A Nordic initiative for a more personal and accurate diagnostic pathway for prostate cancer

Non peer reviewe

Cost-Effectiveness Analysis of Stockholm 3 Testing Compared to PSA as the Primary Blood Test in the Prostate Cancer Diagnostic Pathway:A Decision Tree Approach

OBJECTIVE: This study evaluated the cost effectiveness of using Stockholm 3 (STHLM3) testing compared to the prostate-specific antigen (PSA) test in the diagnostic pathway for prostate cancer. METHODS: We created a decision tree model for PSA (current standard) and STHLM3 (new alternative). Cost effectiveness was evaluated in a hypothetical cohort of male individuals aged 50–69 years. The study applied a Danish hospital perspective with a time frame restricted to the prostate cancer diagnostic pathway, beginning with the initial PSA/STHLM3 test, and ending with biopsy and histopathological diagnosis. Estimated values from the decision-analytical model were used to calculate the incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses were conducted to test the robustness of the base-case analysis. RESULTS: The model-based analysis revealed that STHLM3 testing was more effective than the PSA, but also more costly, with an incremental cost-effectiveness ratio of €511.7 (95% credible interval, 359.9–674.3) for each additional correctly classified individual. In the deterministic sensitivity analysis, variations in the cost of STHLM3 had the greatest influence on the incremental cost-effectiveness ratio. In the probabilistic sensitivity analysis, all iterations were positioned in the north-east quadrant of the incremental cost-effectiveness scatterplot. At a willingness to pay of €700 for an additional correctly classified individual, STHLM3 had a 100% probability of being cost effective. CONCLUSIONS: Compared to the PSA test as the initial testing modality in the prostate cancer diagnostic workup, STHLM3 testing showed improved incremental effectiveness, however, at additional costs. The results were sensitive to the cost of the STHLM3 test; therefore, a lower cost of the STHLM3 test would improve its cost effectiveness compared with PSA tests. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40258-022-00741-0

The Icsbp locus is a common proviral insertion site in mature B-cell lymphomas/plasmacytomas induced by exogenous murine leukemia virus

AbstractICSBP (interferon consensus sequence binding protein)/IRF8 (interferon regulatory factor 8) is an interferon gamma-inducible transcription factor expressed predominantly in hematopoietic cells, and down-regulation of this factor has been observed in chronic myelogenous leukemia and acute myeloid leukemia in man. By screening about 1200 murine leukemia virus (MLV)-induced lymphomas, we found proviral insertions at the Icsbp locus in 14 tumors, 13 of which were mature B-cell lymphomas or plasmacytomas. Only one was a T-cell lymphoma, although such tumors constituted about half of the samples screened. This indicates that the Icsbp locus can play a specific role in the development of mature B-lineage malignancies. Two proviral insertions in the last Icsbp exon were found to act by a poly(A)-insertion mechanism. The remaining insertions were found within or outside Icsbp. Since our results showed expression of Icsbp RNA and protein in all end-stage tumor samples, a simple tumor suppressor function of ICSBP is not likely. Interestingly, proviral insertions at Icsbp have not been reported from previous extensive screenings of mature B-cell lymphomas induced by endogenous MLVs. We propose that ICSBP might be involved in an early modulation of an immune response to exogenous MLVs that might also play a role in proliferation of the mature B-cell lymphomas

Perceptions about screening for prostate cancer using genetic lifetime risk assessment: a qualitative study

Background Most health authorities do not recommend screening for prostate cancer with PSA tests in asymptomatic patients who are not at increased risk. However, opportunistic screening for prostate cancer is still wanted by many patients and it is widely used in primary care clinics, with potential for overdiagnosis and overtreatment. Better tools for risk assessment have been called for, to better target such opportunistic screening. Our aim was to explore perceptions about prostate cancer risk and subsequent opportunistic screening among patients who were not at increased risk of prostate cancer after a first PSA test plus a genetic lifetime risk assessment. Methods We undertook semi-structured patient interviews with recording and verbatim transcription of interviews. Data were analysed thematically. Results Three themes were identified: uncertainty of the nature of prostate cancer; perceived benefits of testing; and conflicting public health recommendations. Prostate cancer was spoken of as an inescapable risk in older age. The aphorism “you die with it, not from it” was prominent in the interviews but patients focused on the benefits of testing now rather than the future risks associated with treatment relating to potential overdiagnosis. Many expressed frustration with perceived mixed messages about early detection of cancer, in which on one side men feel that they are encouraged to seek medical testing to act responsibly regarding the most common cancer disease in men, and on the other side they are asked to refrain from opportunistic testing for prostate cancer. Taken together, personal risks of prostate cancer were perceived as high in spite of a normal PSA test and a genetic lifetime risk assessment showing no increased risk. Conclusion Patients saw prostate cancer risk as high and increasing with age. They focused on the perceived benefit of early detection using PSA testing. It was also commonly acknowledged that most cases are indolent causing no symptoms and not shortening life expectancy. There was a frustration with mixed messages about the benefit of early detection and risk of overdiagnosis. These men’s genetic lifetime risk assessment showing no increased risk did not appear to influence current intentions to get PSA testing in the future

The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families

Fast and efficient QTL mapper for thousands of molecular phenotypes

In order to discover quantitative trait loci, multi-dimensional genomic datasets combining DNA-seq and ChiP-/RNA-seq require methods that rapidly correlate tens of thousands of molecular phenotypes with millions of genetic variants while appropriately controlling for multiple testing

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score >= 7, stage T3-T4, PSA >= 10ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n=71,856), Asian (n=2,382), and African (n=6,253) genetic ancestries (p<10(-180)). Comparing the 80(th)/20(th) PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset. A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset

Association between copy number alterations estimated using low-pass whole genome sequencing of formalin-fixed paraffin-embedded prostate tumor tissue and cancer-specific clinical parameters

Abstract Copy number alterations (CNAs) are frequently observed in early-stage prostate cancer and are associated with disease recurrence and tumor aggressiveness. Cost-effective assessment of CNAs could enhance clinical utility of CNAs. Here, we combined the cost-effectiveness of low-pass (low coverage) whole genome sequencing (LPWGS) and the routine availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue for assessing CNAs in a cohort of 187 men with early-stage localised prostate cancer. We detected well known CNAs in 8p, 8q, 13q and 16q and recurrent gains of the oncogene MYC and losses of the tumor suppressor genes NKX3-1, PTEN and RB1, indicating assay reliability. The estimated burden of CNAs was significantly associated with Gleason score, pathological T stage, surgical margin status and biochemical recurrence. Further, genomic losses or gains in specific chromosomal arms were significantly associated with worse BCR-free survival. Copy number signatures extracted from the LPWGS data showed potential for risk stratifying patients, where signatures S1 and S2 showed significant association to worse BCR-free survival compared to S3. Our study provides clinical validation of the associations between CNAs and tumor aggressiveness in an independent and representative RP cohort, while demonstrating the feasibility of performing LPWGS of FFPE tumor tissue for cost-effective assessment of CNAs