Genetically predicted circulating protein biomarkers and ovarian cancer risk.
Genetically predicted circulating protein biomarkers and ovarian cancer risk.
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基因预测循环蛋白生物标志物和卵巢癌风险。
DOI：
10.1016/j.ygyno.2020.11.016
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发表时间：
2021-03
影响因子：
4.7
通讯作者：
Ovarian Cancer Association Consortium
中科院分区：
文献类型：
--
作者：
Considine DPC;Jia G;Shu X;Schildkraut JM;Pharoah PDP;Zheng W;Kar SP;Ovarian Cancer Association Consortium
大多数患有上皮性卵巢癌（EOC）的女性在疾病转移后被诊断出来，并且该组的生存率仍然很低。与发生EOC风险相关的循环蛋白质有可能作为早期检测和诊断的生物标志物。我们整合了大规模的基因组和蛋白质组数据，以确定与EOC风险相关的新血浆蛋白。我们使用与INTERVAL研究中3，301名健康个体的1，329种蛋白质血浆水平最强相关（P<1.5×10−11）的生殖系遗传变异来预测卵巢癌协会联盟（OCAC）的22，406例EOC病例和40，941例对照中这些蛋白质的循环水平。通过将OCAC研究中EOC风险的β系数和标准误与INTERVAL中β系数的倒数进行加权，进行相关性检验。我们鉴定了26种蛋白质，其遗传预测循环水平与EOC风险相关，错误发现率<0.05。这26种蛋白质包括MFAP 2、SEMG 2、DLK 1和NTNG 1，以及一组22种蛋白质，其血浆水平通过染色体9q34.2处的变体预测。所有26个蛋白质关联信号的确定是由高级别的浆液性组织型，包括58%的EOC的情况下，OCAC。区域基因组图证实了26种蛋白质的血浆蛋白水平和EOC风险的遗传相关信号的重叠。通路分析鉴定了26种蛋白质中7种生物通路的富集（P调整<0.05），突出了局灶性粘附-PI 3 K-Akt-mTOR和Notch信号传导的作用。所鉴定的蛋白质进一步阐明了EOC的病因，并且代表了有希望的新EOC生物标志物，用于通过涉及直接测量EOC患者队列中的血浆蛋白的研究进行靶向验证。
Most women with epithelial ovarian cancer (EOC) are diagnosed after the disease has metastasized and survival in this group remains poor. Circulating proteins associated with the risk of developing EOC have the potential to serve as biomarkers for early detection and diagnosis. We integrated large-scale genomic and proteomic data to identify novel plasma proteins associated with EOC risk. We used the germline genetic variants most strongly associated (P<1.5×10−11) with plasma levels of 1,329 proteins in 3,301 healthy individuals from the INTERVAL study to predict circulating levels of these proteins in 22,406 EOC cases and 40,941 controls from the Ovarian Cancer Association Consortium (OCAC). Association testing was performed by weighting the beta coefficients and standard errors for EOC risk from the OCAC study by the inverse of the beta coefficients from INTERVAL. We identified 26 proteins whose genetically predicted circulating levels were associated with EOC risk at false discovery rate<0.05. The 26 proteins included MFAP2, SEMG2, DLK1, and NTNG1 and a group of 22 proteins whose plasma levels were predicted by variants at chromosome 9q34.2. All 26 protein association signals identified were driven by association with the high-grade serous histotype that comprised 58% of the EOC cases in OCAC. Regional genomic plots confirmed overlap of the genetic association signal underlying both plasma protein level and EOC risk for the 26 proteins. Pathway analysis identified enrichment of seven biological pathways among the 26 proteins (Padjusted<0.05), highlighting roles for Focal Adhesion-PI3K-Akt-mTOR and Notch signaling. The identified proteins further illuminate the etiology of EOC and represent promising new EOC biomarkers for targeted validation by studies involving direct measurement of plasma proteins in EOC patient cohorts.
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DOI：
10.1038/mtna.2014.49
发表时间：
2014-10-07
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
--
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
DOI：
10.1016/s0140-6736(17)31928-1
发表时间：
2017-11-25
期刊：
Lancet (London, England)
影响因子：
--
作者：
Di Angelantonio E;Thompson SG;Kaptoge S;Moore C;Walker M;Armitage J;Ouwehand WH;Roberts DJ;Danesh J;INTERVAL Trial Group
通讯作者：
INTERVAL Trial Group
影响因子：
30.8
作者：
Kuchenbaecker, Karoline B.;Ramus, Susan J.;Tyrer, Jonathan;Lee, Andrew;Shen, Howard C.;Beesley, Jonathan;Lawrenson, Kate;McGuffog, Lesley;Healey, Sue;Lee, Janet M.;Spindler, Tassja J.;Lin, Yvonne G.;Pejovic, Tanja;Bean, Yukie;Li, Qiyuan;Coetzee, Simon;Hazelett, Dennis;Miron, Alexander;Southey, Melissa;Terry, Mary Beth;Goldgar, David E.;Buys, Saundra S.;Janavicius, Ramunas;Dorfling, Cecilia M.;van Rensburg, Elizabeth J.;Neuhausen, Susan L.;Ding, Yuan Chun;Hansen, Thomas V. O.;Jonson, Lars;Gerdes, Anne-Marie;Ejlertsen, Bent;Barrowdale, Daniel;Dennis, Joe;Benitez, Javier;Osorio, Ana;Garcia, Maria Jose;Komenaka, Ian;Weitzel, Jeffrey N.;Ganschow, Pamela;Peterlongo, Paolo;Bernard, Loris;Viel, Alessandra;Bonanni, Bernardo;Peissel, Bernard;Manoukian, Siranoush;Radice, Paolo;Papi, Laura;Ottini, Laura;Fostira, Florentia;Konstantopoulou, Irene;Garber, Judy;Frost, Debra;Perkins, Jo;Platte, Radka;Ellis, Steve;Godwin, Andrew K.;Schmutzler, Rita Katharina;Meindl, Alfons;Engel, Christoph;Sutter, Christian;Sinilnikova, Olga M.;Damiola, Francesca;Mazoyer, Sylvie;Stoppa-Lyonnet, Dominique;Claes, Kathleen;De Leeneer, Kim;Kirk, Judy;Rodriguez, Gustavo C.;Piedmonte, Marion;O'Malley, David M.;de la Hoya, Miguel;Caldes, Trinidad;Aittomaeki, Kristiina;Nevanlinna, Heli;Collee, J. Margriet;Rookus, Matti A.;Oosterwijk, Jan C.;Tihomirova, Laima;Tung, Nadine;Hamann, Ute;Isaccs, Claudine;Tischkowitz, Marc;Imyanitov, Evgeny N.;Caligo, Maria A.;Campbell, Ian G.;Hogervorst, Frans B. L.;Olah, Edith;Diez, Orland;Blanco, Ignacio;Brunet, Joan;Lazaroso, Conxi;Angel Pujana, Miguel;Jakubowska, Anna;Gronwald, Jacek;Lubinski, Jan;Sukiennicki, Grzegorz;Barkardottir, Rosa B.;Plante, Marie;Simard, Jacques;Soucy, Penny;Montagna, Marco;Tognazzo, Silvia;Teixeira, Manuel R.;Pankratz, Vernon S.;Wang, Xianshu;Lindor, Noralane;Szabo, Csilla I.;Kauff, Noah;Vijai, Joseph;Aghajanian, Carol A.;Pfeiler, Georg;Berger, Andreas;Singer, Christian F.;Tea, Muy-Kheng;Phelan, Catherine M.;Greene, Mark H.;Mai, Phuong L.;Rennert, Gad;Mulligan, Anna Marie;Tchatchou, Sandrine;Andrulis, Irene L.;Glendon, Gord;Toland, Amanda Ewart;Jensen, Uffe Birk;Kruse, Torben A.;Thomassen, Mads;Bojesen, Anders;Zidan, Jamal;Friedman, Eitan;Laitman, Yael;Soller, Maria;Liljegren, Annelie;Arver, Brita;Einbeigi, Zakaria;Stenmark-Askmalm, Marie;Olopade, Olufunmilayo I.;Nussbaum, Robert L.;Rebbeck, Timothy R.;Nathanson, Katherine L.;Domchek, Susan M.;Lu, Karen H.;Karlan, Beth Y.;Walsh, Christine;Lester, Jenny;Hein, Alexander;Ekici, Arif B.;Beckmann, Matthias W.;Fasching, Peter A.;Lambrechts, Diether;Van Nieuwenhuysen, Els;Vergote, Ignace;Lambrechts, Sandrina;Dicks, Ed;Doherty, Jennifer A.;Wicklund, Kristine G.;Rossing, Mary Anne;Rudolph, Anja;Chang-Claude, Jenny;Wang-Gohrke, Shan;Eilber, Ursula;Moysich, Kirsten B.;Odunsi, Kunle;Sucheston, Lara;Lele, Shashi;Wilkens, Lynne R.;Goodman, Marc T.;Thompson, Pamela J.;Shvetsov, Yurii B.;Runnebaum, Ingo B.;Duerst, Matthias;Hillemanns, Peter;Doerk, Thilo;Antonenkova, Natalia;Bogdanova, Natalia;Leminen, Arto;Pelttari, Liisa M.;Butzow, Ralf;Modugno, Francesmary;Kelley, Joseph L.;Edwards, Robert P.;Ness, Roberta B.;du Bois, Andreas;Heitz, Florian;Schwaab, Ira;Harter, Philipp;Matsuo, Keitaro;Hosono, Satoyo;Orsulic, Sandra;Jensen, Allan;Kjaer, Susanne Kruger;Hogdall, Estrid;Hasmad, Hanis Nazihah;Azmi, Mat Adenan Noor;Teo, Soo-Hwang;Woo, Yin-Ling;Fridley, Brooke L.;Goode, Ellen L.;Cunningham, Julie M.;Vierkant, Robert A.;Bruinsma, Fiona;Giles, Graham G.;Liang, Dong;Hildebrandt, Michelle A. T.;Wu, Xifeng;Levine, Douglas A.;Bisogna, Maria;Berchuck, Andrew;Iversen, Edwin S.;Schildkraut, Joellen M.;Concannon, Patrick;Weber, Rachel Palmieri;Cramer, Daniel W.;Terry, Kathryn L.;Poole, Elizabeth M.;Tworoger, Shelley S.;Bandera, Elisa V.;Orlow, Irene;Olson, Sara H.;Krakstad, Camilla;Salvesen, Helga B.;Tangen, Ingvild L.;Bjorge, Line;van Altena, Anne M.;Aben, Katja K. H.;Kiemeney, Lambertus A.;Massuger, Leon F. A. G.;Kellar, Melissa;Brooks-Wilson, Angela;Kelemen, Linda E.;Cook, Linda S.;Le, Nhu D.;Cybulski, Cezary;Yang, Hannah;Lissowska, Jolanta;Brinton, Louise A.;Wentzensen, Nicolas;Hogdall, Claus;Lundvall, Lene;Nedergaard, Lotte;Baker, Helen;Song, Honglin;Eccles, Diana;McNeish, Ian;Paul, James;Carty, Karen;Siddiqui, Nadeem;Glasspool, Rosalind;Whittemore, Alice S.;Rothstein, Joseph H.;McGuire, Valerie;Sieh, Weiva;Ji, Bu-Tian;Zheng, Wei;Shu, Xiao-Ou;Gao, Yu-Tang;Rosen, Barry;Risch, Harvey A.;McLaughlin, John R.;Narod, Steven A.;Monteiro, Alvaro N.;Chen, Ann;Lin, Hui-Yi;Permuth-Wey, Jenny;Sellers, Thomas A.;Tsai, Ya-Yu;Chen, Zhihua;Ziogas, Argyrios;Anton-Culver, Hoda;Gentry-Maharaj, Aleksandra;Menon, Usha;Harrington, Patricia;Lee, Alice W.;Wu, Anna H.;Pearce, Celeste L.;Coetzee, Gerry;Pike, Malcolm C.;Dansonka-Mieszkowska, Agnieszka;Timorek, Agnieszka;Rzepecka, Iwona K.;Kupryjanczyk, Jolanta;Freedman, Matt;Noushmehr, Houtan;Easton, Douglas F.;Offit, Kenneth;Couch, Fergus J.;Gayther, Simon;Pharoah, Paul P.;Antoniou, Antonis C.;Chenevix-Trench, Georgia
通讯作者：
Chenevix-Trench, Georgia
影响因子：
5.9
作者：
Enroth, Stefan;Berggrund, Malin;Gyllensten, Ulf
通讯作者：
Gyllensten, Ulf