Combined Effect of a Polygenic Risk Score and Rare Genetic Variants on Prostate Cancer Risk.
Combined Effect of a Polygenic Risk Score and Rare Genetic Variants on Prostate Cancer Risk.
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DOI：
10.1016/j.eururo.2021.04.013
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发表时间：
2021-08
期刊：
影响因子：
23.4
通讯作者：
Haiman CA
中科院分区：
文献类型：
--
作者：
Darst BF;Sheng X;Eeles RA;Kote-Jarai Z;Conti DV;Haiman CA
虽然已知前列腺癌具有强大的遗传基础，并受常见和罕见变异的影响，但迄今为止，调查这些遗传风险因素综合影响的能力有限。我们对来自英国生物银行（UK Biobank）的81,094名男性进行了调查，其中包括3568例前列腺癌病例，以检查罕见致病性/可能致病性/有害（P/LP/D）种系变异和常见前列腺癌风险变异的综合影响，使用多基因风险评分（PRS）来测量前列腺癌风险。HOXB13、BRCA2、ATM和CHEK2 P/LP/D携带者患前列腺癌的绝对风险从9%到56%不等，非携带者患前列腺癌的绝对风险从2%到31%不等，在85岁时，分别处于最低和最高PRS十分位数的男性。高渗透的HOXB13 G84E前列腺癌风险变异在最低PRS五分位数的病例中最常见（4.4%），在最高PRS五分位数的病例中最不常见（0.5%,p = 0.005），而在对照组中，不同PRS的频率无统计学差异。虽然罕见和常见的变异对前列腺癌的发病有强烈而明显的影响，但将罕见和常见的变异结合起来考虑，将有助于更准确地估计男性患前列腺癌的终生风险。我们发现，罕见变异所传递的前列腺癌风险可能会根据个体的常见风险变异的遗传特征而变化。这意味着，为了全面评估前列腺癌的遗传风险，考虑罕见和常见变异是很重要的。
Although prostate cancer is known to have a strong genetic basis and is influenced by both common and rare variants, the ability to investigate the combined effect of such genetic risk factors has been limited to date. We conducted an investigation of 81 094 men from the UK Biobank, including 3568 prostate cancer cases, to examine the combined effect of rare pathogenic/likely pathogenic/deleterious (P/LP/D) germline variants and common prostate cancer risk variants, measured using a polygenic risk score (PRS), on prostate cancer risk. The absolute risk of prostate cancer for HOXB13, BRCA2, ATM, and CHEK2 P/LP/D carriers ranged from 9% to 56%, and the absolute risk in noncarriers ranged from 2% to 31%, by age 85 yr, for men in the lowest and highest PRS decile, respectively. The high-penetrant HOXB13 G84E prostate cancer risk variant was most common in cases in the lowest PRS quintile (4.4%) and least common in cases in the highest PRS quintile (0.5%; p = 0.005), whereas there was no statistically significant difference in frequencies by PRS in controls. While rare and common variants strongly and distinctly influence prostate cancer onset, consideration of rare and common variants in conjunction will lead to more precise estimates of a man’s lifetime risk of prostate cancer. We found that the risk of prostate cancer conveyed by rare variants could vary depending on an individual’s genetic profile of common risk variants. This implies that in order to comprehensively assess genetic risk of prostate cancer, it is important to consider both rare and common variants.
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影响因子：
23.4
作者：
Shi, Zhuqing;Platz, Elizabeth A.;Xu, Jianfeng
通讯作者：
Xu, Jianfeng
DOI：
10.1200/jco.2016.69.4935
发表时间：
2017-07-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Lecarpentier J;Silvestri V;Kuchenbaecker KB;Barrowdale D;Dennis J;McGuffog L;Soucy P;Leslie G;Rizzolo P;Navazio AS;Valentini V;Zelli V;Lee A;Amin Al Olama A;Tyrer JP;Southey M;John EM;Conner TA;Goldgar DE;Buys SS;Janavicius R;Steele L;Ding YC;Neuhausen SL;Hansen TVO;Osorio A;Weitzel JN;Toss A;Medici V;Cortesi L;Zanna I;Palli D;Radice P;Manoukian S;Peissel B;Azzollini J;Viel A;Cini G;Damante G;Tommasi S;Peterlongo P;Fostira F;Hamann U;Evans DG;Henderson A;Brewer C;Eccles D;Cook J;Ong KR;Walker L;Side LE;Porteous ME;Davidson R;Hodgson S;Frost D;Adlard J;Izatt L;Eeles R;Ellis S;Tischkowitz M;EMBRACE;Godwin AK;Meindl A;Gehrig A;Dworniczak B;Sutter C;Engel C;Niederacher D;Steinemann D;Hahnen E;Hauke J;Rhiem K;Kast K;Arnold N;Ditsch N;Wang-Gohrke S;Wappenschmidt B;Wand D;Lasset C;Stoppa-Lyonnet D;Belotti M;Damiola F;Barjhoux L;Mazoyer S;GEMO Study Collaborators;Van Heetvelde M;Poppe B;De Leeneer K;Claes KBM;de la Hoya M;Garcia-Barberan V;Caldes T;Perez Segura P;Kiiski JI;Aittomäki K;Khan S;Nevanlinna H;van Asperen CJ;HEBON;Vaszko T;Kasler M;Olah E;Balmaña J;Gutiérrez-Enríquez S;Diez O;Teulé A;Izquierdo A;Darder E;Brunet J;Del Valle J;Feliubadalo L;Pujana MA;Lazaro C;Arason A;Agnarsson BA;Johannsson OT;Barkardottir RB;Alducci E;Tognazzo S;Montagna M;Teixeira MR;Pinto P;Spurdle AB;Holland H;KConFab Investigators;Lee JW;Lee MH;Lee J;Kim SW;Kang E;Kim Z;Sharma P;Rebbeck TR;Vijai J;Robson M;Lincoln A;Musinsky J;Gaddam P;Tan YY;Berger A;Singer CF;Loud JT;Greene MH;Mulligan AM;Glendon G;Andrulis IL;Toland AE;Senter L;Bojesen A;Nielsen HR;Skytte AB;Sunde L;Jensen UB;Pedersen IS;Krogh L;Kruse TA;Caligo MA;Yoon SY;Teo SH;von Wachenfeldt A;Huo D;Nielsen SM;Olopade OI;Nathanson KL;Domchek SM;Lorenchick C;Jankowitz RC;Campbell I;James P;Mitchell G;Orr N;Park SK;Thomassen M;Offit K;Couch FJ;Simard J;Easton DF;Chenevix-Trench G;Schmutzler RK;Antoniou AC;Ottini L
通讯作者：
Ottini L
影响因子：
2.1
作者：
Li, Dalin;Lewinger, Juan Pablo;Gauderman, William J.;Murcray, Cassandra Elizabeth;Conti, David
通讯作者：
Conti, David
影响因子：
8.8
作者：
Lu, Tianyuan;Zhou, Sirui;Richards, J. Brent
通讯作者：
Richards, J. Brent
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G