Case-only Methods Identified Genetic Loci Predicting a Subgroup of Men with Reduced Risk of High-grade Prostate Cancer by Finasteride

被引:4
作者
Dai, James Y. [1 ,2 ]
LeBlanc, Michael [1 ,2 ]
Goodman, Phyllis J. [1 ]
Lucia, M. Scott [3 ]
Thompson, Ian M. [4 ]
Tangen, Catherine M. [1 ]
机构
[1] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA
[2] Univ Washington, Dept Biostat, Washington, DC USA
[3] Univ Colorado, Denver Sch Med, Denver, CO 80202 USA
[4] Canc Therapy & Res Ctr San Antonio, San Antonio, TX USA
关键词
PREVENTION TRIAL; CLINICAL-TRIALS; POLYMORPHISMS; SENSITIVITY; ASSOCIATION; DESIGN;
D O I
10.1158/1940-6207.CAPR-18-0284
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
In the Prostate Cancer Prevention Trial (PCPT), genotypes that may modify the effect of finasteride on the risk of prostate cancer have not been identified. Germline genetic data from 1,157 prostate cancer cases in PCPT were analyzed by case-only methods. Geno-types included 357 SNPs from 83 candidate genes in androgen metabolism, inflammation, circadian rhythm, and other pathways. Univariate case-only analysis was conducted to evaluate whether individual SNPs modified the finasteride effect on the risk of high-grade and low-grade prostate cancer. Case-only classification trees and random forests, which are powerful machine learning methods with resampling-based controls for model complexity, were employed to identify a predictive signature for genotype-specific treatment effects. Accounting for multiple testing, a single SNP in SRD5A1 gene (rs472402) significantly modified the finasteride effect on high-grade prostate cancer (Gleason score > 6) in PCPT(family-wise error rate < 0.05). Men carrying CC genotype at this locus had a 55% reduction of the risk in developing high-grade cancer when assigned to finasteride (RR = 0.45; 95% confidence interval, 0.27-0.75). Additional effect-modifying SNPs with moderate statistical significance were identified by case-only trees and random forests. A prediction model built by the case-only random forest method with 28 selected SNPs classified 37% of PCPT men to have reduced risk of high-grade prostate cancer when taking finasteride, while the others have increased risk. In conclusion, case-only methods identified SNPs that modified the effect of finasteride on the risk of high-grade prostate cancer and predicted a subgroup of men who had reduced cancer risk by finasteride.
引用
收藏
页码:113 / 120
页数:8
相关论文
共 26 条
[1]   Effect of Dutasteride on the Risk of Prostate Cancer. [J].
Andriole, Gerald L. ;
Bostwick, David G. ;
Brawley, Otis W. ;
Gomella, Leonard G. ;
Marberger, Michael ;
Montorsi, Francesco ;
Pettaway, Curtis A. ;
Tammela, Teuvo L. ;
Teloken, Claudio ;
Tindall, Donald J. ;
Somerville, Matthew C. ;
Wilson, Timothy H. ;
Fowler, Ivy L. ;
Rittmaster, Roger S. .
NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (13) :1192-1202
[2]  
[Anonymous], CANC AMONG MEN
[3]  
Breslow N E, 1987, IARC Sci Publ, P1
[4]   Adding genetic risk score to family history identifies twice as many high-risk men for prostate cancer: Results from the prostate cancer prevention trial [J].
Chen, Haitao ;
Liu, Xu ;
Brendler, Charles B. ;
Ankerst, Donna P. ;
Leach, Robin J. ;
Goodman, Phyllis J. ;
Lucia, M. Scott ;
Tangen, Catherine M. ;
Wang, Li ;
Hsu, Fang-Chi ;
Sun, Jielin ;
Kader, A. Karim ;
Isaacs, William B. ;
Helfand, Brian T. ;
Zheng, S. Lilly ;
Thompson, Ian M. ;
Platz, Elizabeth A. ;
Xu, Jianfeng .
PROSTATE, 2016, 76 (12) :1120-1129
[5]   Circadian genes and risk of prostate cancer in the prostate cancer prevention trial [J].
Chu, Lisa W. ;
Till, Cathee ;
Yang, Baiyu ;
Tangen, Catherine M. ;
Goodman, Phyllis J. ;
Yu, Kai ;
Zhu, Yong ;
Han, Summer ;
Hoque, Ashraful M. ;
Ambrosone, Christine ;
Thompson, Ian ;
Leach, Robin ;
Hsing, Ann W. .
MOLECULAR CARCINOGENESIS, 2018, 57 (03) :462-466
[6]   Case-only approach to identifying markers predicting treatment effects on the relative risk scale [J].
Dai, James Y. ;
Liang, C. Jason ;
LeBlanc, Michael ;
Prentice, Ross L. ;
Janes, Holly .
BIOMETRICS, 2018, 74 (02) :753-763
[7]   Augmented Case-Only Designs for Randomized Clinical Trials with Failure Time Endpoints [J].
Dai, James Y. ;
Zhang, Xinyi Cindy ;
Wang, Ching-Yun ;
Kooperberg, Charles .
BIOMETRICS, 2016, 72 (01) :30-38
[8]   Transition of a Clinical Trial into Translational Research: The Prostate Cancer Prevention Trial Experience [J].
Goodman, Phyllis J. ;
Tangen, Catherine M. ;
Kristal, Alan R. ;
Thompson, Ian M. ;
Lucia, M. Scott ;
Platz, Elizabeth A. ;
Figg, William D. ;
Hoque, Ashraful ;
Hsing, Ann ;
Neuhouser, Marian L. ;
Parnes, Howard L. ;
Reichardt, Juergen K. V. ;
Santella, Regina M. ;
Till, Cathee ;
Lippman, Scott M. .
CANCER PREVENTION RESEARCH, 2010, 3 (12) :1523-1533
[9]   The prostate cancer prevention trial: Design, biases and interpretation of study results [J].
Goodman, PJ ;
Thompson, IM ;
Tangen, CM ;
Crowley, JJ ;
Ford, LG ;
Coltman, CA .
JOURNAL OF UROLOGY, 2006, 175 (06) :2234-2242
[10]   Genome-Wide Association Study of d-Amphetamine Response in Healthy Volunteers Identifies Putative Associations, Including Cadherin 13 (CDH13) [J].
Hart, Amy B. ;
Engelhardt, Barbara E. ;
Wardle, Margaret C. ;
Sokoloff, Greta ;
Stephens, Matthew ;
de Wit, Harriet ;
Palmer, Abraham A. .
PLOS ONE, 2012, 7 (08)