnia and stress were used as indicators of psychological distress. Socio-economic factors included education, employment status and household income. Mortality data consisted of unnatural causes of death (suicide, accidents and violence, and alcohol-related mortality) and coronary heart disease (CHD) mortality. Adjusted hazard ratios were calculated using the Cox regression model. RESULTS: In unnatural mortality, psychological distress accounted for some of the employment status (11-31%) and income level (4-16%) differences among both men and women, and for the differences related to the educational level (5-12%) among men; the educational level was associated statistically significantly with unnatural mortality only among men. Psychological distress had minor or no contribution to socio-economic differences in CHD mortality. CONCLUSIONS: Psychological distress partly accounted for socio-economic disparities in unnatural mortality. Further studies are needed to explore the role and mechanisms of psychological distress associated with socio-economic differences in cause-specific mortality.