A systems genetics approach identifies CXCL14, ITGAX, and LPCAT2 as novel aggressive prostate cancer susceptibility genes.
A systems genetics approach identifies CXCL14, ITGAX, and LPCAT2 as novel aggressive prostate cancer susceptibility genes.
复制标题
DOI：
10.1371/journal.pgen.1004809
复制
发表时间：
2014-11
期刊：
影响因子：
4.5
通讯作者：
Crawford NP
中科院分区：
文献类型：
--
作者：
Williams KA;Lee M;Hu Y;Andreas J;Patel SJ;Zhang S;Chines P;Elkahloun A;Chandrasekharappa S;Gutkind JS;Molinolo AA;Crawford NP
虽然前列腺癌通常是一个无痛的过程，但一部分男性会发展为这种疾病的侵袭性，致命性形式。我们假设生殖系变异调节侵袭性前列腺癌的易感性。这项工作的目标是使用神经内分泌前列腺癌的C57 BL/6-Tg（TRAMP）8247 Ng/J（TRAMP）小鼠模型来鉴定易感基因。在转基因阳性（TRAMPxNOD/ShiLtJ）F2互交雄性（n = 228）中进行数量性状基因座（QTL）定位，这有助于鉴定与侵袭性疾病发展相关的11个基因座。 来自126个（TRAMPxNOD/ShiLtJ）F2原发性肿瘤的微阵列数据用于对QTL内的候选基因进行优先级排序，其中当候选基因同时具有高水平的表达-性状相关性和近端表达QTL时被认为是高优先级的。这个过程使得能够鉴定35个侵袭性前列腺肿瘤发生的候选基因。这些基因在人类前列腺癌侵袭性形式中的作用使用两种并行方法进行了研究。首先，在两个人类前列腺基因表达数据集中的逻辑回归分析揭示了五个基因（CXCL 14、ITGAX、LPCAT 2、RNASEH 2A和ZNF 322）的表达水平与侵袭性前列腺癌正相关，并且两个基因（CCL 19和HIST 1H 1A）对侵袭性前列腺癌具有保护作用。在两个人前列腺癌肿瘤基因表达数据集中，与侵袭性疾病正相关的五个基因的高于平均水平的表达与患者结局一致相关。其次，这五个基因中的三个（CXCL 14，ITGAX和LPCAT 2）在由1，172名前列腺癌患者组成的人类GWAS队列中具有与侵袭性疾病发展相关的多态性。这项研究是使用系统遗传学方法成功鉴定侵袭性前列腺癌新易感基因的第一个例子。这些方法将有助于识别驱动侵袭性疾病易感性的新生殖系因素，并允许对这些致命形式的前列腺癌的新见解。前列腺癌是一种非常常见的疾病，据估计，2014年它将占美国男性新发癌症病例的27%。然而，只有不到13%的被诊断者会死于前列腺癌，大多数男性死于不相关的原因。用于识别男性致命前列腺癌风险的测试是不准确的，这导致过度治疗，不必要的患者痛苦，并代表了重大的公共卫生负担。许多研究表明，遗传性遗传变异显著改变了对致命性前列腺癌的易感性，尽管对此负责的基因的身份大多是未知的。在这里，我们使用前列腺癌的小鼠模型来识别这些基因。我们通过育种将遗传性遗传变异引入这种小鼠模型，并使用遗传作图技术鉴定了35个与侵袭性疾病相关的基因。这些基因中的三个的水平在具有更侵袭性病程的人类前列腺癌中始终异常。此外，这三个基因的遗传差异与男性致命性前列腺癌的标志物有关。这种方法使我们对遗传变异如何影响前列腺癌的致命形式有了独特的见解。
Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n = 228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will facilitate the identification of novel germline factors driving aggressive disease susceptibility and allow for new insights into these deadly forms of prostate cancer. Prostate cancer is a remarkably common disease, and in 2014 it is estimated that it will account for 27% of new cancer cases in men in the US. However, less than 13% those diagnosed will succumb to prostate cancer, with most men dying from unrelated causes. The tests used to identify men at risk of fatal prostate cancer are inaccurate, which leads to overtreatment, unnecessary patient suffering, and represents a significant public health burden. Many studies have shown that hereditary genetic variation significantly alters susceptibility to fatal prostate cancer, although the identities of genes responsible for this are mostly unknown. Here, we used a mouse model of prostate cancer to identify such genes. We introduced hereditary genetic variation into this mouse model through breeding, and used a genetic mapping technique to identify 35 genes associated with aggressive disease. The levels of three of these genes were consistently abnormal in human prostate cancers with a more aggressive disease course. Additionally, hereditary differences in these same three genes were associated with markers of fatal prostate cancer in men. This approach has given us unique insights into how hereditary variation influences fatal forms of prostate cancer.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1016/s0197-2456(00)00097-0
发表时间：
2000-12-01
期刊：
CONTROLLED CLINICAL TRIALS
影响因子：
--
作者：
Gohagan, JK;Prorok, PC;Kramer, BS
通讯作者：
Kramer, BS
影响因子：
4.2
作者：
Drake, Thomas A;Schadt, Eric E;Lusis, Aldons J
通讯作者：
Lusis, Aldons J
影响因子：
30.8
作者：
Eeles, Rosalind A.;Al Olama, Ali Amin;Benlloch, Sara;Saunders, Edward J.;Leongamornlert, Daniel A.;Tymrakiewicz, Malgorzata;Ghoussaini, Maya;Luccarini, Craig;Dennis, Joe;Jugurnauth-Little, Sarah;Dadaev, Tokhir;Neal, David E.;Hamdy, Freddie C.;Donovan, Jenny L.;Muir, Ken;Giles, Graham G.;Severi, Gianluca;Wiklund, Fredrik;Gronberg, Henrik;Haiman, Christopher A.;Schumacher, Fredrick;Henderson, Brian E.;Le Marchand, Loic;Lindstrom, Sara;Kraft, Peter;Hunter, David J.;Gapstur, Susan;Chanock, Stephen J.;Berndt, Sonja I.;Albanes, Demetrius;Andriole, Gerald;Schleutker, Johanna;Weischer, Maren;Canzian, Federico;Riboli, Elio;Key, Tim J.;Travis, Ruth C.;Campa, Daniele;Ingles, Sue A.;John, Esther M.;Hayes, Richard B.;Pharoah, Paul D. P.;Pashayan, Nora;Khaw, Kay-Tee;Stanford, Janet L.;Ostrander, Elaine A.;Signorello, Lisa B.;Thibodeau, Stephen N.;Schaid, Dan;Maier, Christiane;Vogel, Walther;Kibel, Adam S.;Cybulski, Cezary;Lubhiski, Jan;Cannon-Albright, Lisa;Brenner, Hermann;Park, Jong Y.;Kaneva, Radka;Batra, Jyotsna;Spurdle, Amanda B.;Clements, Judith A.;Teixeira, Manuel R.;Dicks, Ed;Lee, Andrew;Dunning, Alison M.;Baynes, Caroline;Conroy, Don;Maranian, Melanie J.;Ahmed, Shahana;Govindasami, Koveela;Guy, Michelle;Wilkinson, Rosemary A.;Sawyer, Emma J.;Morgan, Angela;Dearnaley, David P.;Horwich, Alan;Huddart, Robert A.;Khoo, Vincent S.;Parker, Christopher C.;Van As, Nicholas J.;Woodhouse, Christopher J.;Thompson, Alan;Dudderidge, Tim;Ogden, Chris;Cooper, Colin S.;Lophatananon, Artitaya;Cox, Angela;Southey, Melissa C.;Hopper, John L.;English, Dallas R.;Aly, Markus;Adolfsson, Jan;Xu, Jiangfeng;Zheng, Siqun L.;Yeager, Meredith;Kaaks, Rudolf;Diver, W. Ryan;Gaudet, Mia M.;Stern, Mariana C.;Corral, Roman;Joshi, Amit D.;Shahabi, Ahva;Wahlfors, Tiina;Tammela, Teuvo L. J.;Auvinen, Anssi;Virtamo, Jarmo;Klarskov, Peter;Nordestgaard, Borge G.;Roder, M. Andreas;Nielsen, Sune F.;Bojesen, Stig E.;Siddiq, Afshan;FitzGerald, Liesel M.;Kolb, Suzanne;Kwon, Erika M.;Karyadi, Danielle M.;Blot, William J.;Zheng, Wei;Cai, Qiuyin;McDonnell, Shannon K.;Rinckleb, Antje E.;Drake, Bettina;Colditz, Graham;Wokolorczyk, Dominika;Stephenson, Robert A.;Teerlink, Craig;Muller, Heiko;Rothenbacher, Dietrich;Sellers, Thomas A.;Lin, Hui-Yi;Slavov, Chavdar;Mitev, Vanio;Lose, Felicity;Srinivasan, Srilakshmi;Maia, Sofia;Paulo, Paula;Lange, Ethan;Cooney, Kathleen A.;Antoniou, Antonis C.;Vincent, Daniel;Bacot, Francois;Tessier, Daniel C.;Kote-Jarai, Zsofia;Easton, Douglas F.
通讯作者：
Easton, Douglas F.
DOI：
10.1158/1078-0432.ccr-13-3309
发表时间：
2014-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Beltran H;Tomlins S;Aparicio A;Arora V;Rickman D;Ayala G;Huang J;True L;Gleave ME;Soule H;Logothetis C;Rubin MA
通讯作者：
Rubin MA