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5. Charlson Comorbidity Index Based On Hospital Episode Statistics Performs Adequately In Predicting Mortality, But Its Discriminative Ability Diminishes Over Time

Author

Pylväläinen J, Talala K, Murtola T, Taari K, Raitanen J, Tammela TL, and Auvinen A

Subjects
mortality, comorbidity, follow-up studies, hospitalization/statistics and numerical data, Drug Prescriptions /statistics and numerical data, confounding factors (Epidemiology), Infectious and parasitic diseases, RC109-216
Abstract

Juho Pylväläinen,1–3 Kirsi Talala,4 Teemu Murtola,5–7 Kimmo Taari,8 Jani Raitanen,1,9 Teuvo L Tammela,6 Anssi Auvinen1 1Tampere University, Faculty of Social Sciences (Health Sciences), Tampere, Finland; 2Helsinki University, Faculty of Medicine, Department of Diagnostics and Therapeutics, Helsinki, Finland; 3Helsinki University Central Hospital, Medical Imaging Center, Helsinki, Finland; 4Cancer Society of Finland, Finnish Cancer Registry, Mass Screening Registry, Helsinki, Finland; 5Tampere University, Faculty of Medicine and Health Technology, Prostate Cancer Research Center, Tampere, Finland; 6Tampere University Hospital, Department of Urology, Tampere, Finland; 7Seinäjoki Central Hospital, Department of Surgery, Seinäjoki, Finland; 8University of Helsinki and Helsinki University Hospital, Department of Urology, Helsinki, Finland; 9UKK Institute for Health Promotion Research, Tampere, FinlandCorrespondence: Juho PylväläinenHelsinki University Central Hospital, Medical Imaging Center, Haartmaninkatu 3, PO Box 180, 00029, Helsinki, Uusimaa, FinlandTel +358 503239286Email juho.pylvalainen@hus.fiPurpose: To evaluate the performance of Charlson Comorbidity Index (CCI) calculated using hospitalization and medication reimbursement databases in predicting mortality.Patients and methods: Information on hospitalizations was obtained from the national Care Register for Health Care (HILMO) and on medication reimbursements and entitlements for special reimbursements for medications from the Social Insurance Institution for 77,440 men aged 56–71 years at baseline. The subjects were followed up for mortality via Statistics Finland with 20,562 deaths during a 13-year follow-up.Results: Compared to a CCI score of 0, the age-adjusted hazard ratio for all-cause mortality associated with HILMO-based CCI scores of 1, 2 and 3 or more were 2.39 (95% CI 2.29–2.49), 2.96 (95% CI 2.81–3.13) and 6.42 (95% CI 5.95–6.93) at 13 years. The C-statistic was 0.72 at 1, 0.68 at 5 and 0.66 at 13 years, with only minor improvement over age alone (0.10, 0.06 and 0.04 accordingly). Addition of medication data did not improve predictive abilities and medication-based CCI performed poorly on its own.Conclusion: The hospitalization-based CCI, as well as that based on both databases, predicts relative mortality adequately, but its discriminative ability diminishes over time. Conditions related to hospitalizations affect survival more than medications.Keywords: mortality, comorbidity, follow-up studies, hospitalization/statistics and numerical data, drug prescriptions/statistics and numerical data, confounding factors

Published
2019

8. Prognostic index for predicting prostate cancer survival in a randomized screening trial

Author

Neupane, S., Nevalainen, J., Raitanen, J., Talala, K., Kujala, P., Taari, K., Tammela, T.L.J., Steyerberg, E.W., Auvinen, A., Public Health, HUS Abdominal Center, Clinicum, Urologian yksikkö, Department of Surgery, Helsinki University Hospital Area, University of Helsinki, Tampere University, Health Sciences, Department of Pathology, and Clinical Medicine

Subjects
3141 Health care science, prediction model, SDG 3 - Good Health and Well-being, 3122 Cancers, prognostic index, screening trial, 3126 Surgery, anesthesiology, intensive care, radiology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, prostate cancer, lcsh:RC254-282, mortality, Article
Abstract

Simple Summary A prognostic index for predicting survival of localized prostate cancer (PCa) up to 15 and 20 years was developed. The prognostic index performed well for predicting PCa survival among screened and non-screened men. The performance of the prediction model was superior to the European Association of Urology (EAU) risk groups as well as a modified cancer of prostate risk assessment (CAPRA) risk score. We further constructed a simplified risk score in an unscreened population, using the three most relevant predictors. The simplified risk score was applied to predict PCa survival at 10 years from diagnosis to provide more accurate risk estimation as the basis for decision making. We developed and validated a prognostic index to predict survival from prostate cancer (PCa) based on the Finnish randomized screening trial (FinRSPC). Men diagnosed with localized PCa (N = 7042) were included. European Association of Urology risk groups were defined. The follow-up was divided into three periods (0-3, 3-9 and 9-20 years) for development and two corresponding validation periods (3-6 and 9-15 years). A multivariable complementary log-log regression model was used to calculate the full prognostic index. Predicted cause-specific survival at 10 years from diagnosis was calculated for the control arm using a simplified risk score at diagnosis. The full prognostic index discriminates well men with PCa with different survival. The area under the curve (AUC) was 0.83 for both the 3-6 year and 9-15 year validation periods. In the simplified risk score, patients with a low risk score at diagnosis had the most favorable survival, while the outcome was poorest for the patients with high risk scores. The prognostic index was able to distinguish well between men with higher and lower survival, and the simplified risk score can be used as a basis for decision making.

Published
2021

9. Prognostic index for predicting prostate cancer survival in a randomized screening trial: Development and validation

Author

Neupane, S. (Subas), Nevalainen, J. (Jaakko), Raitanen, J. (Jani), Talala, K. (Kirsi), Kujala, P.M. (Paula), Taari, K. (Kimmo), Tammela, T.L.J. (Teuvo L. J.), Steyerberg, E.W. (Ewout), Auvinen, A. (Anssi), Neupane, S. (Subas), Nevalainen, J. (Jaakko), Raitanen, J. (Jani), Talala, K. (Kirsi), Kujala, P.M. (Paula), Taari, K. (Kimmo), Tammela, T.L.J. (Teuvo L. J.), Steyerberg, E.W. (Ewout), and Auvinen, A. (Anssi)

Abstract

We developed and validated a prognostic index to predict survival from prostate cancer (PCa) based on the Finnish randomized screening trial (FinRSPC). Men diagnosed with localized PCa (N = 7042) were included. European Association of Urology risk groups were defined. The follow-up was divided into three periods (0–3, 3–9 and 9–20 years) for development and two corresponding validation periods (3–6 and 9–15 years). A multivariable complementary log–log regression model was used to calculate the full prognostic index. Predicted cause-specific survival at 10 years from diagnosis was calculated for the control arm using a simplified risk score at diagnosis. The full prognostic index discriminates well men with PCa with different survival. The area under the curve (AUC) was 0.83 for both the 3–6 year and 9–15 year validation periods. In the simplified risk score, patients with a low risk score at diagnosis had the most favorable survival, while the outcome was poorest for the patients with high risk scores. The prognostic index was able to distinguish well between men with higher and lower survival, and the simplified risk score can be used as a basis for decision making.

Published
2021
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10. Prognostic Index for Predicting Prostate Cancer Survival in a Randomized Screening Trial: Development and Validation

Author

Neupane, S, Nevalainen, J, Raitanen, J, Talala, K, Kujala, P, Taari, K, Tammela, TL, Steyerberg, Ewout, Auvinen, A, Neupane, S, Nevalainen, J, Raitanen, J, Talala, K, Kujala, P, Taari, K, Tammela, TL, Steyerberg, Ewout, and Auvinen, A

Abstract

We developed and validated a prognostic index to predict survival from prostate cancer (PCa) based on the Finnish randomized screening trial (FinRSPC). Men diagnosed with localized PCa (N = 7042) were included. European Association of Urology risk groups were defined. The follow-up was divided into three periods (0–3, 3–9 and 9–20 years) for development and two corresponding validation periods (3–6 and 9–15 years). A multivariable complementary log–log regression model was used to calculate the full prognostic index. Predicted cause-specific survival at 10 years from diagnosis was calculated for the control arm using a simplified risk score at diagnosis. The full prognostic index discriminates well men with PCa with different survival. The area under the curve (AUC) was 0.83 for both the 3–6 year and 9–15 year validation periods. In the simplified risk score, patients with a low risk score at diagnosis had the most favorable survival, while the outcome was poorest for the patients with high risk scores. The prognostic index was able to distinguish well between men with higher and lower survival, and the simplified risk score can be used as a basis for decision making.

Published
2021

11. Prostate cancer risk prediction using a polygenic risk score

Author

Sipeky, Csilla, Talala, Kirsi, Tammela, Teuvo, Taari, K., Auvinen, Anssi, Schleutker, Johanna, HUS Abdominal Center, Clinicum, Urologian yksikkö, Department of Surgery, University of Helsinki, Helsinki University Hospital Area, Tampere University, Clinical Medicine, and Health Sciences

Subjects
Male, Multifactorial Inheritance, Urology, 3122 Cancers, lcsh:Medicine, SUSCEPTIBILITY, VARIANTS, Polymorphism, Single Nucleotide, BREAST, Article, Cohort Studies, Humans, Genetic Predisposition to Disease, lcsh:Science, Finland, Aged, Retrospective Studies, Aged, 80 and over, HERITABILITY, MORTALITY, lcsh:R, Prostatic Neoplasms, ASSOCIATION, Middle Aged, Prostate-Specific Antigen, 3126 Surgery, anesthesiology, intensive care, radiology, 3141 Health care science, Oncology, Risk factors, lcsh:Q, Biomarkers
Abstract

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

Published
2020

14. Expected impact of MRI related interreader variability on ProScreen prostate cancer screening trial

Author

Hietikko, R., primary, Kilpeläinen, T.P., additional, Kenttämies, A., additional, Ronkainen, J., additional, Ijäs, K., additional, Lind, K., additional, Marjasuo, S., additional, Oksala, J., additional, Oksanen, O., additional, Saarinen, T., additional, Savolainen, R., additional, Taari, K., additional, Tammela, T.L.J., additional, Mirtti, T., additional, Natunen, K., additional, Auvinen, A., additional, and Rannikko, A., additional

Published
2020
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15. Outcomes of prostate cancer screening among men using antidiabetic medication

Author

Vettenranta, A., Murtola, T. J., Talala, K., Taari, K., Stenman, U-H, Tammela, T. L. J., Auvinen, A., Tampere University, Clinical Medicine, Department of Surgery, Health Sciences, HUS Abdominal Center, Clinicum, Urologian yksikkö, Helsinki University Hospital Area, Medicum, and Department of Clinical Chemistry and Hematology

Subjects
Male, Risk, Databases, Factual, Epidemiology, Science, 3122 Cancers, Predictive markers, Article, Diabetes Complications, Humans, Hypoglycemic Agents, Early Detection of Cancer, Finland, Aged, Incidence, Prostate, Prostatic Neoplasms, Middle Aged, Prostate-Specific Antigen, 3126 Surgery, anesthesiology, intensive care, radiology, 3141 Health care science, Treatment Outcome, 3121 General medicine, internal medicine and other clinical medicine, Disease Progression, Medicine, Follow-Up Studies
Abstract

Diabetic men have decreased risk for prostate cancer (PCa) overall and lower PSA compared to non-diabetics. This may affect the outcomes of PSA-based screening. We investigated the effect of PSA-based screening at 4-year intervals on PCa incidence and mortality separately among users and non-users of antidiabetic medication with the hypothesis that screening would detect less low-grade cancer and more high-grade cancer in diabetic men. A cohort of 80,458 men from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) were linked to national prescription database to obtain information on antidiabetic medication purchases. PCa risk and mortality were compared between the FinRSPC screening arm (SA) and the control arm (CA) separately among users and non-users of antidiabetic medication. Among antidiabetic medication users median PSA was lower than in non-users (0.93 and 1.09 ng/ml, respectively, P for difference = 0.001). Screening increased overall PCa incidence compared to CA after the first screen both among medication users and non-users (HR 1.31, 95% CI 1.08-1.60 and HR 1.55, 95% CI 1.44-1.66, respectively). On the second and third screen the difference between SA and CA attenuated only among medication users. Detection of Gleason 6 tumors was lower among medication users, whereas no difference was observed in detection of Gleason 8-10 cancers. Concordantly, screening affected PCa mortality similarly regardless of antidiabetic medication use (HR 0.38, 95% CI 0.14-1.07 and HR 0.19, 95% CI 0.11-0.33 among users and non-users after three screens, respectively. P for difference = 0.18). Median PSA is lower in men using antidiabetic drugs than among non-users. Systematic PSA screening detects less low-risk tumors among medication users, whereas detection of high-risk tumors and mortality effects are similar regardless of medication use. This suggests that antidiabetic medication users may form a suitable target group for PCa screening, with less screening-related overdiagnosis of indolent tumors. publishedVersion

Published
2019

16. Germline variation at 8q24 and prostate cancer risk in men of European ancestry (vol 9, 4616, 2018)

Author

Matejcic, M, Saunders, EJ, Dadaev, T, Brook, MN, Wang, K, Sheng, X, Al Olama, AA, Schumacher, FR, Ingles, SA, Govindasami, K, Benlloch, S, Berndt, SI, Albanes, D, Koutros, S, Muir, K, Stevens, VL, Gapstur, SM, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Pashayan, N, Schleutker, J, Wolk, A, West, C, Mucci, L, Kraft, P, Cancel-Tassin, G, Sorensen, KD, Maehle, L, Grindedal, EM, Strom, SS, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Bensen, JT, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Khaw, K-T, Cannon-Albright, LA, Pandha, H, Thibodeau, SN, Schaid, DJ, Wiklund, F, Chanock, SJ, Easton, DF, Eeles, RA, Kote-Jarai, Z, Conti, DV, Haiman, CA, Henderson, BE, Stern, MC, Thwaites, A, Guy, M, Whitmore, I, Morgan, A, Fisher, C, Hazel, S, Livni, N, Cook, M, Fachal, L, Weinstein, S, Freeman, LEB, Hoover, RN, Machiela, MJ, Lophatananon, A, Carter, BD, Goodman, P, Moya, L, Srinivasan, S, Kedda, M-A, Yeadon, T, Eckert, A, Eklund, M, Cavalli-Bjoerkman, C, Dunning, AM, Sipeky, C, Hakansson, N, Elliott, R, Ranu, H, Giovannucci, E, Turman, C, Hunter, DJ, Cussenot, O, Orntoft, TF, Lane, A, Lewis, SJ, Davis, M, Key, TJ, Brown, P, Kulkarni, GS, Zlotta, AR, Fleshner, NE, Finelli, A, Mao, X, Marzec, J, MacInnis, RJ, Milne, R, Hopper, JL, Aguado, M, Bustamante, M, Castano-Vinyals, G, Gracia-Lavedan, E, Cecchini, L, Stampfer, M, Ma, J, Sellers, TA, Geybels, MS, Park, H, Zachariah, B, Kolb, S, Wokolorczyk, D, Lubinski, J, Kluzniak, W, Nielsen, SF, Weisher, M, Cuk, K, Vogel, W, Luedeke, M, Logothetis, CJ, Paulo, P, Cardoso, M, Maia, S, Silva, MP, Steele, L, Ding, YC, De Meerleer, G, De Langhe, S, Thierens, H, Lim, J, Tan, MH, Ong, AT, Lin, DW, Kachakova, D, Mitkova, A, Mitev, V, Parliament, M, Jenster, G, Bangma, C, Schroder, FH, Truong, T, Koudou, YA, Michael, A, Kierzek, A, Karlsson, A, Broms, M, Wu, H, Aukim-Hastie, C, Tillmans, L, Riska, S, McDonnell, SK, Dearnaley, D, Spurdle, A, Gardiner, R, Hayes, V, Butler, L, Taylor, R, Papargiris, M, Saunders, P, Kujala, P, Talala, K, Taari, K, Bentzen, S, Hicks, B, Vogt, A, Hutchinson, A, Cox, A, George, A, Toi, A, Evans, A, Van der Kwast, TH, Imai, T, Saito, S, Zhao, S-C, Ren, G, Zhang, Y, Yu, Y, Wu, Y, Wu, J, Zhou, B, Pedersen, J, Lobato-Busto, R, Manuel Ruiz-Dominguez, J, Mengual, L, Alcaraz, A, Pow-Sang, J, Herkommer, K, Vlahova, A, Dikov, T, Christova, S, Carracedo, A, Tretarre, B, Rebillard, X, Mulot, C, Adolfsson, J, Stattin, P, Johansson, J-E, Martin, RM, Thompson, IM, Chambers, S, Aitken, J, Horvath, L, Haynes, A-M, Tilley, W, Risbridger, G, Aly, M, Nordstrom, T, Pharoah, P, Tammela, TLJ, Murtola, T, Auvinen, A, Burnet, N, Barnett, G, Andriole, G, Klim, A, Drake, BF, Borre, M, Kerns, S, Ostrer, H, Zhang, H-W, Cao, G, Lin, J, Ling, J, Li, M, Feng, N, Li, J, He, W, Guo, X, Sun, Z, Wang, G, Guo, J, Southey, MC, FitzGerald, LM, Marsden, G, Gomez-Caamano, A, Carballo, A, Peleteiro, P, Calvo, P, Szulkin, R, Llorca, J, Dierssen-Sotos, T, Gomez-Acebo, I, Lin, H-Y, Ostrander, EA, Bisbjerg, R, Klarskov, P, Roder, MA, Iversen, P, Holleczek, B, Stegmaier, C, Schnoeller, T, Bohnert, P, John, EM, Ost, P, Teo, S-H, Gamulin, M, Kulis, T, Kastelan, Z, Slavov, C, Popov, E, Van den Broeck, T, Joniau, S, Larkin, S, Esteban Castelao, J, Martinez, ME, Van Schaik, RHN, Xu, J, Lindstrom, S, Riboli, E, Berry, C, Siddiq, A, Canzian, F, Kolonel, LN, Le Marchand, L, Freedman, M, Cenee, S, Sanchez, M, and Commission of the European Communities

Subjects
Multidisciplinary Sciences, Science & Technology, MD Multidisciplinary, Science & Technology - Other Topics, PRACTICAL Consortium
Abstract

Correction to: Nature Communications; https://doi.org/10.1038/s41467-018-06863-1, published online 5 November 2018.

Published
2019

19. Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

Author

Carter B.D., Kerns S., Ostrer H., Zhang H.-W., Cao G., Lin J., Li M., Feng N., Li J., He W., Guo X., Sun Z., Wang G., Guo J., Southey M.C., FitzGerald L.M., Marsden G., Gomez-Caamano A., Carballo A., Peleteiro P., Calvo P., Szulkin R., Llorca J., Dierssen-Sotos T., Gomez-Acebo I., Lin H.-Y., Ostrander E.A., Bisbjerg R., Klarskov P., Roder M.A., Iversen P., Holleczek B., Stegmaier C., Schnoeller T., Bohnert P., John E.M., Ost P., Teo S.-H., Gamulin M., Kulis T., Kastelan Z., Slavov C., Popov E., Van den Broeck T., Joniau S., Larkin S., Castelao J.E., Martinez M.E., van Schaik R.H.N., Xu J., Lindstrom S., Riboli E., Berry C., Siddiq A., Canzian F., Kolonel L.N., Le Marchand L., Freedman M., Cenee S., Sanchez M., Wiklund F., Chanock S.J., Easton D.F., Eeles R.A., Kote-Jarai Z., Conti D.V., Haiman C.A., Hutchinson A., Ling J., Papargiris M., Matejcic M., Saunders E.J., Dadaev T., Brook M.N., Wang K., Sheng X., Olama A.A.A., Schumacher F.R., Ingles S.A., Govindasami K., Benlloch S., Berndt S.I., Albanes D., Koutros S., Muir K., Stevens V.L., Gapstur S.M., Tangen C.M., Batra J., Clements J., Gronberg H., Pashayan N., Schleutker J., Wolk A., West C., Mucci L., Kraft P., Cancel-Tassin G., Sorensen K.D., Maehle L., Grindedal E.M., Strom S.S., Neal D.E., Hamdy F.C., Donovan J.L., Travis R.C., Hamilton R.J., Rosenstein B., Lu Y.-J., Giles G.G., Kibel A.S., Vega A., Bensen J.T., Kogevinas M., Penney K.L., Park J.Y., Stanford J.L., Cybulski C., Nordestgaard B.G., Brenner H., Maier C., Kim J., Teixeira M.R., Neuhausen S.L., De Ruyck K., Razack A., Newcomb L.F., Lessel D., Kaneva R., Usmani N., Claessens F., Townsend P.A., Dominguez M.G., Roobol M.J., Menegaux F., Khaw K.-T., Cannon-Albright L.A., Pandha H., Thibodeau S.N., Schaid D.J., Henderson B.E., Stern M.C., Thwaites A., Guy M., Whitmore I., Morgan A., Fisher C., Hazel S., Livni N., Cook M., Fachal L., Weinstein S., Beane Freeman L.E., Hoover R.N., Machiela M.J., Lophatananon A., Goodman P., Moya L., Srinivasan S., Kedda M.-A., Yeadon T., Eckert A., Eklund M., Cavalli-Bjoerkman C., Dunning A.M., Sipeky C., Hakansson N., Elliott R., Ranu H., Giovannucci E., Turman C., Hunter D.J., Cussenot O., Orntoft T.F., Lane A., Lewis S.J., Davis M., Key T.J., Brown P., Kulkarni G.S., Zlotta A.R., Fleshner N.E., Finelli A., Mao X., Marzec J., MacInnis R.J., Milne R., Hopper J.L., Aguado M., Bustamante M., Castano-Vinyals G., Gracia-Lavedan E., Cecchini L., Stampfer M., Ma J., Sellers T.A., Geybels M.S., Park H., Zachariah B., Kolb S., Wokolorczyk D., Jan Lubinski, Kluzniak W., Nielsen S.F., Weisher M., Cuk K., Vogel W., Luedeke M., Logothetis C.J., Paulo P., Cardoso M., Maia S., Silva M.P., Steele L., Ding Y.C., De Meerleer G., De Langhe S., Thierens H., Lim J., Tan M.H., Ong A.T., Lin D.W., Kachakova D., Mitkova A., Mitev V., Parliament M., Jenster G., Bangma C., Schroder F.H., Truong T., Koudou Y.A., Michael A., Kierzek A., Karlsson A., Broms M., Wu H., Aukim-Hastie C., Tillmans L., Riska S., McDonnell S.K., Dearnaley D., Spurdle A., Gardiner R., Hayes V., Butler L., Taylor R., Saunders P., Kujala P., Talala K., Taari K., Bentzen S., Hicks B., Vogt A., Cox A., George A., Toi A., Evans A., van der Kwast T.H., Imai T., Saito S., Zhao S.-C., Ren G., Zhang Y., Yu Y., Wu Y., Wu J., Zhou B., Pedersen J., Lobato-Busto R., Ruiz-Dominguez J.M., Mengual L., Alcaraz A., Pow-Sang J., Herkommer K., Vlahova A., Dikov T., Christova S., Carracedo A., Tretarre B., Rebillard X., Mulot C., Jan Adolfsson, Stattin P., Johansson J.-E., Martin R.M., Thompson I.M., Chambers S., Aitken J., Horvath L., Haynes A.-M., Tilley W., Risbridger G., Aly M., Nordstrom T., Pharoah P., Tammela T.L.J., Murtola T., Auvinen A., Burnet N., Barnett G., Andriole G., Klim A., Drake B.F., Borre M., Carter B.D., Kerns S., Ostrer H., Zhang H.-W., Cao G., Lin J., Li M., Feng N., Li J., He W., Guo X., Sun Z., Wang G., Guo J., Southey M.C., FitzGerald L.M., Marsden G., Gomez-Caamano A., Carballo A., Peleteiro P., Calvo P., Szulkin R., Llorca J., Dierssen-Sotos T., Gomez-Acebo I., Lin H.-Y., Ostrander E.A., Bisbjerg R., Klarskov P., Roder M.A., Iversen P., Holleczek B., Stegmaier C., Schnoeller T., Bohnert P., John E.M., Ost P., Teo S.-H., Gamulin M., Kulis T., Kastelan Z., Slavov C., Popov E., Van den Broeck T., Joniau S., Larkin S., Castelao J.E., Martinez M.E., van Schaik R.H.N., Xu J., Lindstrom S., Riboli E., Berry C., Siddiq A., Canzian F., Kolonel L.N., Le Marchand L., Freedman M., Cenee S., Sanchez M., Wiklund F., Chanock S.J., Easton D.F., Eeles R.A., Kote-Jarai Z., Conti D.V., Haiman C.A., Hutchinson A., Ling J., Papargiris M., Matejcic M., Saunders E.J., Dadaev T., Brook M.N., Wang K., Sheng X., Olama A.A.A., Schumacher F.R., Ingles S.A., Govindasami K., Benlloch S., Berndt S.I., Albanes D., Koutros S., Muir K., Stevens V.L., Gapstur S.M., Tangen C.M., Batra J., Clements J., Gronberg H., Pashayan N., Schleutker J., Wolk A., West C., Mucci L., Kraft P., Cancel-Tassin G., Sorensen K.D., Maehle L., Grindedal E.M., Strom S.S., Neal D.E., Hamdy F.C., Donovan J.L., Travis R.C., Hamilton R.J., Rosenstein B., Lu Y.-J., Giles G.G., Kibel A.S., Vega A., Bensen J.T., Kogevinas M., Penney K.L., Park J.Y., Stanford J.L., Cybulski C., Nordestgaard B.G., Brenner H., Maier C., Kim J., Teixeira M.R., Neuhausen S.L., De Ruyck K., Razack A., Newcomb L.F., Lessel D., Kaneva R., Usmani N., Claessens F., Townsend P.A., Dominguez M.G., Roobol M.J., Menegaux F., Khaw K.-T., Cannon-Albright L.A., Pandha H., Thibodeau S.N., Schaid D.J., Henderson B.E., Stern M.C., Thwaites A., Guy M., Whitmore I., Morgan A., Fisher C., Hazel S., Livni N., Cook M., Fachal L., Weinstein S., Beane Freeman L.E., Hoover R.N., Machiela M.J., Lophatananon A., Goodman P., Moya L., Srinivasan S., Kedda M.-A., Yeadon T., Eckert A., Eklund M., Cavalli-Bjoerkman C., Dunning A.M., Sipeky C., Hakansson N., Elliott R., Ranu H., Giovannucci E., Turman C., Hunter D.J., Cussenot O., Orntoft T.F., Lane A., Lewis S.J., Davis M., Key T.J., Brown P., Kulkarni G.S., Zlotta A.R., Fleshner N.E., Finelli A., Mao X., Marzec J., MacInnis R.J., Milne R., Hopper J.L., Aguado M., Bustamante M., Castano-Vinyals G., Gracia-Lavedan E., Cecchini L., Stampfer M., Ma J., Sellers T.A., Geybels M.S., Park H., Zachariah B., Kolb S., Wokolorczyk D., Jan Lubinski, Kluzniak W., Nielsen S.F., Weisher M., Cuk K., Vogel W., Luedeke M., Logothetis C.J., Paulo P., Cardoso M., Maia S., Silva M.P., Steele L., Ding Y.C., De Meerleer G., De Langhe S., Thierens H., Lim J., Tan M.H., Ong A.T., Lin D.W., Kachakova D., Mitkova A., Mitev V., Parliament M., Jenster G., Bangma C., Schroder F.H., Truong T., Koudou Y.A., Michael A., Kierzek A., Karlsson A., Broms M., Wu H., Aukim-Hastie C., Tillmans L., Riska S., McDonnell S.K., Dearnaley D., Spurdle A., Gardiner R., Hayes V., Butler L., Taylor R., Saunders P., Kujala P., Talala K., Taari K., Bentzen S., Hicks B., Vogt A., Cox A., George A., Toi A., Evans A., van der Kwast T.H., Imai T., Saito S., Zhao S.-C., Ren G., Zhang Y., Yu Y., Wu Y., Wu J., Zhou B., Pedersen J., Lobato-Busto R., Ruiz-Dominguez J.M., Mengual L., Alcaraz A., Pow-Sang J., Herkommer K., Vlahova A., Dikov T., Christova S., Carracedo A., Tretarre B., Rebillard X., Mulot C., Jan Adolfsson, Stattin P., Johansson J.-E., Martin R.M., Thompson I.M., Chambers S., Aitken J., Horvath L., Haynes A.-M., Tilley W., Risbridger G., Aly M., Nordstrom T., Pharoah P., Tammela T.L.J., Murtola T., Auvinen A., Burnet N., Barnett G., Andriole G., Klim A., Drake B.F., and Borre M.

Abstract

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 x 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.Copyright © 2018, The Author(s).

Published
2019

20. Erratum to: Germline variation at 8q24 and prostate cancer risk in men of European ancestry (Nature Communications, (2018), 9, 1, (4616), 10.1038/s41467-018-06863-1).

Author

Wang G., Lessel D., Kaneva R., Usmani N., Kastelan Z., Slavov C., Popov E., Van den Broeck T., Joniau S., Larkin S., Castelao J.E., Martinez M.E., van Schaik R.H.N., Xu J., Lindstrom S., Riboli E., Berry C., Siddiq A., Canzian F., Kolonel L.N., Le Marchand L., Freedman M., Cenee S., Sanchez M., Wiklund F., Chanock S.J., Easton D.F., Eeles R.A., Kote-Jarai Z., Conti D.V., Haiman C.A., Hutchinson A., Ling J., Papargiris M., Matejcic M., Saunders E.J., Dadaev T., Brook M.N., Wang K., Sheng X., Olama A.A.A., Schumacher F.R., Ingles S.A., Govindasami K., Benlloch S., Berndt S.I., Albanes D., Koutros S., Muir K., Stevens V.L., Gapstur S.M., Tangen C.M., Batra J., Clements J., Gronberg H., Pashayan N., Schleutker J., Wolk A., West C., Mucci L., Kraft P., Cancel-Tassin G., Sorensen K.D., Maehle L., Grindedal E.M., Strom S.S., Neal D.E., Hamdy F.C., Donovan J.L., Travis R.C., Hamilton R.J., Rosenstein B., Lu Y.-J., Giles G.G., Kibel A.S., Vega A., Bensen J.T., Kogevinas M., Penney K.L., Park J.Y., Stanford J.L., Cybulski C., Nordestgaard B.G., Brenner H., Maier C., Kim J., Teixeira M.R., Neuhausen S.L., De Ruyck K., Razack A., Newcomb L.F., Claessens F., Townsend P.A., Gago-Dominguez M., Roobol M.J., Menegaux F., Khaw K.-T., Cannon-Albright L.A., Pandha H., Thibodeau S.N., Schaid D.J., Henderson B.E., Stern M.C., Thwaites A., Guy M., Whitmore I., Morgan A., Fisher C., Hazel S., Livni N., Cook M., Fachal L., Weinstein S., Beane Freeman L.E., Hoover R.N., Machiela M.J., Lophatananon A., Carter B.D., Goodman P., Moya L., Srinivasan S., Kedda M.-A., Yeadon T., Eckert A., Eklund M., Cavalli-Bjoerkman C., Dunning A.M., Sipeky C., Hakansson N., Elliott R., Ranu H., Giovannucci E., Turman C., Hunter D.J., Cussenot O., Orntoft T.F., Lane A., Lewis S.J., Davis M., Key T.J., Brown P., Kulkarni G.S., Zlotta A.R., Fleshner N.E., Finelli A., Mao X., Marzec J., MacInnis R.J., Milne R., Hopper J.L., Aguado M., Bustamante M., Castano-Vinyals G., Gracia-Lavedan E., Cecchini L., Stampfer M., Ma J., Sellers T.A., Geybels M.S., Park H., Zachariah B., Kolb S., Wokolorczyk D., Lubinski J., Kluzniak W., Nielsen S.F., Weisher M., Cuk K., Vogel W., Luedeke M., Logothetis C.J., Paulo P., Cardoso M., Maia S., Silva M.P., Steele L., Ding Y.C., De Meerleer G., De Langhe S., Thierens H., Lim J., Tan M.H., Ong A.T., Lin D.W., Kachakova D., Mitkova A., Mitev V., Parliament M., Jenster G., Bangma C., Schroder F.H., Truong T., Koudou Y.A., Michael A., Kierzek A., Karlsson A., Broms M., Wu H., Aukim-Hastie C., Tillmans L., Riska S., McDonnell S.K., Dearnaley D., Spurdle A., Gardiner R., Hayes V., Butler L., Taylor R., Saunders P., Kujala P., Talala K., Taari K., Bentzen S., Hicks B., Vogt A., Cox A., George A., Toi A., Evans A., van der Kwast T.H., Imai T., Saito S., Zhao S.-C., Ren G., Zhang Y., Yu Y., Wu Y., Wu J., Zhou B., Pedersen J., Lobato-Busto R., Ruiz-Dominguez J.M., Mengual L., Alcaraz A., Pow-Sang J., Herkommer K., Vlahova A., Dikov T., Christova S., Carracedo A., Tretarre B., Rebillard X., Mulot C., Adolfsson J., Stattin P., Johansson J.-E., Martin R.M., Thompson I.M., Chambers S., Aitken J., Horvath L., Haynes A.-M., Tilley W., Risbridger G., Aly M., Nordstrom T., Pharoah P., Tammela T.L.J., Murtola T., Auvinen A., Burnet N., Barnett G., Andriole G., Klim A., Drake B.F., Borre M., Kerns S., Ostrer H., Zhang H.-W., Cao G., Lin J., Li M., Feng N., Li J., He W., Guo X., Sun Z., Guo J., Southey M.C., FitzGerald L.M., Marsden G., Gomez-Caamano A., Carballo A., Peleteiro P., Calvo P., Szulkin R., Llorca J., Dierssen-Sotos T., Gomez-Acebo I., Lin H.-Y., Ostrander E.A., Bisbjerg R., Klarskov P., Roder M.A., Iversen P., Holleczek B., Stegmaier C., Schnoeller T., Bohnert P., John E.M., Ost P., Teo S.-H., Gamulin M., Kulis T., Wang G., Lessel D., Kaneva R., Usmani N., Kastelan Z., Slavov C., Popov E., Van den Broeck T., Joniau S., Larkin S., Castelao J.E., Martinez M.E., van Schaik R.H.N., Xu J., Lindstrom S., Riboli E., Berry C., Siddiq A., Canzian F., Kolonel L.N., Le Marchand L., Freedman M., Cenee S., Sanchez M., Wiklund F., Chanock S.J., Easton D.F., Eeles R.A., Kote-Jarai Z., Conti D.V., Haiman C.A., Hutchinson A., Ling J., Papargiris M., Matejcic M., Saunders E.J., Dadaev T., Brook M.N., Wang K., Sheng X., Olama A.A.A., Schumacher F.R., Ingles S.A., Govindasami K., Benlloch S., Berndt S.I., Albanes D., Koutros S., Muir K., Stevens V.L., Gapstur S.M., Tangen C.M., Batra J., Clements J., Gronberg H., Pashayan N., Schleutker J., Wolk A., West C., Mucci L., Kraft P., Cancel-Tassin G., Sorensen K.D., Maehle L., Grindedal E.M., Strom S.S., Neal D.E., Hamdy F.C., Donovan J.L., Travis R.C., Hamilton R.J., Rosenstein B., Lu Y.-J., Giles G.G., Kibel A.S., Vega A., Bensen J.T., Kogevinas M., Penney K.L., Park J.Y., Stanford J.L., Cybulski C., Nordestgaard B.G., Brenner H., Maier C., Kim J., Teixeira M.R., Neuhausen S.L., De Ruyck K., Razack A., Newcomb L.F., Claessens F., Townsend P.A., Gago-Dominguez M., Roobol M.J., Menegaux F., Khaw K.-T., Cannon-Albright L.A., Pandha H., Thibodeau S.N., Schaid D.J., Henderson B.E., Stern M.C., Thwaites A., Guy M., Whitmore I., Morgan A., Fisher C., Hazel S., Livni N., Cook M., Fachal L., Weinstein S., Beane Freeman L.E., Hoover R.N., Machiela M.J., Lophatananon A., Carter B.D., Goodman P., Moya L., Srinivasan S., Kedda M.-A., Yeadon T., Eckert A., Eklund M., Cavalli-Bjoerkman C., Dunning A.M., Sipeky C., Hakansson N., Elliott R., Ranu H., Giovannucci E., Turman C., Hunter D.J., Cussenot O., Orntoft T.F., Lane A., Lewis S.J., Davis M., Key T.J., Brown P., Kulkarni G.S., Zlotta A.R., Fleshner N.E., Finelli A., Mao X., Marzec J., MacInnis R.J., Milne R., Hopper J.L., Aguado M., Bustamante M., Castano-Vinyals G., Gracia-Lavedan E., Cecchini L., Stampfer M., Ma J., Sellers T.A., Geybels M.S., Park H., Zachariah B., Kolb S., Wokolorczyk D., Lubinski J., Kluzniak W., Nielsen S.F., Weisher M., Cuk K., Vogel W., Luedeke M., Logothetis C.J., Paulo P., Cardoso M., Maia S., Silva M.P., Steele L., Ding Y.C., De Meerleer G., De Langhe S., Thierens H., Lim J., Tan M.H., Ong A.T., Lin D.W., Kachakova D., Mitkova A., Mitev V., Parliament M., Jenster G., Bangma C., Schroder F.H., Truong T., Koudou Y.A., Michael A., Kierzek A., Karlsson A., Broms M., Wu H., Aukim-Hastie C., Tillmans L., Riska S., McDonnell S.K., Dearnaley D., Spurdle A., Gardiner R., Hayes V., Butler L., Taylor R., Saunders P., Kujala P., Talala K., Taari K., Bentzen S., Hicks B., Vogt A., Cox A., George A., Toi A., Evans A., van der Kwast T.H., Imai T., Saito S., Zhao S.-C., Ren G., Zhang Y., Yu Y., Wu Y., Wu J., Zhou B., Pedersen J., Lobato-Busto R., Ruiz-Dominguez J.M., Mengual L., Alcaraz A., Pow-Sang J., Herkommer K., Vlahova A., Dikov T., Christova S., Carracedo A., Tretarre B., Rebillard X., Mulot C., Adolfsson J., Stattin P., Johansson J.-E., Martin R.M., Thompson I.M., Chambers S., Aitken J., Horvath L., Haynes A.-M., Tilley W., Risbridger G., Aly M., Nordstrom T., Pharoah P., Tammela T.L.J., Murtola T., Auvinen A., Burnet N., Barnett G., Andriole G., Klim A., Drake B.F., Borre M., Kerns S., Ostrer H., Zhang H.-W., Cao G., Lin J., Li M., Feng N., Li J., He W., Guo X., Sun Z., Guo J., Southey M.C., FitzGerald L.M., Marsden G., Gomez-Caamano A., Carballo A., Peleteiro P., Calvo P., Szulkin R., Llorca J., Dierssen-Sotos T., Gomez-Acebo I., Lin H.-Y., Ostrander E.A., Bisbjerg R., Klarskov P., Roder M.A., Iversen P., Holleczek B., Stegmaier C., Schnoeller T., Bohnert P., John E.M., Ost P., Teo S.-H., Gamulin M., and Kulis T.

Abstract

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.Copyright © 2019, The Author(s).

Published
2019

23. A population-based randomized trial of early detection of clinically significant prostate cancer (ProScreen): Pilot phase results

Author

Rannikko, A., primary, Kilpeläinen, T., additional, Matikainen, M., additional, Kenttämies, A., additional, Petas, A., additional, Santti, H., additional, Mirtti, T., additional, Rinta-Kiikka, I., additional, Kujala, P., additional, Taari, K., additional, Natunen, K., additional, Lilja, H., additional, Tammela, T., additional, and Auvinen, A., additional

Published
2019
Full Text
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30. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.

Author

Stampfer M., Ranu H., Hicks B., Vogt A., Cox A., Davis M., Brown P., George A., Marsden G., Lane A., Lewis S.J., Berry C., Kulkarni G.S., Toi A., Evans A., Zlotta A.R., Van Der Kwast T.H., Imai T., Saito S., Marzec J., Cao G., Lin J., Li M., Zhao S.-C., Ren G., Yu Y., Wu Y., Wu J., Zhou B., Zhang Y., Li J., He W., Guo J., Pedersen J., Hopper J.L., Milne R., Klim A., Carballo A., Lobato-Busto R., Peleteiro P., Calvo P., Aguado M., Ruiz-Dominguez J.M., Cecchini L., Mengual L., Alcaraz A., Bustamante M., Gracia-Lavedan E., Dierssen-Sotos T., Gomez-Acebo I., Pow-Sang J., Park H., Zachariah B., Kluzniak W., Kolb S., Klarskov P., Stegmaier C., Vogel W., Herkommer K., Bohnert P., Maia S., Silva M.P., De Langhe S., Thierens H., Tan M.H., Ong A.T., Kastelan Z., Popov E., Kachakova D., Mitkova A., Vlahova A., Dikov T., Christova S., Carracedo A., Bangma C., Schroder F.H., Cenee S., Tretarre B., Rebillard X., Mulot C., Sanchez M., Adolfsson J., Stattin P., Johansson J.-E., Cavalli-Bjoerkman C., Karlsson A., Broms M., Wu H., Tillmans L., Riska S., Freedman M., Wiklund F., Chanock S., Henderson B.E., Easton D.F., Haiman C.A., Eeles R.A., Conti D.V., Kote-Jarai Z., Hutchinson A., Ling J., Papargiris M., Dadaev T., Saunders E.J., Newcombe P.J., Anokian E., Leongamornlert D.A., Brook M.N., Cieza-Borrella C., Mijuskovic M., Wakerell S., Olama A.A.A., Schumacher F.R., Berndt S.I., Benlloch S., Ahmed M., Goh C., Sheng X., Zhang Z., Muir K., Govindasami K., Lophatananon A., Stevens V.L., Gapstur S.M., Carter B.D., Tangen C.M., Goodman P., Thompson I.M., Batra J., Chambers S., Moya L., Clements J., Horvath L., Tilley W., Risbridger G., Gronberg H., Aly M., Nordstrom T., Pharoah P., Pashayan N., Schleutker J., Tammela T.L.J., Sipeky C., Auvinen A., Albanes D., Weinstein S., Wolk A., Hakansson N., West C., Dunning A.M., Burnet N., Mucci L., Giovannucci E., Andriole G., Cussenot O., Cancel-Tassin G., Koutros S., Freeman L.E.B., Sorensen K.D., Orntoft T.F., Borre M., Maehle L., Grindedal E.M., Neal D.E., Donovan J.L., Hamdy F.C., Martin R.M., Travis R.C., Key T.J., Hamilton R.J., Fleshner N.E., Finelli A., Ingles S.A., Stern M.C., Rosenstein B., Kerns S., Ostrer H., Lu Y.-J., Zhang H.-W., Feng N., Mao X., Guo X., Wang G., Sun Z., Giles G.G., Southey M.C., MacInnis R.J., Fitzgerald L.M., Kibel A.S., Drake B.F., Vega A., Gomez-Caamano A., Fachal L., Szulkin R., Eklund M., Kogevinas M., Llorca J., Castano-Vinyals G., Penney K.L., Park J.Y., Sellers T.A., Lin H.-Y., Stanford J.L., Cybulski C., Wokolorczyk D., Lubinski J., Ostrander E.A., Geybels M.S., Nordestgaard Bo.G., Nielsen S.F., Weisher M., Bisbjerg R., Roder M.A., Iversen P., Brenner H., Cuk K., Holleczek B., Maier C., Luedeke M., Schnoeller T., Kim J., Logothetis C.J., John E.M., Teixeira M.R., Paulo P., Cardoso M., Neuhausen S.L., Steele L., Ding Y.C., De Ruyck K., De Meerleer G., Ost P., Razack A., Lim J., Teo S.-H., Lin D.W., Newcomb L.F., Lessel D., Gamulin M., Kulis T., Kaneva R., Usmani N., Slavov C., Mitev V., Parliament M., Singhal S., Claessens F., Joniau S., Van Den Broeck T., Larkin S., Townsend P.A., Aukim-Hastie C., Gago-Dominguez M., Castelao J.E., Martinez M.E., Roobol M.J., Jenster G., Van Schaik R.H.N., Menegaux F., Truong T., Koudou Y.A., Xu J., Khaw K.-T., Cannon-Albright L., Pandha H., Michael A., Kierzek A., Thibodeau S.N., McDonnell S.K., Schaid D.J., Lindstrom S., Turman C., Ma J., Hunter D.J., Riboli E., Siddiq A., Canzian F., Kolonel L.N., Le Marchand L., Hoover R.N., Machiela M.J., Kraft P., Cook M., Thwaites A., Guy M., Whitmore I., Morgan A., Fisher C., Hazel S., Livni N., Spurdle A., Srinivasan S., Kedda M.-A., Aitken J., Gardiner R., Hayes V., Butler L., Taylor R., Yeadon T., Eckert A., Saunders P., Haynes A.-M., Kujala P., Talala K., Murtola T., Taari K., Dearnaley D., Barnett G., Bentzen So., Elliott R., Stampfer M., Ranu H., Hicks B., Vogt A., Cox A., Davis M., Brown P., George A., Marsden G., Lane A., Lewis S.J., Berry C., Kulkarni G.S., Toi A., Evans A., Zlotta A.R., Van Der Kwast T.H., Imai T., Saito S., Marzec J., Cao G., Lin J., Li M., Zhao S.-C., Ren G., Yu Y., Wu Y., Wu J., Zhou B., Zhang Y., Li J., He W., Guo J., Pedersen J., Hopper J.L., Milne R., Klim A., Carballo A., Lobato-Busto R., Peleteiro P., Calvo P., Aguado M., Ruiz-Dominguez J.M., Cecchini L., Mengual L., Alcaraz A., Bustamante M., Gracia-Lavedan E., Dierssen-Sotos T., Gomez-Acebo I., Pow-Sang J., Park H., Zachariah B., Kluzniak W., Kolb S., Klarskov P., Stegmaier C., Vogel W., Herkommer K., Bohnert P., Maia S., Silva M.P., De Langhe S., Thierens H., Tan M.H., Ong A.T., Kastelan Z., Popov E., Kachakova D., Mitkova A., Vlahova A., Dikov T., Christova S., Carracedo A., Bangma C., Schroder F.H., Cenee S., Tretarre B., Rebillard X., Mulot C., Sanchez M., Adolfsson J., Stattin P., Johansson J.-E., Cavalli-Bjoerkman C., Karlsson A., Broms M., Wu H., Tillmans L., Riska S., Freedman M., Wiklund F., Chanock S., Henderson B.E., Easton D.F., Haiman C.A., Eeles R.A., Conti D.V., Kote-Jarai Z., Hutchinson A., Ling J., Papargiris M., Dadaev T., Saunders E.J., Newcombe P.J., Anokian E., Leongamornlert D.A., Brook M.N., Cieza-Borrella C., Mijuskovic M., Wakerell S., Olama A.A.A., Schumacher F.R., Berndt S.I., Benlloch S., Ahmed M., Goh C., Sheng X., Zhang Z., Muir K., Govindasami K., Lophatananon A., Stevens V.L., Gapstur S.M., Carter B.D., Tangen C.M., Goodman P., Thompson I.M., Batra J., Chambers S., Moya L., Clements J., Horvath L., Tilley W., Risbridger G., Gronberg H., Aly M., Nordstrom T., Pharoah P., Pashayan N., Schleutker J., Tammela T.L.J., Sipeky C., Auvinen A., Albanes D., Weinstein S., Wolk A., Hakansson N., West C., Dunning A.M., Burnet N., Mucci L., Giovannucci E., Andriole G., Cussenot O., Cancel-Tassin G., Koutros S., Freeman L.E.B., Sorensen K.D., Orntoft T.F., Borre M., Maehle L., Grindedal E.M., Neal D.E., Donovan J.L., Hamdy F.C., Martin R.M., Travis R.C., Key T.J., Hamilton R.J., Fleshner N.E., Finelli A., Ingles S.A., Stern M.C., Rosenstein B., Kerns S., Ostrer H., Lu Y.-J., Zhang H.-W., Feng N., Mao X., Guo X., Wang G., Sun Z., Giles G.G., Southey M.C., MacInnis R.J., Fitzgerald L.M., Kibel A.S., Drake B.F., Vega A., Gomez-Caamano A., Fachal L., Szulkin R., Eklund M., Kogevinas M., Llorca J., Castano-Vinyals G., Penney K.L., Park J.Y., Sellers T.A., Lin H.-Y., Stanford J.L., Cybulski C., Wokolorczyk D., Lubinski J., Ostrander E.A., Geybels M.S., Nordestgaard Bo.G., Nielsen S.F., Weisher M., Bisbjerg R., Roder M.A., Iversen P., Brenner H., Cuk K., Holleczek B., Maier C., Luedeke M., Schnoeller T., Kim J., Logothetis C.J., John E.M., Teixeira M.R., Paulo P., Cardoso M., Neuhausen S.L., Steele L., Ding Y.C., De Ruyck K., De Meerleer G., Ost P., Razack A., Lim J., Teo S.-H., Lin D.W., Newcomb L.F., Lessel D., Gamulin M., Kulis T., Kaneva R., Usmani N., Slavov C., Mitev V., Parliament M., Singhal S., Claessens F., Joniau S., Van Den Broeck T., Larkin S., Townsend P.A., Aukim-Hastie C., Gago-Dominguez M., Castelao J.E., Martinez M.E., Roobol M.J., Jenster G., Van Schaik R.H.N., Menegaux F., Truong T., Koudou Y.A., Xu J., Khaw K.-T., Cannon-Albright L., Pandha H., Michael A., Kierzek A., Thibodeau S.N., McDonnell S.K., Schaid D.J., Lindstrom S., Turman C., Ma J., Hunter D.J., Riboli E., Siddiq A., Canzian F., Kolonel L.N., Le Marchand L., Hoover R.N., Machiela M.J., Kraft P., Cook M., Thwaites A., Guy M., Whitmore I., Morgan A., Fisher C., Hazel S., Livni N., Spurdle A., Srinivasan S., Kedda M.-A., Aitken J., Gardiner R., Hayes V., Butler L., Taylor R., Yeadon T., Eckert A., Saunders P., Haynes A.-M., Kujala P., Talala K., Murtola T., Taari K., Dearnaley D., Barnett G., Bentzen So., and Elliott R.

Abstract

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.Copyright © 2018 The Author(s).

Published
2018

35. An Intraprostatic Modified Release Formulation of Antiandrogen 2-Hydroxyflutamide for Localized Prostate Cancer

Author

Tammela, T L, Häggman, Michael, Ladjevardi, Sam, Taari, K, Isotalo, T, Lennernäs, Hans, Weis, Jan, von Below, Catrin, Wassberg, Cecilia, Lennernäs, B, Tolf, Anna, Axén, N, Gölander, C-G, Ahlström, Håkan, Tammela, T L, Häggman, Michael, Ladjevardi, Sam, Taari, K, Isotalo, T, Lennernäs, Hans, Weis, Jan, von Below, Catrin, Wassberg, Cecilia, Lennernäs, B, Tolf, Anna, Axén, N, Gölander, C-G, and Ahlström, Håkan

Abstract

PURPOSE: To investigate tolerability, safety and antitumor effects of a novel intra-prostatic depot formulation of antiandrogen 2-hydroxyflutamide (2-HOF in NanoZolid(®)) in men with localized prostate cancer (PCa). MATERIALS AND METHODS: Two clinical trials, LPC-002 and LPC-003, were conducted on a total of 47 men. The formulation was injected transrectally into the prostate with ultrasound guidance. In LPC-002 the effects on prostate specific antigen (PSA) and prostate volume (PV) were measured over 6 months on 24 patients. In LPC-003, antitumor effects were evaluated with histopathology, magnetic resonance imaging (MRI) including spectroscopy (MRS) during 6 or 8 weeks on 23 patients. In both studies, testosterone and 2-HOF in plasma were measured, as well as quality-of-life parameters. RESULTS: In LPC-002 (mean dose 690 mg) a reduction in PSA and PV was observed. The nadir values for PSA and PV were on average 24.9 % and 14.0 % below baseline, respectively. When increasing the dose in LPC-003 (920 mg and 1740 mg), the average PSA dropped 16 % and 23 %, respectively, after 6 and 8 weeks. MRI/MRS showed morphological changes and a global drop in metabolite concentrations following treatment indicating an antitumor response. The injections did not result in hormone related side effects. In total, three serious adverse events were reported, all resolved by oral antibiotic treatment. CONCLUSIONS: The intraprostatic injections of 2-HOF depot formulations indicated anti-tumor effects and proved safe and tolerable. However, for better anti-cancer effects higher doses and better dose distribution are suggested.

Published
2017
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36. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author

Gusev, A, Shi, H, Kichaev, G, Pomerantz, M, Li, F, Long, HW, Ingles, SA, Kittles, RA, Strom, SS, Rybicki, BA, Nemesure, B, Isaacs, WB, Zheng, W, Pettaway, CA, Yeboah, ED, Tettey, Y, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Chokkalingam, AP, John, EM, Murphy, AB, Signorello, LB, Carpten, J, Leske, MC, Wu, S-Y, Hennis, AJM, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Witte, JS, Casey, G, Kaggwa, S, Cook, MB, Stram, DO, Blot, WJ, Eeles, RA, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Southey, MC, Fitzgerald, LM, Gronberg, H, Wiklund, F, Aly, M, Henderson, BE, Schleutker, J, Wahlfors, T, Tammela, TLJ, Nordestgaard, BG, Key, TJ, Travis, RC, Neal, DE, Donovan, JL, Hamdy, FC, Pharoah, P, Pashayan, N, Khaw, K-T, Stanford, JL, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Maier, C, Vogel, W, Luedeke, M, Herkommer, K, Kibel, AS, Cybulski, C, Wokolorczyk, D, Kluzniak, W, Cannon-Albright, L, Teerlink, C, Brenner, H, Dieffenbach, AK, Arndt, V, Park, JY, Sellers, TA, Lin, H-Y, Slavov, C, Kaneva, R, Mitev, V, Batra, J, Spurdle, A, Clements, JA, Teixeira, MR, Pandha, H, Michael, A, Paulo, P, Maia, S, Kierzek, A, Conti, DV, Albanes, D, Berg, C, Berndt, SI, Campa, D, Crawford, ED, Diver, WR, Gapstur, SM, Gaziano, JM, Giovannucci, E, Hoover, R, Hunter, DJ, Johansson, M, Kraft, P, Le Marchand, L, Lindstrom, S, Navarro, C, Overvad, K, Riboli, E, Siddiq, A, Stevens, VL, Trichopoulos, D, Vineis, P, Yeager, M, Trynka, G, Raychaudhuri, S, Schumacher, FR, Price, AL, Freedman, ML, Haiman, CA, Pasaniuc, B, Cook, M, Guy, M, Govindasami, K, Leongamornlert, D, Sawyer, EJ, Wilkinson, R, Saunders, EJ, Tymrakiewicz, M, Dadaev, T, Morgan, A, Fisher, C, Hazel, S, Livni, N, Lophatananon, A, Pedersen, J, Hopper, JL, Adolfson, J, Stattin, P, Johansson, J-E, Cavalli-Bjoerkman, C, Karlsson, A, Broms, M, Auvinen, A, Kujala, P, Maeaettaenen, L, Murtola, T, Taari, K, Weischer, M, Nielsen, SF, Klarskov, P, Roder, A, Iversen, P, Wallinder, H, Gustafsson, S, Cox, A, Brown, P, George, A, Marsden, G, Lane, A, Davis, M, Tillmans, L, Riska, S, Wang, L, Rinckleb, A, Lubiski, J, Stegmaier, C, Pow-Sang, J, Park, H, Radlein, S, Rincon, M, Haley, J, Zachariah, B, Kachakova, D, Popov, E, Mitkova, A, Vlahova, A, Dikov, T, Christova, S, Heathcote, P, Wood, G, Malone, G, Saunders, P, Eckert, A, Yeadon, T, Kerr, K, Collins, A, Turner, M, Srinivasan, S, Kedda, M-A, Alexander, K, Omara, T, Wu, H, Henrique, R, Pinto, P, Santos, J, Barros-Silva, J, and Consortium, PRACTICAL

Subjects
urologic and male genital diseases
Abstract

Although genome-wide association studies have identified over 100 risk loci that explain ~33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Published
2016

40. Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort

Author

Bonilla, C, Lewis, SJ, Martin, RM, Donovan, JL, Hamdy, FC, Neal, DE, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Pashayan, N, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Smith, GD, Cook, M, Morga, A, Lophatananon, A, Fisher, C, Leongamornlert, D, Saunders, EJ, Sawyer, EJ, Govindasami, K, Tymrakiewicz, M, Guy, M, Livni, N, Wilkinson, R, Jugurnauth-Little, S, Hazel, S, Dadaev, T, Southey, MC, Fitzgerald, LM, Pedersen, J, Hopper, J, Karlsson, A, Cavalli-Bjoerkman, C, Johansson, JE, Adolfson, J, Aly, M, Broms, M, Stattin, P, Henderson, BE, Schumacher, F, Auvinen, A, Taari, K, Maeaettaenen, L, Kujala, P, Murtola, T, Tammela, TLJ, Sipeky, C, Roder, MA, Iversen, P, Klarskov, P, Nielsen, SF, Weischer, M, Bonilla, C, Lewis, SJ, Martin, RM, Donovan, JL, Hamdy, FC, Neal, DE, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Pashayan, N, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Smith, GD, Cook, M, Morga, A, Lophatananon, A, Fisher, C, Leongamornlert, D, Saunders, EJ, Sawyer, EJ, Govindasami, K, Tymrakiewicz, M, Guy, M, Livni, N, Wilkinson, R, Jugurnauth-Little, S, Hazel, S, Dadaev, T, Southey, MC, Fitzgerald, LM, Pedersen, J, Hopper, J, Karlsson, A, Cavalli-Bjoerkman, C, Johansson, JE, Adolfson, J, Aly, M, Broms, M, Stattin, P, Henderson, BE, Schumacher, F, Auvinen, A, Taari, K, Maeaettaenen, L, Kujala, P, Murtola, T, Tammela, TLJ, Sipeky, C, Roder, MA, Iversen, P, Klarskov, P, Nielsen, SF, and Weischer, M

Abstract

© 2016 Bonilla et al. Background: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach. Methods: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample. Results: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade. Conclusions: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.

Published
2016

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