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Clinical validity and utility of genetic risk scores in prostate cancer

Asian Journal of Andrology 2016年第4期18卷 509-514页

作者： Brian T Helfand James Kearns carly conran Jianfeng Xu Department of Surgery NorthShore University HealthSystem Program for Personalized Cancer Care Evanston IL 60201 USA.

Current issues related to prostate cancer （PCa） clinical care （e.g., over-screening, over-diagnosis, and over-treatment of nonaggressive PCa） call for risk assessment tools that can be combined with family history （FH） to stratify disease risk among men in the general population. Since 2007, genome-wide association studies （GWASs） have identified more than 100 SNPs associated with PCa susceptibility. In this review, we discuss （1） the validity of these PCa risk-associated SNPs, individually and collectively; （2） the various methods used for measuring the cumulative effect of multiple SNPs, including genetic risk score （GRS）; （3） the adequate number of SNPs needed for risk assessment; （4） reclassification of risk based on evolving numbers of SNPs used to calculate genetic risk, （5） risk assessment for men from various racial groups, and （6） the clinical utility of genetic risk assessment. In conclusion, data available to date support the clinical validity of PCa risk-associated SNPs and GRS in risk assessment among men with or without FH. PCa risk-associated SNPs are not intended for diagnostic use; rather, they should be used the same way as FH. Combining GRS and FH can significantly improve the performance of risk assessment. Improved risk assessment may have important clinical utility in targeted PCa testing. However, clinical trials are urgently needed to evaluate this clinical utility as well as the acceptance of GRS by patients and physicians.

关键词： genetic risk score prostate cancer pyramid model single nucleotide polymorphisms

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Race-specific genetic risk score is more accurate than nonrace-specific genetic risk score for predicting prostate cancer and high-grade diseases

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Asian Journal of Andrology 2016年第4期18卷 525-529页

作者： Rong Na Dingwei Ye Jun Qi Fang Liu Xiaoling Lin Brian T Helfand Charles B Brendler carly conran Jian Gong Yishuo Wu Xu Gao Yaqing Chen S Lilly Zheng Zengnan Mo Qiang Ding Yinghao Sun Jianfeng Xu Department of Urology Huashan Hospital Fudan University Shanghai China Fudan Institute of Urology Huashan Hospital Fudan University Shanghai China Program for Personalized Cancer Care NorthShore University HealthSystem Evanston Illinois USA Health Communication Institute School of Public Health Fudan University Shanghai China Department of Urology Shanghai Cancer Center Fudan University Shanghai China Department of Urology Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China Division of Urology NorthShore University HealthSystem Evanston Illinois USA Department of Urology Shanghai Changhai Hospital The Second Military Medical University Shanghai China Department of Medical Ultrasonic Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China Center for Genomic and Personalized Medicine Guangxi Medical University Nanning China

Genetic risk score （GRS） based on disease risk-associated single nucleotide polymorphisms （SNPs） is an informative tool that can be used to provide inherited information for specific diseases in addition to family history, However, it is still unknown whether only SNPs that are implicated in a specific racial group should be used when calculating GRSs. The objective of this study is to compare the performance of race-specific GRS and nonrace-specitic GRS for predicting prostate cancer （PCa） among 1338 patients underwent prostate biopsy in Shanghai, China. A race-specific GRS was calculated with seven PCa risk-associated SNPs implicated in East Asians （GRS7）, and a nonrace-specific GRS was calculated based on 76 PCa risk-associated SNPs implicated in at least one racial group （GRS76）. The means of GRS7 and GRS76 were 1.19 and 1.85, respectively, in the study population. Higher GRS7 and GRS76 were independent predictors for PCa and high-grade PCa in univariate and multivariate analyses. GRS7 had a better area under the receiver-operating curve （AUC） than GRS76 for discriminating PCa （0.602 vs 0.573） and high-grade PCa （0.603 vs 0.575） but did not reach statistical significance. GRS7 had a better （up to 13% at different cutoffs） positive predictive value （PPV） than GRS76. In conclusion, a race-specific GRS is more robust and has a better performance when predicting PCa in East Asian men than a GRS calculated using SNPs that are not shown to be associated with East Asians.

关键词： Chinese genetic risk score genome-wide association study prostate cancer single nucleotide polymorphism

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Personalized prostate cancer care： from screening totreatment

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Asian Journal of Andrology 2016年第4期18卷 505-508页

作者： carly A conran Charles B Brendler Jianfeng Xu Program for Personalized Cancer Care NorthShore University HealthSystem 1001 University Place Evanston IL 60201 USA.

Unprecedented progress has been made in genomic personalized medicine in the last several years, allowing for more individualized healthcare assessments and recommendations than ever before. However, most of this progress in prostate cancer （PCa） care has focused on developing and selecting therapies for late-stage disease. To address this issue of limited focus, we propose a model for incorporating genomic-based personalized medicine into all levels of PCa care, from prevention and screening to diagnosis, and ultimately to the treatment of both early-stage and late-stage cancers. We have termed this strategy the ＂Pyramid Model＂ of personalized cancer care. In this perspective paper, our objective is to demonstrate the potential application of the Pyramid Model to PCa care. This proactive and comprehensive personalized cancer care approach has the potential to achieve three important medical goals： reducing mortality, improving quality of life and decreasing both individual and societal healthcare costs.

关键词： genetic risk score prostate cancer pyramid model single nucleotide polymorphisms

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Population-standardized genetic risk score： the SNP-based method of choice for inherited risk assessment of prostate cancer

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Asian Journal of Andrology 2016年第4期18卷 520-524页

作者： carly A conran Rong Na Haitao Chen Deke Jiang Xiaoling Lin S Lilly Zheng Charles B Brendler Jianfeng Xu NorthShore University HealthSystem Program for Personalized Cancer Care 1001 University Place Evanston IL 60201 USA Fudan Institute of Urology Huashan Hospital Fudan University 12 Mid-Wulumuqi Road Shanghai 200040 P.R. China Center for Genomic Translational Medicine and Prevention School of Public Health Fudan University 138 Yixueyuan Road Shanghai 200032 RR. China.

Several different approaches are available to clinicians for determining prostate cancer （PCa） risk. The clinical validity of various PCa risk assessment methods utilizing single nucleotide polymorphisms （SNPs） has been established; however, these SNP-based methods have not been compared. The objective of this study was to compare the three most commonly used SNP-based methods for PCa risk assessment. Participants were men （n = 1654） enrolled in a prospective study of PCa development. Genotypes of 59 PCa risk-associated SNPs were available in this cohort. Three methods of calculating SNP-based genetic risk scores （GRSs） were used for the evaluation of individual disease risk such as risk allele count （GRS-RAC）, weighted risk allele count （GRS-wRAC）, and population-standardized genetic risk score （GRS-PS）. Mean GRSs were calculated, and performances were compared using area under the receiver operating characteristic curve （AUC） and positive predictive value （PPV）. All SNP-based methods were found to be independently associated with PCa （all P 〈 0.05; hence their clinical validity）. The mean GRSs in men with or without PCa using GRS-RAC were 55.15 and 53.46, respectively, using GRS-wRAC were 7.42 and 6.97, respectively, and using GRS-PS were 1.12 and 0.84, respectively （all P 〈 0.05 for differences between patients with or without PCa）. All three SNP-based methods performed similarly in discriminating PCa from non-PCa based on AUC and in predicting PCa risk based on PPV （all P 〉 0.05 for comparisons between the three methods）, and all three SNP-based methods had a significantly higher AUC than family history （all P 〈 0.05）. Results from this study suggest that while the three most commonly used SNP-based methods performed similarly in discriminating PCa from non-PCa at the population level, GRS-PS is the method of choice for risk assessment at the individual level because its value （where 1.0 represents average population risk） can be easily interpreted regardless of the number of risk-associated SNPs used in the

关键词： genetic risk score prostate cancer single nucleotide polymorphisms

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