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Genetically adjusted PSA levels for prostate cancer screening

Kachuri, Linda ; Hoffmann, Thomas J ; Jiang, Yu ; Berndt, Sonja I ; Shelley, John P ; Schaffer, Kerry R ; Machiela, Mitchell J ; Freedman, Neal D ; Huang, Wen-Yi and Li, Shengchao A , et al. (2023) In Nature Medicine 29(6). p.1412-1423
Abstract

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10
-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS
PSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly... (More)

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10
-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS
PSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10
-14, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10
-12, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10
-4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Medicine
volume
29
issue
6
pages
1412 - 1423
publisher
Nature Publishing Group
external identifiers
  • pmid:37264206
  • scopus:85160847402
ISSN
1546-170X
DOI
10.1038/s41591-023-02277-9
language
English
LU publication?
yes
additional info
© 2023. The Author(s).
id
4bae3c8d-b5ed-49b2-852b-fa4559427b24
date added to LUP
2023-06-10 12:11:14
date last changed
2024-02-19 20:42:37
@article{4bae3c8d-b5ed-49b2-852b-fa4559427b24,
  abstract     = {{<p>Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P &lt; 5 × 10<br>
 -8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS<br>
 PSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score &lt;7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10<br>
 -14, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10<br>
 -12, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10<br>
 -4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.<br>
 </p>}},
  author       = {{Kachuri, Linda and Hoffmann, Thomas J and Jiang, Yu and Berndt, Sonja I and Shelley, John P and Schaffer, Kerry R and Machiela, Mitchell J and Freedman, Neal D and Huang, Wen-Yi and Li, Shengchao A and Easterlin, Ryder and Goodman, Phyllis J and Till, Cathee and Thompson, Ian and Lilja, Hans and Van Den Eeden, Stephen K and Chanock, Stephen J and Haiman, Christopher A and Conti, David V and Klein, Robert J and Mosley, Jonathan D and Graff, Rebecca E and Witte, John S}},
  issn         = {{1546-170X}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{1412--1423}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Medicine}},
  title        = {{Genetically adjusted PSA levels for prostate cancer screening}},
  url          = {{http://dx.doi.org/10.1038/s41591-023-02277-9}},
  doi          = {{10.1038/s41591-023-02277-9}},
  volume       = {{29}},
  year         = {{2023}},
}