Incorporating known genetic variants does not improve the accuracy of psa testing to identify high risk prostate cancer on biopsy

Gilbert, Rebecca, Martin, Richard M., Evans, David M., Tilling, Kate, Smith, George Davey, Kemp, John P., Lane, J. Athene, Hamdy, Freddie C., Neal, David E., Donovan, Jenny L. and Metcalfe, Chris (2015) Incorporating known genetic variants does not improve the accuracy of psa testing to identify high risk prostate cancer on biopsy. PL o S One, 10 10: 1-17. doi:10.1371/journal.pone.0136735

Author Gilbert, Rebecca
Martin, Richard M.
Evans, David M.
Tilling, Kate
Smith, George Davey
Kemp, John P.
Lane, J. Athene
Hamdy, Freddie C.
Neal, David E.
Donovan, Jenny L.
Metcalfe, Chris
Title Incorporating known genetic variants does not improve the accuracy of psa testing to identify high risk prostate cancer on biopsy
Journal name PL o S One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2015-10-01
Sub-type Article (original research)
DOI 10.1371/journal.pone.0136735
Open Access Status DOI
Volume 10
Issue 10
Start page 1
End page 17
Total pages 17
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Formatted abstract
Introduction: Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels.

Materials and Methods: Men with PSA between 3-10ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7–10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men.

Results: The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AU C = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)).

Conclusion: We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10ng/mL). Replication and gaining more accurate estimates of the effects of the 4 PSA-SNPs and additional variants associated with PSA levels and not prostate cancer could be obtained from subsequent GWAS from larger prospective studies.
Keyword Genomewide association
Susceptibility loci
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 2 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
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