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1. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Author

Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon Y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Offman J., Kote-Jarai Z., Eeles R.A., Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon Y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Offman J., Kote-Jarai Z., and Eeles R.A.

Abstract

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHOD(S): The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3.0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This

Published
2022

3. Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Author

Teixeira M.R., Rhiem K., Izatt L., Tripathi V., Cardoso M., Foulkes W.D., Aprikian A., van Randeraad H., Davidson R., Longmuir M., Ruijs M.W.G., Adank M., Williams R., Andrews L., Murphy D.G., Halliday D., Walker L., Liljegren A., Carlsson S., Azzabi A., Jobson I., Morton C., Shackleton K., Snape K., Hanson H., Harris M., Tischkowitz M., Taylor A., Kirk J., Susman R., Chen-Shtoyerman R., Spigelman A., Pachter N., Ahmed M., Ramon y Cajal T., Zgajnar J., Brewer C., Gadea N., Brady A.F., van Os T., Gallagher D., Johannsson O., Donaldson A., Barwell J., Nicolai N., Friedman E., Obeid E., Greenhalgh L., Murthy V., Copakova L., Saya S., McGrath J., Cooke P., Ronlund K., Richardson K., Henderson A., Teo S.H., Arun B., Kast K., Dias A., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Eccles D.M., Tricker K., Eyfjord J., Falconer A., Foster C., Gronberg H., Hamdy F.C., Stefansdottir V., Khoo V., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A., Moynihan C., Rennert G., Suri M., Wilson P., Dudderidge T., Offman J., Kote-Jarai Z., Vickers A., Lilja H., Eeles R.A., Helderman van den Enden A.T.J.M., Page E.C., Bancroft E.K., Brook M.N., Assel M., Hassan Al Battat M., Thomas S., Taylor N., Chamberlain A., Pope J., Raghallaigh H.N., Evans D.G., Rothwell J., Maehle L., Grindedal E.M., James P., Mascarenhas L., McKinley J., Side L., Thomas T., van Asperen C., Vasen H., Kiemeney L.A., Ringelberg J., Jensen T.D., Osther P.J.S., Helfand B.T., Genova E., Oldenburg R.A., Cybulski C., Wokolorczyk D., Ong K.-R., Huber C., Lam J., Taylor L., Salinas M., Feliubadalo L., Oosterwijk J.C., van Zelst-Stams W., Cook J., Rosario D.J., Domchek S., Powers J., Buys S., O'Toole K., Ausems M.G.E.M., Schmutzler R.K., Teixeira M.R., Rhiem K., Izatt L., Tripathi V., Cardoso M., Foulkes W.D., Aprikian A., van Randeraad H., Davidson R., Longmuir M., Ruijs M.W.G., Adank M., Williams R., Andrews L., Murphy D.G., Halliday D., Walker L., Liljegren A., Carlsson S., Azzabi A., Jobson I., Morton C., Shackleton K., Snape K., Hanson H., Harris M., Tischkowitz M., Taylor A., Kirk J., Susman R., Chen-Shtoyerman R., Spigelman A., Pachter N., Ahmed M., Ramon y Cajal T., Zgajnar J., Brewer C., Gadea N., Brady A.F., van Os T., Gallagher D., Johannsson O., Donaldson A., Barwell J., Nicolai N., Friedman E., Obeid E., Greenhalgh L., Murthy V., Copakova L., Saya S., McGrath J., Cooke P., Ronlund K., Richardson K., Henderson A., Teo S.H., Arun B., Kast K., Dias A., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Eccles D.M., Tricker K., Eyfjord J., Falconer A., Foster C., Gronberg H., Hamdy F.C., Stefansdottir V., Khoo V., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A., Moynihan C., Rennert G., Suri M., Wilson P., Dudderidge T., Offman J., Kote-Jarai Z., Vickers A., Lilja H., Eeles R.A., Helderman van den Enden A.T.J.M., Page E.C., Bancroft E.K., Brook M.N., Assel M., Hassan Al Battat M., Thomas S., Taylor N., Chamberlain A., Pope J., Raghallaigh H.N., Evans D.G., Rothwell J., Maehle L., Grindedal E.M., James P., Mascarenhas L., McKinley J., Side L., Thomas T., van Asperen C., Vasen H., Kiemeney L.A., Ringelberg J., Jensen T.D., Osther P.J.S., Helfand B.T., Genova E., Oldenburg R.A., Cybulski C., Wokolorczyk D., Ong K.-R., Huber C., Lam J., Taylor L., Salinas M., Feliubadalo L., Oosterwijk J.C., van Zelst-Stams W., Cook J., Rosario D.J., Domchek S., Powers J., Buys S., O'Toole K., Ausems M.G.E.M., and Schmutzler R.K.

Abstract

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. Objective(s): To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. Design, setting, and participants: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. Outcome measurements and statistical analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. Results and limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at

Published
2019

4. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition (vol 118, pg 266, 2018)

Author

Mikropoulos, C., Selkirk, C.G.H., Saya, S., Bancroft, E., Vertosick, E., Dadaev, T., Brendler, C., Page, E., Dias, A., Evans, D.G., Rothwell, J., Maehle, L., Axcrona, K., Richardson, K., Eccles, D., Jensen, T., Osther, P.J., Asperen, C.J. van, Vasen, H., Kiemeney, L.A., Ringelberg, J., Cybulski, C., Wokolorczyk, D., Hart, R., Glover, W., Lam, J., Taylor, L., Salinas, M., Feliubadalo, L., Oldenburg, R., Cremers, R., Verhaegh, G., Zelst-Stams, W.A. van, Oosterwijk, J.C., Cook, J., Rosario, D.J., Buys, S.S., Conner, T., Domchek, S., Powers, J., Ausems, M.G.E.M., Teixeira, M.R., Maia, S., Izatt, L., Schmutzler, R., Rhiem, K., Foulkes, W.D., Boshari, T., Davidson, R., Ruijs, M., Helderman-van den Enden, A.T.J.M., Andrews, L., Walker, L., Snape, K., Henderson, A., Jobson, I., Lindeman, G.J., Liljegren, A., Harris, M., Adank, M.A., Kirk, J., Taylor, A., Susman, R., Chen-Shtoyerman, R., Pachter, N., Spigelman, A., Side, L., Zgajnar, J., Mora, J., Brewer, C., Gadea, N., Brady, A.F., Gallagher, D., Os, T. van, Donaldson, A., Stefansdottir, V., Barwell, J., James, P.A., Murphy, D., Friedman, E., Nicolai, N., Greenhalgh, L., Obeid, E., Murthy, V., Copakova, L., McGrath, J., Teo, S.H., Strom, S., Kast, K., Leongamornlert, D.A., Chamberlain, A., Pope, J., Newlin, A.C., Aaronson, N., Ardern-Jones, A., Bangma, C., Castro, E., Dearnaley, D., Eyfjord, J., Falconer, A., Foster, C.S., Gronberg, H., Hamdy, F.C., Johannsson, O., Khoo, V., Lubinski, J., Grindedal, E.M., McKinley, J., Shackleton, K., Mitra, A.V., Moynihan, C., Rennert, G., Suri, M., Tricker, K., Moss, S., Kote-Jarai, Z., Vickers, A., Lilja, H., Helfand, B.T., Eeles, R.A., and IMPACT Study Collaborators

Published
2018

5. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Author

Mikropoulos, C., Selkirk, C.G.H., Saya, S., Bancroft, E., Vertosick, E., Dadaev, T., Brendler, C., Page, E., Dias, A., Evans, D.G., Rothwell, J., Maehle, L., Axcrona, K., Richardson, K., Eccles, D., Jensen, T., Osther, P.J., Asperen, C.J. van, Vasen, H., Kiemeney, L.A., Ringelberg, J., Cybulski, C., Wokolorczyk, D., Hart, R., Glover, W., Lam, J., Taylor, L., Salinas, M., Feliubadalo, L., Oldenburg, R., Cremers, R., Verhaegh, G., Zelst-Stams, W.A. van, Oosterwijk, J.C., Cook, J., Rosario, D.J., Buys, S.S., Conner, T., Domchek, S., Powers, J., Ausems, M.G.E.M., Teixeira, M.R., Maia, S., Izatt, L., Schmutzler, R., Rhiem, K., Foulkes, W.D., Boshari, T., Davidson, R., Ruijs, M., Helderman-van den Enden, A.T.J.M., Andrews, L., Walker, L., Snape, K., Henderson, A., Jobson, I., Lindeman, G.J., Liljegren, A., Harris, M., Adank, M.A., Kirk, J., Taylor, A., Susman, R., Chen-Shtoyerman, R., Pachter, N., Spigelman, A., Side, L., Zgajnar, J., Mora, J., Brewer, C., Gadea, N., Brady, A.F., Gallagher, D., Os, T. van, Donaldson, A., Stefansdottir, V., Barwell, J., James, P.A., Murphy, D., Friedman, E., Nicolai, N., Greenhalgh, L., Obeid, E., Murthy, V., Copakova, L., McGrath, J., Teo, S.H., Strom, S., Kast, K., Leongamornlert, D.A., Chamberlain, A., Pope, J., Newlin, A.C., Aaronson, N., Ardern-Jones, A., Bangma, C., Castro, E., Dearnaley, D., Eyfjord, J., Falconer, A., Foster, C.S., Gronberg, H., Hamdy, F.C., Johannsson, O., Khoo, V., Lubinski, J., Grindedal, E.M., McKinley, J., Shackleton, K., Mitra, A.V., Moynihan, C., Rennert, G., Suri, M., Tricker, K., Moss, S., Kote-Jarai, Z., Vickers, A., Lilja, H., Helfand, B.T., Eeles, R.A., and IMPACT Study Collaborators

Subjects
predictive model, prostate cancer, BRCA1, urologic and male genital diseases, genetic predisposition, BRCA2, PSA velocity
Abstract

Background: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. Methods: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. Results: 1634 participants had >= 3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml(-1), PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P = 0.031) and BRCA2 status and PSAV (P = 0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. Conclusions: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

Published
2018

6. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Author

Mikropoulos, Christos, Selkirk, C., Saya, Sibel, Bancroft, Elizabeth, Vertosick, Emily, Dadaev, Tokhir, Kiemeney, L.A., Cremers, R.G., Verhaegh, G.W., Zelst-Stams, W.A. van, Helfand, B.T., Eeles, R.A., Mikropoulos, Christos, Selkirk, C., Saya, Sibel, Bancroft, Elizabeth, Vertosick, Emily, Dadaev, Tokhir, Kiemeney, L.A., Cremers, R.G., Verhaegh, G.W., Zelst-Stams, W.A. van, Helfand, B.T., and Eeles, R.A.

Abstract

Contains fulltext : 184032.pdf (publisher's version ) (Open Access)

Published
2018

7. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

Author

Izatt L., Davidson R., Ruijs M., Helderman-Van Den Enden A.T., Andrews L., Walker L., Snape K., Henderson A., Jobson I., Lindeman G.J., Liljegren A., Harris M., Adank M.A., Kirk J., Taylor A., Susman R., Chen-Shtoyerman R., Pachter N., Spigelman A., Side L., Zgajnar J., Mora J., Brewer C., Gadea N., Brady A.F., Gallagher D., Van Os T., Donaldson A., Stefansdottir V., Barwell J., James P.A., Murphy D., Friedman E., Nicolai N., Greenhalgh L., Obeid E., Murthy V., Copakova L., McGrath J., Teo S.-H., Strom S., Kast K., Leongamornlert D.A., Chamberlain A., Pope J., Newlin A.C., Aaronson N., Ardern-Jones A., Bangma C., Castro E., Dearnaley D., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lubinski J., Grindedal E.M., McKinley J., Shackleton K., Mitra A.V., Moynihan C., Rennert G., Suri M., Tricker K., Moss S., Kote-Jarai Z., Vickers A., Lilja H., Helfand B.T., Eeles R.A., Mikropoulos C., Selkirk C.G.H., Saya S., Bancroft E., Vertosick E., Dadaev T., Brendler C., Page E., Dias A., Evans D.G., Rothwell J., Maehle L., Axcrona K., Richardson K., Eccles D., Jensen T., Osther P.J., Van Asperen C.J., Vasen H., Kiemeney L.A., Ringelberg J., Cybulski C., Wokolorczyk D., Hart R., Glover W., Lam J., Taylor L., Salinas M., Feliubadalo L., Oldenburg R., Cremers R., Verhaegh G., Van Zelst-Stams W.A., Oosterwijk J.C., Cook J., Rosario D.J., Buys S.S., Conner T., Domchek S., Powers J., Ausems M.G., Teixeira M.R., Maia S., Schmutzler R., Rhiem K., Foulkes W.D., Boshari T., Izatt L., Davidson R., Ruijs M., Helderman-Van Den Enden A.T., Andrews L., Walker L., Snape K., Henderson A., Jobson I., Lindeman G.J., Liljegren A., Harris M., Adank M.A., Kirk J., Taylor A., Susman R., Chen-Shtoyerman R., Pachter N., Spigelman A., Side L., Zgajnar J., Mora J., Brewer C., Gadea N., Brady A.F., Gallagher D., Van Os T., Donaldson A., Stefansdottir V., Barwell J., James P.A., Murphy D., Friedman E., Nicolai N., Greenhalgh L., Obeid E., Murthy V., Copakova L., McGrath J., Teo S.-H., Strom S., Kast K., Leongamornlert D.A., Chamberlain A., Pope J., Newlin A.C., Aaronson N., Ardern-Jones A., Bangma C., Castro E., Dearnaley D., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lubinski J., Grindedal E.M., McKinley J., Shackleton K., Mitra A.V., Moynihan C., Rennert G., Suri M., Tricker K., Moss S., Kote-Jarai Z., Vickers A., Lilja H., Helfand B.T., Eeles R.A., Mikropoulos C., Selkirk C.G.H., Saya S., Bancroft E., Vertosick E., Dadaev T., Brendler C., Page E., Dias A., Evans D.G., Rothwell J., Maehle L., Axcrona K., Richardson K., Eccles D., Jensen T., Osther P.J., Van Asperen C.J., Vasen H., Kiemeney L.A., Ringelberg J., Cybulski C., Wokolorczyk D., Hart R., Glover W., Lam J., Taylor L., Salinas M., Feliubadalo L., Oldenburg R., Cremers R., Verhaegh G., Van Zelst-Stams W.A., Oosterwijk J.C., Cook J., Rosario D.J., Buys S.S., Conner T., Domchek S., Powers J., Ausems M.G., Teixeira M.R., Maia S., Schmutzler R., Rhiem K., Foulkes W.D., and Boshari T.

Abstract

Background:Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. Method(s):PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. Result(s):1634 participants had 3/43 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml -l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. Conclusion(s):PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

Published
2018

8. Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer

Author

Stacey, S.N., Kehr, B., Gudmundsson, J., Zink, F., Jonasdottir, A., Gudjonsson, S.A., Sigurdsson, A., Halldorsson, B.V., Agnarsson, B.A., Benediktsdottir, K.R., Aben, K.K.H., Vermeulen, S.H., Cremers, R.G., Panadero, A., Helfand, B.T., Cooper, P.R., Donovan, J.L., Hamdy, F.C., Jinga, V., Okamoto, I., Jonasson, J.G., Tryggvadottir, L., Johannsdottir, H., Kristinsdottir, A.M., Masson, G., Magnusson, O.T., Iordache, P.D., Helgason, A., Helgason, H., Sulem, P., Gudbjartsson, D.F., Kong, A., Jonsson, E., Barkardottir, R.B., Einarsson, G.V., Rafnar, T., Thorsteinsdottir, U., Mates, I.N., Neal, D.E., Catalona, W.J., Mayordomo, J.I., Kiemeney, L.A., Thorleifsson, G., Stefansson, K., Stacey, S.N., Kehr, B., Gudmundsson, J., Zink, F., Jonasdottir, A., Gudjonsson, S.A., Sigurdsson, A., Halldorsson, B.V., Agnarsson, B.A., Benediktsdottir, K.R., Aben, K.K.H., Vermeulen, S.H., Cremers, R.G., Panadero, A., Helfand, B.T., Cooper, P.R., Donovan, J.L., Hamdy, F.C., Jinga, V., Okamoto, I., Jonasson, J.G., Tryggvadottir, L., Johannsdottir, H., Kristinsdottir, A.M., Masson, G., Magnusson, O.T., Iordache, P.D., Helgason, A., Helgason, H., Sulem, P., Gudbjartsson, D.F., Kong, A., Jonsson, E., Barkardottir, R.B., Einarsson, G.V., Rafnar, T., Thorsteinsdottir, U., Mates, I.N., Neal, D.E., Catalona, W.J., Mayordomo, J.I., Kiemeney, L.A., Thorleifsson, G., and Stefansson, K.

Abstract

Contains fulltext : 172827.pdf (publisher's version ) (Open Access), Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 x 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 x 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 x 10(-7)).

Published
2016

9. A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

Author

Gudmundsson, J., Sulem, P., Gudbjartsson, D.F., Masson, G., Agnarsson, B.A., Benediktsdottir, K.R., Sigurdsson, A., Magnusson, O.T., Gudjonsson, S.A., Magnusdottir, D.N., Johannsdottir, H., Helgadottir, H.T., Stacey, S.N., Jonasdottir, A., Olafsdottir, S.B., Thorleifsson, G., Jonasson, J.G., Tryggvadottir, L., Navarrete, S., Fuertes, F., Helfand, B.T., Hu, Q., Csiki, I.E., Mates, I.N., Jinga, V., Aben, K.K.H., Oort, I.M. van, Vermeulen, S., Donovan, J.L., Hamdy, F.C., Ng, C.F., Chiu, P.K., Lau, K.M., Ng, M.C., Gulcher, J.R., Kong, A., Catalona, W.J., Mayordomo, J.I., Einarsson, G.V., Barkardottir, R.B., Jonsson, E., Mates, D., Neal, D.E., Kiemeney, L.A.L.M., Thorsteinsdottir, U., Rafnar, T., Stefansson, K., Gudmundsson, J., Sulem, P., Gudbjartsson, D.F., Masson, G., Agnarsson, B.A., Benediktsdottir, K.R., Sigurdsson, A., Magnusson, O.T., Gudjonsson, S.A., Magnusdottir, D.N., Johannsdottir, H., Helgadottir, H.T., Stacey, S.N., Jonasdottir, A., Olafsdottir, S.B., Thorleifsson, G., Jonasson, J.G., Tryggvadottir, L., Navarrete, S., Fuertes, F., Helfand, B.T., Hu, Q., Csiki, I.E., Mates, I.N., Jinga, V., Aben, K.K.H., Oort, I.M. van, Vermeulen, S., Donovan, J.L., Hamdy, F.C., Ng, C.F., Chiu, P.K., Lau, K.M., Ng, M.C., Gulcher, J.R., Kong, A., Catalona, W.J., Mayordomo, J.I., Einarsson, G.V., Barkardottir, R.B., Jonsson, E., Mates, D., Neal, D.E., Kiemeney, L.A.L.M., Thorsteinsdottir, U., Rafnar, T., and Stefansson, K.

Abstract

Contains fulltext : 108025.pdf (publisher's version ) (Closed access), In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 x 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2)

Published
2012

10. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

Author

Stacey, S.N., Sulem, P., Jonasdottir, A., Masson, G., Gudmundsson, J., Gudbjartsson, D.F., Magnusson, O.T., Gudjonsson, S.A., Sigurgeirsson, B., Thorisdottir, K., Ragnarsson, R., Benediktsdottir, K.R., Nexo, B.A., Tjonneland, A., Overvad, K., Rudnai, P., Gurzau, E, Koppova, K., Hemminki, K., Corredera, C., Fuentelsaz, V., Grasa, P., Navarrete, S., Fuertes, F., Garcia-Prats, M.D., Sanambrosio, E., Panadero, A., Juan, A. de, Garcia, A., Rivera, F., Planelles, D., Soriano, V., Requena, C., Aben, K.K.H., Rossum, M.M. van, Cremers, R.G.H.M., Oort, I.M. van, Spronsen, D.J. van, Schalken, J.A., Peters, W.H.M., Helfand, B.T., Donovan, J.L., Hamdy, F.C., Badescu, D., Codreanu, O., Jinga, M., Csiki, I.E., Constantinescu, V., Badea, P., Mates, I.N., Dinu, D.E., Constantin, A., Mates, D., Kristjansdottir, S., Agnarsson, B.A., Jonsson, E., Barkardottir, R.B., Einarsson, G.V., Sigurdsson, F., Moller, P.H., Stefansson, T., Valdimarsson, T., Johannsson, O.T., Sigurdsson, H., Jonsson, T., Jonasson, J.G., Tryggvadottir, L., Rice, T., Hansen, H.M., Xiao, Y., Lachance, D.H., Kosel, M.L., Decker, P.A., Thorleifsson, G., Johannsdottir, H., Helgadottir, H.T., Sigurdsson, A., Steinthorsdottir, V., Lindblom, A., Sandler, R.S., Keku, T.O., Banasik, K., Jorgensen, T., Witte, D.R., Hansen, T., Pedersen, O., Jinga, V., Neal, D.E., Catalona, W.J., Wrensch, M., Wiencke, J., Jenkins, R.B., Nagore, E., Vogel, U., Kiemeney, L.A.L.M., Kumar, R., Mayordomo, J.I., Olafsson, J.H., et al., Stacey, S.N., Sulem, P., Jonasdottir, A., Masson, G., Gudmundsson, J., Gudbjartsson, D.F., Magnusson, O.T., Gudjonsson, S.A., Sigurgeirsson, B., Thorisdottir, K., Ragnarsson, R., Benediktsdottir, K.R., Nexo, B.A., Tjonneland, A., Overvad, K., Rudnai, P., Gurzau, E, Koppova, K., Hemminki, K., Corredera, C., Fuentelsaz, V., Grasa, P., Navarrete, S., Fuertes, F., Garcia-Prats, M.D., Sanambrosio, E., Panadero, A., Juan, A. de, Garcia, A., Rivera, F., Planelles, D., Soriano, V., Requena, C., Aben, K.K.H., Rossum, M.M. van, Cremers, R.G.H.M., Oort, I.M. van, Spronsen, D.J. van, Schalken, J.A., Peters, W.H.M., Helfand, B.T., Donovan, J.L., Hamdy, F.C., Badescu, D., Codreanu, O., Jinga, M., Csiki, I.E., Constantinescu, V., Badea, P., Mates, I.N., Dinu, D.E., Constantin, A., Mates, D., Kristjansdottir, S., Agnarsson, B.A., Jonsson, E., Barkardottir, R.B., Einarsson, G.V., Sigurdsson, F., Moller, P.H., Stefansson, T., Valdimarsson, T., Johannsson, O.T., Sigurdsson, H., Jonsson, T., Jonasson, J.G., Tryggvadottir, L., Rice, T., Hansen, H.M., Xiao, Y., Lachance, D.H., Kosel, M.L., Decker, P.A., Thorleifsson, G., Johannsdottir, H., Helgadottir, H.T., Sigurdsson, A., Steinthorsdottir, V., Lindblom, A., Sandler, R.S., Keku, T.O., Banasik, K., Jorgensen, T., Witte, D.R., Hansen, T., Pedersen, O., Jinga, V., Neal, D.E., Catalona, W.J., Wrensch, M., Wiencke, J., Jenkins, R.B., Nagore, E., Vogel, U., Kiemeney, L.A.L.M., Kumar, R., Mayordomo, J.I., Olafsson, J.H., and et al.

Abstract

Contains fulltext : 97569.pdf (publisher's version ) (Closed access), To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 x 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 x 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 x 10(-6)), glioma (OR = 2.35, P = 1.0 x 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 x 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).

Published
2011

11. Genetic correction of PSA values using sequence variants associated with PSA levels.

Author

Gudmundsson, J., Besenbacher, S., Sulem, P., Gudbjartsson, D.F., Olafsson, I., Arinbjarnarson, S., Agnarsson, B.A., Benediktsdottir, K.R., Isaksson, H.J., Kostic, J.P., Gudjonsson, S.A., Stacey, S.N., Gylfason, A, Sigurdsson, A., Holm, H., Bjornsdottir, U.S., Eyjolfsson, G.I., Navarrete, S., Fuertes, F., Garcia-Prats, M.D., Polo, E., Checherita, I.A., Jinga, M., Badea, P., Aben, K.K.H., Schalken, J.A., Oort, I.M. van, Sweep, C.G.J., Helfand, B.T., Davis, M., Donovan, J.L., Hamdy, F.C., Kristjansson, K., Gulcher, J.R., Masson, G., Kong, A., Catalona, W.J., Mayordomo, J.I., Geirsson, G., Einarsson, G.V., Barkardottir, R.B., Jonsson, E., Jinga, V., Mates, D., Kiemeney, L.A.L.M., Neal, D.E., Thorsteinsdottir, U., Rafnar, T., Stefansson, K., Gudmundsson, J., Besenbacher, S., Sulem, P., Gudbjartsson, D.F., Olafsson, I., Arinbjarnarson, S., Agnarsson, B.A., Benediktsdottir, K.R., Isaksson, H.J., Kostic, J.P., Gudjonsson, S.A., Stacey, S.N., Gylfason, A, Sigurdsson, A., Holm, H., Bjornsdottir, U.S., Eyjolfsson, G.I., Navarrete, S., Fuertes, F., Garcia-Prats, M.D., Polo, E., Checherita, I.A., Jinga, M., Badea, P., Aben, K.K.H., Schalken, J.A., Oort, I.M. van, Sweep, C.G.J., Helfand, B.T., Davis, M., Donovan, J.L., Hamdy, F.C., Kristjansson, K., Gulcher, J.R., Masson, G., Kong, A., Catalona, W.J., Mayordomo, J.I., Geirsson, G., Einarsson, G.V., Barkardottir, R.B., Jonsson, E., Jinga, V., Mates, D., Kiemeney, L.A.L.M., Neal, D.E., Thorsteinsdottir, U., Rafnar, T., and Stefansson, K.

Abstract

Item does not contain fulltext, Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 x 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.

Published
2010

12. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility.

Author

Gudmundsson, J., Sulem, P., Gudbjartsson, D.F., Blondal, T., Gylfason, A, Agnarsson, B.A., Benediktsdottir, K.R., Magnusdottir, D.N., Orlygsdottir, G., Jakobsdottir, M., Stacey, S.N., Sigurdsson, A., Wahlfors, T., Tammela, T., Breyer, J.P., McReynolds, K.M., Bradley, K.M., Saez, B., Godino, J., Navarrete, S., Fuertes, F., Murillo, L., Polo, E., Aben, K.K.H., Oort, I.M. van, Suarez, B.K., Helfand, B.T., Kan, D., Zanone, C., Frigge, M.L., Kristjansson, K., Gulcher, J.R., Einarsson, G.V., Jonsson, E., Catalona, W.J., Mayordomo, J.I., Kiemeney, L.A.L.M., Smith, J.R., Schleutker, J., Barkardottir, R.B., Kong, A., Thorsteinsdottir, U., Rafnar, T., Stefansson, K., Gudmundsson, J., Sulem, P., Gudbjartsson, D.F., Blondal, T., Gylfason, A, Agnarsson, B.A., Benediktsdottir, K.R., Magnusdottir, D.N., Orlygsdottir, G., Jakobsdottir, M., Stacey, S.N., Sigurdsson, A., Wahlfors, T., Tammela, T., Breyer, J.P., McReynolds, K.M., Bradley, K.M., Saez, B., Godino, J., Navarrete, S., Fuertes, F., Murillo, L., Polo, E., Aben, K.K.H., Oort, I.M. van, Suarez, B.K., Helfand, B.T., Kan, D., Zanone, C., Frigge, M.L., Kristjansson, K., Gulcher, J.R., Einarsson, G.V., Jonsson, E., Catalona, W.J., Mayordomo, J.I., Kiemeney, L.A.L.M., Smith, J.R., Schleutker, J., Barkardottir, R.B., Kong, A., Thorsteinsdottir, U., Rafnar, T., and Stefansson, K.

Abstract

Contains fulltext : 80628.pdf (publisher's version ) (Closed access), We report a prostate cancer genome-wide association follow-on study. We discovered four variants associated with susceptibility to prostate cancer in several European populations: rs10934853[A] (OR = 1.12, P = 2.9 x 10(-10)) on 3q21.3; two moderately correlated (r2 = 0.07) variants, rs16902094[G] (OR = 1.21, P = 6.2 x 10(-15)) and rs445114[T] (OR = 1.14, P = 4.7 x 10(-10)), on 8q24.21; and rs8102476[C] (OR = 1.12, P = 1.6 x 10(-11)) on 19q13.2. We also refined a previous association signal on 11q13 with the SNP rs11228565[A] (OR = 1.23, P = 6.7 x 10(-12)). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, we estimated that carriers in the top 1.3% of the risk distribution are at a 2.5 times greater risk of developing the disease than members of the general population.

Published
2009

13. Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer.

Author

Gudmundsson, J., Sulem, P., Rafnar, T., Bergthorsson, J.T., Manolescu, A., Gudbjartsson, D.F., Agnarsson, B.A., Sigurdsson, A., Benediktsdottir, K.R., Blondal, T., Jakobsdottir, M., Stacey, S.N., Kostic, J., Kristinsson, K.T., Birgisdottir, B., Ghosh, S., Magnusdottir, D., Thorlacius, S., Thorleifsson, G., Zheng, S.L., Sun, J., Chang, B.L., Elmore, J.B., Breyer, J.P., McReynolds, K.M., Bradley, K.M., Yaspan, B.L., Wiklund, F., Stattin, P, Lindstrom, S., Adami, H.O., McDonnell, S.K., Schaid, D.J., Cunningham, J.M., Wang, L., Cerhan, J.R., Sauver, J.L. St, Isaacs, S.D., Wiley, K.E., Partin, A.W., Walsh, P.C., Polo, S., Ruiz-Echarri, M., Navarrete, S., Fuertes, F., Saez, B., Godino, J., Weijerman, P.C., Swinkels, D.W., Aben, K.K.H., Witjes, J.A., Suarez, B.K., Helfand, B.T., Frigge, M.L., Kristjansson, K., Ober, C., Jonsson, E., Einarsson, G.V., Xu, J., Gronberg, H., Smith, J.R., Thibodeau, S.N., Isaacs, W.B., Catalona, W.J., Mayordomo, J.I., Kiemeney, L.A.L.M., Barkardottir, R.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Stefansson, K., Gudmundsson, J., Sulem, P., Rafnar, T., Bergthorsson, J.T., Manolescu, A., Gudbjartsson, D.F., Agnarsson, B.A., Sigurdsson, A., Benediktsdottir, K.R., Blondal, T., Jakobsdottir, M., Stacey, S.N., Kostic, J., Kristinsson, K.T., Birgisdottir, B., Ghosh, S., Magnusdottir, D., Thorlacius, S., Thorleifsson, G., Zheng, S.L., Sun, J., Chang, B.L., Elmore, J.B., Breyer, J.P., McReynolds, K.M., Bradley, K.M., Yaspan, B.L., Wiklund, F., Stattin, P, Lindstrom, S., Adami, H.O., McDonnell, S.K., Schaid, D.J., Cunningham, J.M., Wang, L., Cerhan, J.R., Sauver, J.L. St, Isaacs, S.D., Wiley, K.E., Partin, A.W., Walsh, P.C., Polo, S., Ruiz-Echarri, M., Navarrete, S., Fuertes, F., Saez, B., Godino, J., Weijerman, P.C., Swinkels, D.W., Aben, K.K.H., Witjes, J.A., Suarez, B.K., Helfand, B.T., Frigge, M.L., Kristjansson, K., Ober, C., Jonsson, E., Einarsson, G.V., Xu, J., Gronberg, H., Smith, J.R., Thibodeau, S.N., Isaacs, W.B., Catalona, W.J., Mayordomo, J.I., Kiemeney, L.A.L.M., Barkardottir, R.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., and Stefansson, K.

Abstract

Contains fulltext : 70723.pdf (publisher's version ) (Closed access), We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.

Published
2008

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