Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.
Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.
复制标题
DOI：
10.1158/0008-5472.can-15-2980
复制
发表时间：
2016-09-01
期刊：
影响因子：
11.2
通讯作者：
African American Breast Cancer Consortium (AABC) and African Ancestry Prostate Cancer Consortium (AAPC)
中科院分区：
文献类型：
--
作者：
Fehringer G;Kraft P;Pharoah PD;Eeles RA;Chatterjee N;Schumacher FR;Schildkraut JM;Lindström S;Brennan P;Bickeböller H;Houlston RS;Landi MT;Caporaso N;Risch A;Amin Al Olama A;Berndt SI;Giovannucci EL;Grönberg H;Kote-Jarai Z;Ma J;Muir K;Stampfer MJ;Stevens VL;Wiklund F;Willett WC;Goode EL;Permuth JB;Risch HA;Reid BM;Bezieau S;Brenner H;Chan AT;Chang-Claude J;Hudson TJ;Kocarnik JK;Newcomb PA;Schoen RE;Slattery ML;White E;Adank MA;Ahsan H;Aittomäki K;Baglietto L;Blomquist C;Canzian F;Czene K;Dos-Santos-Silva I;Eliassen AH;Figueroa JD;Flesch-Janys D;Fletcher O;Garcia-Closas M;Gaudet MM;Johnson N;Hall P;Hazra A;Hein R;Hofman A;Hopper JL;Irwanto A;Johansson M;Kaaks R;Kibriya MG;Lichtner P;Liu J;Lund E;Makalic E;Meindl A;Müller-Myhsok B;Muranen TA;Nevanlinna H;Peeters PH;Peto J;Prentice RL;Rahman N;Sanchez MJ;Schmidt DF;Schmutzler RK;Southey MC;Tamimi R;Travis RC;Turnbull C;Uitterlinden AG;Wang Z;Whittemore AS;Yang XR;Zheng W;Buchanan DD;Casey G;Conti DV;Edlund CK;Gallinger S;Haile RW;Jenkins M;Le Marchand L;Li L;Lindor NM;Schmit SL;Thibodeau SN;Woods MO;Rafnar T;Gudmundsson J;Stacey SN;Stefansson K;Sulem P;Chen YA;Tyrer JP;Christiani DC;Wei Y;Shen H;Hu Z;Shu XO;Shiraishi K;Takahashi A;Bossé Y;Obeidat M;Nickle D;Timens W;Freedman ML;Li Q;Seminara D;Chanock SJ;Gong J;Peters U;Gruber SB;Amos CI;Sellers TA;Easton DF;Hunter DJ;Haiman CA;Henderson BE;Hung RJ;Ovarian Cancer Association Consortium (OCAC);PRACTICAL Consortium;Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON);Colorectal Transdisciplinary (CORECT) Study;African American Breast Cancer Consortium (AABC) and African Ancestry Prostate Cancer Consortium (AAPC)
识别具有多效性关联的基因变异能够揭示影响多种癌症的常见通路。我们采用两阶段方法，对来自GAME - ON / GECCO网络的肺癌、卵巢癌、乳腺癌、前列腺癌和结直肠癌进行全基因组关联研究（61851例病例，61820例对照）以识别多效性基因座。研究结果在独立的关联研究中得到了重复验证（55789例病例，330490例对照）。我们在1q22处发现了一种涉及乳腺癌和肺鳞状细胞癌的新型多效性关联，eQTL分析显示其与肺中ADAM15 / THBS3基因表达有关。我们还发现了一个已知的与乳腺癌相关的基因座CASP8 / ALS2CR12与前列腺癌有关，一个位于CDKN2B - AS1的已知癌症基因座，其不同的变异与肺腺癌和前列腺癌相关，并证实了一个乳腺癌BRCA2基因座与肺癌和浆液性卵巢癌的关联。这是迄今为止针对多个癌症相关基因座的多效性进行的最大规模的研究，确定了癌症发生和发展的常见机制。
Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression.