TY - JOUR
T1 - Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels
AU - Parikh, Hemang
AU - Wang, Zhaoming
AU - Pettigrew, Kerry A.
AU - Jia, Jinping
AU - Daugherty, Sarah
AU - Yeager, Meredith
AU - Jacobs, Kevin B.
AU - Hutchinson, Amy
AU - Burdett, Laura
AU - Cullen, Michael
AU - Qi, Liqun
AU - Boland, Joseph
AU - Collins, Irene
AU - Albert, Thomas J.
AU - Vatten, Lars J.
AU - Hveem, Kristian
AU - Njølstad, Inger
AU - Cancel-Tassin, Geraldine
AU - Cussenot, Olivier
AU - Valeri, Antoine
AU - Virtamo, Jarmo
AU - Thun, Michael J.
AU - Feigelson, Heather Spencer
AU - Diver, W. Ryan
AU - Chatterjee, Nilanjan
AU - Thomas, Gilles
AU - Albanes, Demetrius
AU - Chanock, Stephen J.
AU - Hunter, David J.
AU - Hoover, Robert
AU - Hayes, Richard B.
AU - Berndt, Sonja I.
AU - Sampson, Joshua
AU - Amundadottir, Laufey
N1 - Funding Information:
Acknowledgments This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH). K.A.P was supported through an ‘‘Ireland-Northern Ireland-National Cancer Institute Cancer Consortium, Joint Research Project in Cancer’’ fellowship and a Royal Society international travel grant. The authors thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, NCI, the screening center investigators and staff of the PLCO Cancer Screening Trial, Mr. Thomas Riley and staff at Information Management Services, Inc., and Ms. Barbara O’Brien and staff at Westat, Inc. for their contributions to the PLCO Cancer Screening Trial. Finally, we acknowledge and thank the study participants for donating their time and making this study possible. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.
PY - 2011/6
Y1 - 2011/6
N2 - Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56 kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case-control studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P = 0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P = 3.41 × 10-4, per-allele trend odds ratio (OR) = 0.77, 95% CI = 0.67-0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage <III (P = 4.72 × 10-5, per-allele trend OR = 0.68, 95% CI = 0.57-0.82) and not for advanced cases with Gleason score >8 or stage ≥III (P = 0.31, per-allele trend OR = 1.12, 95% CI = 0.90-1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61 ng/ml, 95% CI = 1.49-1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12 ng/ml, 95% CI = 0.96-1.28) (P = 9.70 × 10 -5). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy.
AB - Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56 kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case-control studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P = 0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P = 3.41 × 10-4, per-allele trend odds ratio (OR) = 0.77, 95% CI = 0.67-0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage <III (P = 4.72 × 10-5, per-allele trend OR = 0.68, 95% CI = 0.57-0.82) and not for advanced cases with Gleason score >8 or stage ≥III (P = 0.31, per-allele trend OR = 1.12, 95% CI = 0.90-1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61 ng/ml, 95% CI = 1.49-1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12 ng/ml, 95% CI = 0.96-1.28) (P = 9.70 × 10 -5). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy.
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U2 - 10.1007/s00439-011-0953-5
DO - 10.1007/s00439-011-0953-5
M3 - Article
C2 - 21318478
AN - SCOPUS:79959749784
VL - 129
SP - 675
EP - 685
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 6
ER -