Polygenic hazard score to guide screening for aggressive - prostate cancer: development and validation in large scale - cohorts
Teuvo LJ Tammela; Wojciech Kluzniak; Paul Pharoah; Chavdar Slavov; Fredrik Wiklund; Jenny L Donovan; Sune F Nielsen; Rasmus Bisbjerg; Ole A Andreassen; Tim J Key; ZSofia Kote-Jarai; Sara Benlloch Garcia; Roshan Karunamuni; Katarina Cuk; Manuel R Teixeira; Rosalind A Eeles; Dominika Wokolorczyk; Kay-Tee Khaw; Csilla Sipeky; Verena Zuber; Walther Vogel; Yunpeng Wang; David E Neal; Adam S Kibel; Christiane Maier; Vanio Mitev; Kai-Uwe Saum; Ali Amin Al Olama; Sofia Maia; Lisa Cannon-Albright; Paula Paulo; Manuel Luedeke; The PRACTICAL Consortium; Kathleen Herkommer; J Kellogg Parsons; Radka Kaneva; Jyotsna Batra; Hermann Brenner; Freddie C Hamdy; Johanna Schleutker; Jong Y Park; Amanda Spurdle; Maren Weischer; Peter Iversen; David S Karow; Ruth C Travis; Henrik Grönberg; Andrzej Kierzek; Cezary Cybulski; Agnieszka Michael; M Andreas Røder; Thomas A Sellers; Kenneth Muir; Douglas F Easton; Judith A Clements; Anders M Dale; Chun Chieh Fan; Børge G Nordestgaard; Nora Pashayan; Ian G Mills; Markus Aly; Tyler M Seibert; Hardev Pandha
Polygenic hazard score to guide screening for aggressive - prostate cancer: development and validation in large scale - cohorts
Teuvo LJ Tammela
Wojciech Kluzniak
Paul Pharoah
Chavdar Slavov
Fredrik Wiklund
Jenny L Donovan
Sune F Nielsen
Rasmus Bisbjerg
Ole A Andreassen
Tim J Key
ZSofia Kote-Jarai
Sara Benlloch Garcia
Roshan Karunamuni
Katarina Cuk
Manuel R Teixeira
Rosalind A Eeles
Dominika Wokolorczyk
Kay-Tee Khaw
Csilla Sipeky
Verena Zuber
Walther Vogel
Yunpeng Wang
David E Neal
Adam S Kibel
Christiane Maier
Vanio Mitev
Kai-Uwe Saum
Ali Amin Al Olama
Sofia Maia
Lisa Cannon-Albright
Paula Paulo
Manuel Luedeke
The PRACTICAL Consortium
Kathleen Herkommer
J Kellogg Parsons
Radka Kaneva
Jyotsna Batra
Hermann Brenner
Freddie C Hamdy
Johanna Schleutker
Jong Y Park
Amanda Spurdle
Maren Weischer
Peter Iversen
David S Karow
Ruth C Travis
Henrik Grönberg
Andrzej Kierzek
Cezary Cybulski
Agnieszka Michael
M Andreas Røder
Thomas A Sellers
Kenneth Muir
Douglas F Easton
Judith A Clements
Anders M Dale
Chun Chieh Fan
Børge G Nordestgaard
Nora Pashayan
Ian G Mills
Markus Aly
Tyler M Seibert
Hardev Pandha
BMJ PUBLISHING GROUP
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042718839
https://urn.fi/URN:NBN:fi-fe2021042718839
Tiivistelmä
OBJECTIVESTo develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age.DESIGNAnalysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score >= 7, stage T3-T4, PSA (prostate specific antigen) concentration >= 10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa.SETTINGMultiple institutions that were members of international PRACTICAL consortium.PARTICIPANTSAll consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men.MAIN OUTCOME MEASURESPrediction with hazard score of age of onset of aggressive cancer in validation set.RESULTSIn the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z= 11.2, P< 10(-16)). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P= 0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score.CONCLUSIONSPolygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.
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