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26 results on '"Burdett, Laurie"'

1. Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Author

Shi, Jianxin, Shiraishi, Kouya, Choi, Jiyeon, Matsuo, Keitaro, Chen, Tzu-Yu, Dai, Juncheng, Hung, Rayjean J, Chen, Kexin, Shu, Xiao-Ou, Kim, Young Tae, Landi, Maria Teresa, Lin, Dongxin, Zheng, Wei, Yin, Zhihua, Zhou, Baosen, Song, Bao, Wang, Jiucun, Seow, Wei Jie, Song, Lei, Chang, I-Shou, Hu, Wei, Chien, Li-Hsin, Cai, Qiuyin, Hong, Yun-Chul, Kim, Hee Nam, Wu, Yi-Long, Wong, Maria Pik, Richardson, Brian Douglas, Funderburk, Karen M, Li, Shilan, Zhang, Tongwu, Breeze, Charles, Wang, Zhaoming, Blechter, Batel, Bassig, Bryan A, Kim, Jin Hee, Albanes, Demetrius, Wong, Jason Y Y, Shin, Min-Ho, Chung, Lap Ping, Yang, Yang, An, She-Juan, Zheng, Hong, Yatabe, Yasushi, Zhang, Xu-Chao, Kim, Young-Chul, Caporaso, Neil E, Chang, Jiang, Ho, James Chung Man, Kubo, Michiaki, Daigo, Yataro, Song, Minsun, Momozawa, Yukihide, Kamatani, Yoichiro, Kobayashi, Masashi, Okubo, Kenichi, Honda, Takayuki, Hosgood, Dean H, Kunitoh, Hideo, Patel, Harsh, Watanabe, Shun-Ichi, Miyagi, Yohei, Nakayama, Haruhiko, Matsumoto, Shingo, Horinouchi, Hidehito, Tsuboi, Masahiro, Hamamoto, Ryuji, Goto, Koichi, Ohe, Yuichiro, Takahashi, Atsushi, Goto, Akiteru, Minamiya, Yoshihiro, Hara, Megumi, Nishida, Yuichiro, Takeuchi, Kenji, Wakai, Kenji, Matsuda, Koichi, Murakami, Yoshinori, Shimizu, Kimihiro, Suzuki, Hiroyuki, Saito, Motonobu, Ohtaki, Yoichi, Tanaka, Kazumi, Wu, Tangchun, Wei, Fusheng, Dai, Hongji, Machiela, Mitchell J, Su, Jian, Kim, Yeul Hong, Oh, In-Jae, Lee, Victor Ho Fun, Chang, Gee-Chen, Tsai, Ying-Huang, Chen, Kuan-Yu, Huang, Ming-Shyan, Su, Wu-Chou, Chen, Yuh-Min, Seow, Adeline, Park, Jae Yong, Kweon, Sun-Seog, Chen, Kun-Chieh, Gao, Yu-Tang, Qian, Biyun, Wu, Chen, Lu, Daru, Liu, Jianjun, Schwartz, Ann G, Houlston, Richard, Spitz, Margaret R, Gorlov, Ivan P, Wu, Xifeng, Yang, Ping, Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E, Johansson, Mattias, Risch, Angela, Bickeböller, Heike, Ji, Bu-Tian, Wichmann, H-Erich, Christiani, David C, Rennert, Gadi, Arnold, Susanne, Brennan, Paul, McKay, James, Field, John K, Shete, Sanjay S, Le Marchand, Loic, Liu, Geoffrey, Andrew, Angeline, Kiemeney, Lambertus A, Zienolddiny-Narui, Shan, Grankvist, Kjell, Johansson, Mikael, Cox, Angela, Taylor, Fiona, Yuan, Jian-Min, Lazarus, Philip, Schabath, Matthew B, Aldrich, Melinda C, Jeon, Hyo-Sung, Jiang, Shih Sheng, Sung, Jae Sook, Chen, Chung-Hsing, Hsiao, Chin-Fu, Jung, Yoo Jin, Guo, Huan, Hu, Zhibin, Burdett, Laurie, Yeager, Meredith, Hutchinson, Amy, Hicks, Belynda, Liu, Jia, Zhu, Bin, Berndt, Sonja I, Wu, Wei, Wang, Junwen, Li, Yuqing, Choi, Jin Eun, Park, Kyong Hwa, Sung, Sook Whan, Liu, Li, Kang, Chang Hyun, Wang, Wen-Chang, Xu, Jun, Guan, Peng, Tan, Wen, Yu, Chong-Jen, Yang, Gong, Sihoe, Alan Dart Loon, Chen, Ying, Choi, Yi Young, Kim, Jun Suk, Yoon, Ho-Il, Park, In Kyu, Xu, Ping, He, Qincheng, Wang, Chih-Liang, Hung, Hsiao-Han, Vermeulen, Roel C H, Cheng, Iona, Wu, Junjie, Lim, Wei-Yen, Tsai, Fang-Yu, Chan, John K C, Li, Jihua, Chen, Hongyan, Lin, Hsien-Chih, Jin, Li, Liu, Jie, Sawada, Norie, Yamaji, Taiki, Wyatt, Kathleen, Li, Shengchao A, Ma, Hongxia, Zhu, Meng, Wang, Zhehai, Cheng, Sensen, Li, Xuelian, Ren, Yangwu, Chao, Ann, Iwasaki, Motoki, Zhu, Junjie, Jiang, Gening, Fei, Ke, Wu, Guoping, Chen, Chih-Yi, Chen, Chien-Jen, Yang, Pan-Chyr, Yu, Jinming, Stevens, Victoria L, Fraumeni, Joseph F, Chatterjee, Nilanjan, Gorlova, Olga Y, Hsiung, Chao Agnes, Amos, Christopher I, Shen, Hongbing, Chanock, Stephen J, Rothman, Nathaniel, Kohno, Takashi, Lan, Qing, and IRAS OH Epidemiology Chemical Agents

Subjects
Humans, Genetic Predisposition to Disease, Asia, Eastern/epidemiology, Lung Neoplasms/epidemiology, Polymorphism, Single Nucleotide, Adenocarcinoma of Lung/genetics, Genome-Wide Association Study
Abstract

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Published
2023

2. Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Author

Berndt, Sonja I, Vijai, Joseph, Benavente, Yolanda, Camp, Nicola J, Nieters, Alexandra, Wang, Zhaoming, Smedby, Karin E, Kleinstern, Geffen, Hjalgrim, Henrik, Besson, Caroline, Skibola, Christine F, Morton, Lindsay M, Brooks-Wilson, Angela R, Teras, Lauren R, Breeze, Charles, Arias, Joshua, Adami, Hans-Olov, Albanes, Demetrius, Anderson, Kenneth C, Ansell, Stephen M, Bassig, Bryan, Becker, Nikolaus, Bhatti, Parveen, Birmann, Brenda M, Boffetta, Paolo, Bracci, Paige M, Brennan, Paul, Brown, Elizabeth E, Burdett, Laurie, Cannon-Albright, Lisa A, Chang, Ellen T, Chiu, Brian C H, Chung, Charles C, Clavel, Jacqueline, Cocco, Pierluigi, Colditz, Graham, Conde, Lucia, Conti, David V, Cox, David G, Curtin, Karen, Casabonne, Delphine, De Vivo, Immaculata, Diver, W Ryan, Dogan, Ahmet, Edlund, Christopher K, Foretova, Lenka, Fraumeni, Joseph F, Gabbas, Attilio, Ghesquières, Hervé, Giles, Graham G, Glaser, Sally, Glenn, Martha, Glimelius, Bengt, Gu, Jian, Habermann, Thomas M, Haiman, Christopher A, Haioun, Corinne, Hofmann, Jonathan N, Holford, Theodore R, Holly, Elizabeth A, Hutchinson, Amy, Izhar, Aalin, Jackson, Rebecca D, Jarrett, Ruth F, Kaaks, Rudolph, Kane, Eleanor, Kolonel, Laurence N, Kong, Yinfei, Kraft, Peter, Kricker, Anne, Lake, Annette, Lan, Qing, Lawrence, Charles, Li, Dalin, Liebow, Mark, Link, Brian K, Magnani, Corrado, Maynadie, Marc, McKay, James, Melbye, Mads, Miligi, Lucia, Milne, Roger L, Molina, Thierry J, Monnereau, Alain, Montalvan, Rebecca, North, Kari E, Novak, Anne J, Onel, Kenan, Purdue, Mark P, Rand, Kristin A, Riboli, Elio, Riby, Jacques, Roman, Eve, Salles, Gilles, Sborov, Douglas W, Severson, Richard K, Shanafelt, Tait D, Smith, Martyn T, Smith, Alexandra, Song, Kevin W, Song, Lei, Southey, Melissa C, Spinelli, John J, Staines, Anthony, Stephens, Deborah, Sutherland, Heather J, Tkachuk, Kaitlyn, Thompson, Carrie A, Tilly, Hervé, Tinker, Lesley F, Travis, Ruth C, Turner, Jenny, Vachon, Celine M, Vajdic, Claire M, Van Den Berg, Anke, Van Den Berg, David J, Vermeulen, Roel C H, Vineis, Paolo, Wang, Sophia S, Weiderpass, Elisabete, Weiner, George J, Weinstein, Stephanie, Doo, Nicole Wong, Ye, Yuanqing, Yeager, Meredith, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zhang, Yawei, Zheng, Tongzhang, Ziv, Elad, Sampson, Joshua, Chatterjee, Nilanjan, Offit, Kenneth, Cozen, Wendy, Wu, Xifeng, Cerhan, James R, Chanock, Stephen J, Slager, Susan L, Rothman, Nathaniel, IRAS OH Epidemiology Chemical Agents, Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), and IRAS OH Epidemiology Chemical Agents

Subjects
Cancer Research, Lymphoma, Lymphoma, Non-Hodgkin, Hematology, Single Nucleotide, Polymorphism, Single Nucleotide, Germ Cells, Oncology, Risk Factors, Lymphoma, Non-Hodgkin/genetics, Case-Control Studies, Humans, Genetic Predisposition to Disease, Polymorphism, Non-Hodgkin/genetics, Genome-Wide Association Study
Abstract

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

Published
2022

3. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author

Machiela, Mitchell J., Grünewald, Thomas G. P., Surdez, Didier, Reynaud, Stephanie, Mirabeau, Olivier, Karlins, Eric, Rubio, Rebeca Alba, Zaidi, Sakina, Grossetete-Lalami, Sandrine, Ballet, Stelly, Lapouble, Eve, Laurence, Valérie, Michon, Jean, Pierron, Gaelle, Kovar, Heinrich, Gaspar, Nathalie, Kontny, Udo, González-Neira, Anna, Picci, Piero, Alonso, Javier, Patino-Garcia, Ana, Corradini, Nadège, Bérard, Perrine Marec, Freedman, Neal D., Rothman, Nathaniel, Dagnall, Casey L., Burdett, Laurie, Jones, Kristine, Manning, Michelle, Wyatt, Kathleen, Zhou, Weiyin, Yeager, Meredith, Cox, David G., Hoover, Robert N., Khan, Javed, Armstrong, Gregory T., Leisenring, Wendy M., Bhatia, Smita, Robison, Leslie L., Kulozik, Andreas E., Kriebel, Jennifer, Meitinger, Thomas, Metzler, Markus, Hartmann, Wolfgang, Strauch, Konstantin, Kirchner, Thomas, Dirksen, Uta, Morton, Lindsay M., Mirabello, Lisa, Tucker, Margaret A., Tirode, Franck, Chanock, Stephen J., and Delattre, Olivier

Abstract

Nature Communications 9(1), 3184 (2018). doi:10.1038/s41467-018-05537-2

Published
2018
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4. Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry

Author

Figueroa, Jonine D, Middlebrooks, Candace D, Banday, A Rouf, Ye, Yuanqing, Garcia-Closas, Montserrat, Chatterjee, Nilanjan, Koutros, Stella, Kiemeney, Lambertus A, Rafnar, Thorunn, Bishop, Timothy, Furberg, Helena, Matullo, Giuseppe, Golka, Klaus, Gago-Dominguez, Manuela, Taylor, Jack A, Fletcher, Tony, Siddiq, Afshan, Cortessis, Victoria K, Kooperberg, Charles, Cussenot, Olivier, Benhamou, Simone, Prescott, Jennifer, Porru, Stefano, Dinney, Colin P, Malats, Núria, Baris, Dalsu, Purdue, Mark P, Jacobs, Eric J, Albanes, Demetrius, Wang, Zhaoming, Chung, Charles C, Vermeulen, Sita H, Aben, Katja K, Galesloot, Tessel E, Thorleifsson, Gudmar, Sulem, Patrick, Stefansson, Kari, Kiltie, Anne E, Harland, Mark, Teo, Mark, Offit, Kenneth, Vijai, Joseph, Bajorin, Dean, Kopp, Ryan, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Selinski, Silvia, Hengstler, Jan G, Gerullis, Holger, Ovsiannikov, Daniel, Blaszkewicz, Meinolf, Castelao, Jose Esteban, Calaza, Manuel, Martinez, Maria Elena, Cordeiro, Patricia, Xu, Zongli, Panduri, Vijayalakshmi, Kumar, Rajiv, Gurzau, Eugene, Koppova, Kvetoslava, Bueno-De-Mesquita, H Bas, Ljungberg, Börje, Clavel-Chapelon, Françoise, Weiderpass, Elisabete, Krogh, Vittorio, Dorronsoro, Miren, Travis, Ruth C, Tjønneland, Anne, Brennan, Paul, Chang-Claude, Jenny, Riboli, Elio, Conti, David, Stern, Marianna C, Pike, Malcolm C, Van Den Berg, David, Yuan, Jian-Min, Hohensee, Chancellor, Jeppson, Rebecca P, Cancel-Tassin, Geraldine, Roupret, Morgan, Comperat, Eva, Turman, Constance, De Vivo, Immaculata, Giovannucci, Edward, Hunter, David J, Kraft, Peter, Lindstrom, Sara, Carta, Angela, Pavanello, Sofia, Arici, Cecilia, Mastrangelo, Giuseppe, Kamat, Ashish M, Zhang, Liren, Gong, Yilei, Pu, Xia, Hutchinson, Amy, Burdett, Laurie, Wheeler, William A, and Karagas, Margaret R

Subjects
Male, Urologic Diseases, Medical and Health Sciences, Chromosomes, Linkage Disequilibrium, White People, Risk Factors, Genetics, Humans, 2.1 Biological and endogenous factors, Pair 13, Genetic Predisposition to Disease, Polymorphism, Aetiology, Genetic Association Studies, Cancer, Genetics & Heredity, Tumor, Prevention, Human Genome, Single Nucleotide, Biological Sciences, Urinary Bladder Neoplasms, Case-Control Studies, Female, Pair 20, Biomarkers, Human, Genome-Wide Association Study, Biotechnology
Abstract

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

Published
2016

5. Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

Author

Machiela, Mitchell J, Zhou, Weiyin, Karlins, Eric, Sampson, Joshua N, Freedman, Neal D, Yang, Qi, Hicks, Belynda, Dagnall, Casey, Hautman, Christopher, Jacobs, Kevin B, Abnet, Christian C, Aldrich, Melinda C, Amos, Christopher, Amundadottir, Laufey T, Arslan, Alan A, Beane-Freeman, Laura E, Berndt, Sonja I, Black, Amanda, Blot, William J, Bock, Cathryn H, Bracci, Paige M, Brinton, Louise A, Bueno-de-Mesquita, H Bas, Burdett, Laurie, Buring, Julie E, Butler, Mary A, Canzian, Federico, Carreon, Tania, Chaffee, Kari G, Chang, I-Shou, Chatterjee, Nilanjan, Chen, Chu, Chen, Constance, Chen, Kexin, Chung, Charles C, Cook, Linda S, Bou, Marta Crous, Cullen, Michael, Davis, Faith G, De Vivo, Immaculata, Ding, Ti, Doherty, Jennifer, Duell, Eric J, Epstein, Caroline G, Fan, Jin-Hu, Figueroa, Jonine D, Fraumeni, Joseph F, Friedenreich, Christine M, Fuchs, Charles S, Gallinger, Steven, Gao, Yu-Tang, Gapstur, Susan M, Garcia-Closas, Montserrat, Gaudet, Mia M, Gaziano, J Michael, Giles, Graham G, Gillanders, Elizabeth M, Giovannucci, Edward L, Goldin, Lynn, Goldstein, Alisa M, Haiman, Christopher A, Hallmans, Goran, Hankinson, Susan E, Harris, Curtis C, Henriksson, Roger, Holly, Elizabeth A, Hong, Yun-Chul, Hoover, Robert N, Hsiung, Chao A, Hu, Nan, Hu, Wei, Hunter, David J, Hutchinson, Amy, Jenab, Mazda, Johansen, Christoffer, Khaw, Kay-Tee, Kim, Hee Nam, Kim, Yeul Hong, Kim, Young Tae, Klein, Alison P, Klein, Robert, Koh, Woon-Puay, Kolonel, Laurence N, Kooperberg, Charles, Kraft, Peter, Krogh, Vittorio, Kurtz, Robert C, LaCroix, Andrea, Lan, Qing, Landi, Maria Teresa, Le Marchand, Loic, Li, Donghui, Liang, Xiaolin, Liao, Linda M, Lin, Dongxin, Liu, Jianjun, Lissowska, Jolanta, Lu, Lingeng, Magliocco, Anthony M, and Malats, Nuria

Published
2016

6. Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry

Author

Figueroa, Jonine D. Middlebrooks, Candace D. Banday, A. Rouf and Ye, Yuanqing Garcia-Closas, Montserrat Chatterjee, Nilanjan and Koutros, Stella Kiemeney, Lambertus A. Rafnar, Thorunn and Bishop, Timothy Furberg, Helena Matullo, Giuseppe Golka, Klaus Gago-Dominguez, Manuela Taylor, Jack A. Fletcher, Tony and Siddiq, Afshan Cortessis, Victoria K. Kooperberg, Charles and Cussenot, Olivier Benhamou, Simone Prescott, Jennifer and Porru, Stefano Dinney, Colin P. Malats, Nuria Baris, Dalsu and Purdue, Mark P. Jacobs, Eric J. Albanes, Demetrius Wang, Zhaoming Chung, Charles C. Vermeulen, Sita H. Aben, Katja K. and Galesloot, Tessel E. Thorleifsson, Gudmar Sulem, Patrick and Stefansson, Kari Kiltie, Anne E. Harland, Mark Teo, Mark and Offit, Kenneth Vijai, Joseph Bajorin, Dean Kopp, Ryan and Fiorito, Giovanni Guarrera, Simonetta Sacerdote, Carlotta and Selinski, Silvia Hengstler, Jan G. Gerullis, Holger and Ovsiannikov, Daniel Blaszkewicz, Meinolf Esteban Castelao, Jose and Calaza, Manuel Martinez, Maria Elena Cordeiro, Patricia and Xu, Zongli Panduri, Vijayalakshmi Kumar, Rajiv Gurzau, Eugene Koppova, Kvetoslava Bueno-De-Mesquita, H. Bas and Ljungberg, Borje Clavel-Chapelon, Francoise Weiderpass, Elisabete Krogh, Vittorio Dorronsoro, Miren Travis, Ruth C. and Tjonneland, Anne Brennan, Paul Chang-Claude, Jenny and Riboli, Elio Conti, David Stern, Marianna C. Pike, Malcolm C. Van den Berg, David Yuan, Jian-Min Hohensee, Chancellor and Jeppson, Rebecca P. Cancel-Tassin, Geraldine Roupret, Morgan and Comperat, Eva Turman, Constance De Vivo, Immaculata and Giovannucci, Edward Hunter, David J. Kraft, Peter Lindstrom, Sara Carta, Angela Pavanello, Sofia Arici, Cecilia and Mastrangelo, Giuseppe Kamat, Ashish M. Zhang, Liren Gong, Yilei Pu, Xia Hutchinson, Amy Burdett, Laurie Wheeler, William A. Karagas, Margaret R. Johnson, Alison Schned, Alan and Hosain, G. M. Monawar Schwenn, Molly Kogevinas, Manolis and Tardon, Adonina Serra, Consol Carrato, Alfredo and Garcia-Closas, Reina Lloreta, Josep Andriole, Jr., Gerald and Grubb, III, Robert Black, Amanda Diver, W. Ryan Gapstur, Susan M. Weinstein, Stephanie Virtamo, Jarmo Haiman, Christopher A. Landi, Maria Teresa Caporaso, Neil E. and Fraumeni, Jr., Joseph F. Vineis, Paolo Wu, Xifeng Chanock, Stephen J. Silverman, Debra T. Prokunina-Olsson, Ludmila and Rothman, Nathaniel

Abstract

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1x 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P

Published
2016

7. Genome-wide association studies of gastric adenocarcinoma and esophageal squamous cell carcinoma identify a shared susceptibility locus in PLCE1 at 10q23

Author

Abnet, Christian C, Freedman, Neal D, Hu, Nan, Wang, Zhaoming, Yu, Kai, Shu, Xiao-Ou, Yuan, Jian-Min, Zheng, Wei, Dawsey, Sanford M, Dong, Linda M, Lee, Maxwell P, Ding, Ti, Qiao, You-Lin, Gao, Yu-Tang, Koh, Woon-Puay, Xiang, Yong-Bing, Tang, Ze-Zhong, Fan, Jin-Hu, Wang, Chaoyu, Wheeler, William, Gail, Mitchell H, Yeager, Meredith, Yuenger, Jeff, Hutchinson, Amy, Jacobs, Kevin B, Giffen, Carol A, Burdett, Laurie, Jr, Joseph F Fraumeni, Tucker, Margaret A, Chow, Wong-Ho, Goldstein, Alisa M, Chanock, Stephen J, and Taylor, Philip R

Subjects
Male, Esophageal Neoplasms, Chromosomes, Human, Pair 10, Adenocarcinoma, digestive system diseases, Article, Linkage Disequilibrium, Phosphoinositide Phospholipase C, Asian People, Gene Frequency, Genetic Loci, Stomach Neoplasms, Case-Control Studies, Carcinoma, Squamous Cell, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

We conducted a genome-wide association study of gastric cancer and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 SNPs. We report a combined analysis of 2,240 gastric cancer cases, 2,115 ESCC cases and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex and study, multiple variants at 10q23 had genome-wide significance for gastric cancer and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for gastric cancer (P = 8.40 x 10(-9); per-allele odds ratio (OR) = 1.31) and ESCC (P = 3.85 x 10(-9); OR = 1.34). The association with gastric cancer differed by anatomic subsite. For tumors in the cardia the association was stronger (P = 4.19 x 10(-15); OR = 1.57), and for those in the noncardia stomach it was absent (P = 0.44; OR = 1.05). Our findings at 10q23 could provide insight into the high incidence of both cancers in China.

Published
2010

8. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types

Author

Sampson, Joshua N, Wheeler, William A, Yeager, Meredith, Panagiotou, Orestis, Wang, Zhaoming, Berndt, Sonja I, Lan, Qing, Abnet, Christian C, Amundadottir, Laufey T, Figueroa, Jonine D, Landi, Maria Teresa, Mirabello, Lisa, Savage, Sharon A, Taylor, Philip R, De Vivo, Immaculata, McGlynn, Katherine A, Purdue, Mark P, Rajaraman, Preetha, Adami, Hans-Olov, Ahlbom, Anders, Albanes, Demetrius, Amary, Maria Fernanda, An, She-Juan, Andersson, Ulrika, Andriole, Gerald, Andrulis, Irene L, Angelucci, Emanuele, Ansell, Stephen M, Arici, Cecilia, Armstrong, Bruce K, Arslan, Alan A, Austin, Melissa A, Baris, Dalsu, Barkauskas, Donald A, Bassig, Bryan A, Becker, Nikolaus, Benavente, Yolanda, Benhamou, Simone, Berg, Christine, Van Den Berg, David, Bernstein, Leslie, Bertrand, Kimberly A, Birmann, Brenda M, Black, Amanda, Boeing, Heiner, Boffetta, Paolo, Boutron-Ruault, Marie-Christine, Bracci, Paige M, Brinton, Louise, Brooks-Wilson, Angela R, Bueno-de-Mesquita, H Bas, Burdett, Laurie, Buring, Julie, Butler, Mary Ann, Cai, Qiuyin, Cancel-Tassin, Geraldine, Canzian, Federico, Carrato, Alfredo, Carreon, Tania, Carta, Angela, Chan, John KC, Chang, Ellen T, Chang, Gee-Chen, Chang, I-Shou, Chang, Jiang, Chang-Claude, Jenny, Chen, Chien-Jen, Chen, Chih-Yi, Chen, Chu, Chen, Chung-Hsing, Chen, Constance, Chen, Hongyan, Chen, Kexin, Chen, Kuan-Yu, Chen, Kun-Chieh, Chen, Ying, Chen, Ying-Hsiang, Chen, Yi-Song, Chen, Yuh-Min, Chien, Li-Hsin, Chirlaque, María-Dolores, Choi, Jin Eun, Choi, Yi Young, Chow, Wong-Ho, Chung, Charles C, Clavel, Jacqueline, Clavel-Chapelon, Françoise, Cocco, Pierluigi, Colt, Joanne S, Comperat, Eva, Conde, Lucia, Connors, Joseph M, Conti, David, Cortessis, Victoria K, Cotterchio, Michelle, Cozen, Wendy, Crouch, Simon, Crous-Bou, Marta, Cussenot, Olivier, and Davis, Faith G

Subjects
Adult, Asian Continental Ancestry Group, Male, Lung Neoplasms, Lymphoma, European Continental Ancestry Group, Oncology and Carcinogenesis, Bone Neoplasms, Testicular Neoplasms, Neoplasms, Large B-Cell, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, Chronic, Aged, Osteosarcoma, Leukemia, Smoking, B-Cell, Single Nucleotide, Middle Aged, Diffuse, Kidney Neoplasms, Lymphocytic, Urinary Bladder Neoplasms, Tissue Array Analysis, Female, Genome-Wide Association Study
Abstract

BackgroundStudies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.MethodsBetween 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.ResultsGWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.ConclusionOur results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Published
2015

9. Analysis of heritability and shared heritability based on Genome-Wide Association Studies for 13 Cancer Types

Author

Sampson, Joshua N., Wheeler, William A., Yeager, Meredith, Panagiotou, Orestis, Wang, Zhaoming, Berndt, Sonja I., Lan, Qing, Abnet, Christian C., Amundadottir, Laufey T., Figueroa, Jonine D., Landi, Maria Teresa, Mirabello, Lisa, Savage, Sharon A., Taylor, Philip R., Vivo, Immaculata De, McGlynn, Katherine A., Purdue, Mark P., Rajaraman, Preetha, Adami, Hans-Olov, Ahlbom, Anders, Albanes, Demetrius, Amary, Maria Fernanda, An, She-Juan, Andersson, Ulrika, Andriole, Gerald, Andrulis, Irene L., Angelucci, Emanuele, Ansell, Stephen M., Arici, Cecilia, Armstrong, Bruce K., Arslan, Alan A., Austin, Melissa A., Baris, Dalsu, Barkauskas, Donald A., Bassig, Bryan A., Becker, Nikolaus, Benavente, Yolanda, Benhamou, Simone, Berg, Christine, Van Den Berg, David, Bernstein, Leslie, Bertrand, Kimberly A., Birmann, Brenda M., Black, Amanda, Boeing, Heiner, Boffetta, Paolo, Boutron-Ruault, Marie-Christine, Bracci, Paige M., Brinton, Louise, Brooks-Wilson, Angela R., Bueno-de-Mesquita, H. Bas, Burdett, Laurie, Buring, Julie, Butler, Mary Ann, Cai, Qiuyin, Cancel-Tassin, Geraldine, Canzian, Federico, Carrato, Alfredo, Carreon, Tania, Carta, Angela, Chan, John K. C., Chang, Ellen T., Chang, Gee-Chen, Chang, I-Shou, Chang, Jiang, Chang-Claude, Jenny, Chen, Chien-Jen, Chen, Chih-Yi, Chen, Chu, Chen, Chung-Hsing, Chen, Constance, Chen, Hongyan, Chen, Kexin, Chen, Kuan-Yu, Chen, Kun-Chieh, Chen, Ying, Chen, Ying-Hsiang, Chen, Yi-Song, Chen, Yuh-Min, Chien, Li-Hsin, Chirlaque, María-Dolores, Choi, Jin Eun, Choi, Yi Young, Chow, Wong-Ho, Chung, Charles C., Clavel, Jacqueline, Clavel-Chapelon, Françoise, Cocco, Pierluigi, Colt, Joanne S., Comperat, Eva, Conde, Lucia, Connors, Joseph M., Conti, David, Cortessis, Victoria K., Cotterchio, Michelle, Cozen, Wendy, Crouch, Simon, Crous-Bou, Marta, Cussenot, Olivier, Davis, Faith G., Ding, Ti, Diver, W. Ryan, Dorronsoro, Miren, Dossus, Laure, Duell, Eric J., Ennas, Maria Grazia, Erickson, Ralph L., Feychting, Maria, Flanagan, Adrienne M., Foretova, Lenka, Fraumeni, Joseph F., Freedman, Neal D., Beane Freeman, Laura E., Fuchs, Charles, Gago-Dominguez, Manuela, Gallinger, Steven, Gao, Yu-Tang, Gapstur, Susan M., Garcia-Closas, Montserrat, García-Closas, Reina, Gascoyne, Randy D., Gastier-Foster, Julie, Gaudet, Mia M., Gaziano, J. Michael, Giffen, Carol, Giles, Graham G., Giovannucci, Edward, Glimelius, Bengt, Goggins, Michael, Gokgoz, Nalan, Goldstein, Alisa M., Gorlick, Richard, Gross, Myron, Grubb, Robert, Gu, Jian, Guan, Peng, Gunter, Marc, Guo, Huan, Habermann, Thomas M., Haiman, Christopher A., Halai, Dina, Hallmans, Goran, Hassan, Manal, Hattinger, Claudia, He, Qincheng, He, Xingzhou, Helzlsouer, Kathy, Henderson, Brian, Henriksson, Roger, Hjalgrim, Henrik, Hoffman-Bolton, Judith, Hohensee, Chancellor, Holford, Theodore R., Holly, Elizabeth A., Hong, Yun-Chul, Hoover, Robert N., Horn-Ross, Pamela L., Hosain, G. M. Monawar, Hosgood, H. Dean, Hsiao, Chin-Fu, Hu, Nan, Hu, Wei, Hu, Zhibin, Huang, Ming-Shyan, Huerta, Jose-Maria, Hung, Jen-Yu, Hutchinson, Amy, Inskip, Peter D., Jackson, Rebecca D., Jacobs, Eric J., Jenab, Mazda, Jeon, Hyo-Sung, Ji, Bu-Tian, Jin, Guangfu, Jin, Li, Johansen, Christoffer, Johnson, Alison, Jung, Yoo Jin, Kaaks, Rudolph, Kamineni, Aruna, Kane, Eleanor, Kang, Chang Hyun, Karagas, Margaret R., Kelly, Rachel S., Khaw, Kay-Tee, Kim, Christopher, Kim, Hee Nam, Kim, Jin Hee, Kim, Jun Suk, Kim, Yeul Hong, Kim, Young Tae, Kim, Young-Chul, Kitahara, Cari M., Klein, Alison P., Klein, Robert J., Kogevinas, Manolis, Kohno, Takashi, Kolonel, Laurence N., Kooperberg, Charles, Kricker, Anne, Krogh, Vittorio, Kunitoh, Hideo, Kurtz, Robert C., Kweon, Sun-Seog, LaCroix, Andrea, Lawrence, Charles, Lecanda, Fernando, Lee, Victor Ho Fun, Li, Donghui, Li, Haixin, Li, Jihua, Li, Yao-Jen, Li, Yuqing, Liao, Linda M., Liebow, Mark, Lightfoot, Tracy, Lim, Wei-Yen, Lin, Chien-Chung, Lin, Dongxin, Lindstrom, Sara, Linet, Martha S., Link, Brian K., Liu, Chenwei, Liu, Jianjun, Liu, Li, Ljungberg, Börje, Lloreta, Josep, Lollo, Simonetta Di, Lu, Daru, Lund, Eiluv, Malats, Nuria, Mannisto, Satu, Marchand, Loic Le, Marina, Neyssa, Masala, Giovanna, Mastrangelo, Giuseppe, Matsuo, Keitaro, Maynadie, Marc, McKay, James, McKean-Cowdin, Roberta, Melbye, Mads, Melin, Beatrice S., Michaud, Dominique S., Mitsudomi, Tetsuya, Monnereau, Alain, Montalvan, Rebecca, Moore, Lee E., Mortensen, Lotte Maxild, Nieters, Alexandra, North, Kari E., Novak, Anne J., Oberg, Ann L., Offit, Kenneth, Oh, In-Jae, Olson, Sara H., Palli, Domenico, Pao, William, Park, In Kyu, Park, Jae Yong, Park, Kyong Hwa, Patiño-Garcia, Ana, Pavanello, Sofia, Peeters, Petra H. M., Perng, Reury-Perng, Peters, Ulrike, Petersen, Gloria M., Picci, Piero, Pike, Malcolm C., Porru, Stefano, Prescott, Jennifer, Prokunina-Olsson, Ludmila, Qian, Biyun, Qiao, You-Lin, Rais, Marco, Riboli, Elio, Riby, Jacques, Risch, Harvey A., Rizzato, Cosmeri, Rodabough, Rebecca, Roman, Eve, Roupret, Morgan, Ruder, Avima M., de Sanjose, Silvia, Scelo, Ghislaine, Schned, Alan, Schumacher, Fredrick, Schwartz, Kendra, Schwenn, Molly, Scotlandi, Katia, Seow, Adeline, Serra, Consol, Serra, Massimo, Sesso, Howard D., Setiawan, Veronica Wendy, Severi, Gianluca, Severson, Richard K., Shanafelt, Tait D., Shen, Hongbing, Shen, Wei, Shin, Min-Ho, Shiraishi, Kouya, Shu, Xiao-Ou, Siddiq, Afshan, Sierrasesúmaga, Luis, Sihoe, Alan Dart Loon, Skibola, Christine F., Smith, Alex, Smith, Martyn T., Southey, Melissa C., Spinelli, John J., Staines, Anthony, Stampfer, Meir, Stern, Marianna C., Stevens, Victoria L., Stolzenberg-Solomon, Rachael S., Su, Jian, Su, Wu-Chou, Sund, Malin, Sung, Jae Sook, Sung, Sook Whan, Tan, Wen, Tang, Wei, Tardón, Adonina, Thomas, David, Thompson, Carrie A., Tinker, Lesley F., Tirabosco, Roberto, Tjønneland, Anne, Travis, Ruth C., Trichopoulos, Dimitrios, Tsai, Fang-Yu, Tsai, Ying-Huang, Tucker, Margaret, Turner, Jenny, Vajdic, Claire M., Vermeulen, Roel C. H., Villano, Danylo J., Vineis, Paolo, Virtamo, Jarmo, Visvanathan, Kala, Wactawski-Wende, Jean, Wang, Chaoyu, Wang, Chih-Liang, Wang, Jiu-Cun, Wang, Junwen, Wei, Fusheng, Weiderpass, Elisabete, Weiner, George J., Weinstein, Stephanie, Wentzensen, Nicolas, White, Emily, Witzig, Thomas E., Wolpin, Brian M., Wong, Maria Pik, Wu, Chen, Wu, Guoping, Wu, Junjie, Wu, Tangchun, Wu, Wei, Wu, Xifeng, Wu, Yi-Long, Wunder, Jay S., Xiang, Yong-Bing, Xu, Jun, Xu, Ping, Yang, Pan-Chyr, Yang, Tsung-Ying, Ye, Yuanqing, Yin, Zhihua, Yokota, Jun, Yoon, Ho-Il, Yu, Chong-Jen, Yu, Herbert, Yu, Kai, Yuan, Jian-Min, Zelenetz, Andrew, Zeleniuch-Jacquotte, Anne, Zhang, Xu-Chao, Zhang, Yawei, Zhao, Xueying, Zhao, Zhenhong, Zheng, Hong, Zheng, Tongzhang, Zheng, Wei, Zhou, Baosen, Zhu, Meng, Zucca, Mariagrazia, Boca, Simina M., Cerhan, James R., Ferri, Giovanni M., Hartge, Patricia, Hsiung, Chao Agnes, Magnani, Corrado, Miligi, Lucia, Morton, Lindsay M., Smedby, Karin E., Teras, Lauren R., Vijai, Joseph, Wang, Sophia S., Brennan, Paul, Caporaso, Neil E., Hunter, David J., Kraft, Peter, Rothman, Nathaniel, Silverman, Debra T., Slager, Susan L., Chanock, Stephen J., and Chatterjee, Nilanjan

Subjects
Adult, Asian Continental Ancestry Group, Male, Lung Neoplasms, DATABASE, European Continental Ancestry Group, RELATIVES, Bone Neoplasms, Polymorphism, Single Nucleotide, Article, LUNG-CANCER, Testicular Neoplasms, Neoplasms, SWEDEN, LYMPHOMA, Humans, Genetic Predisposition to Disease, FAMILIAL RISK, Oncology & Carcinogenesis, Aged, Osteosarcoma, Science & Technology, MUTATIONS, Smoking, Middle Aged, Leukemia, Lymphocytic, Chronic, B-Cell, PANCREATIC-CANCER, Kidney Neoplasms, MULTIPLE SUSCEPTIBILITY LOCI, INDIVIDUALS, Oncology, Urinary Bladder Neoplasms, Tissue Array Analysis, Female, Lymphoma, Large B-Cell, Diffuse, Life Sciences & Biomedicine, 1112 Oncology And Carcinogenesis, Genome-Wide Association Study
Abstract

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common SNPs for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49,492 cancer cases and 34,131 controls. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% CI = 14% - 37%) and 7% (4% - 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ=0.73, SE=0.28), Diffuse Large B-Cell Lymphoma (DLBCL) and pediatric osteosarcoma (ρ=0.53, SE=0.21), DLBCL and Chronic Lymphocytic Leukemia (CLL) (ρ=0.51, SE=0.18), and bladder and lung (ρ=0.35, SE=0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a non-smoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Published
2015

10. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia

Author

Machiela, Mitchell J, Hsiung, Chao Agnes, Shu, Xiao-Ou, Seow, Wei Jie, Wang, Zhaoming, Matsuo, Keitaro, Hong, Yun-Chul, Seow, Adeline, Wu, Chen, Hosgood, H Dean, Chen, Kexin, Wang, Jiu-Cun, Wen, Wanqing, Cawthon, Richard, Chatterjee, Nilanjan, Hu, Wei, Caporaso, Neil E, Park, Jae Yong, Chen, Chien-Jen, Kim, Yeul Hong, Kim, Young Tae, Landi, Maria Teresa, Shen, Hongbing, Lawrence, Charles, Burdett, Laurie, Yeager, Meredith, Chang, I-Shou, Mitsudomi, Tetsuya, Kim, Hee Nam, Chang, Gee-Chen, Bassig, Bryan A, Tucker, Margaret, Wei, Fusheng, Yin, Zhihua, An, She-Juan, Qian, Biyun, Lee, Victor Ho Fun, Lu, Daru, Liu, Jianjun, Jeon, Hyo-Sung, Hsiao, Chin-Fu, Sung, Jae Sook, Kim, Jin Hee, Gao, Yu-Tang, Tsai, Ying-Huang, Jung, Yoo Jin, Guo, Huan, Hu, Zhibin, Hutchinson, Amy, Wang, Wen-Chang, Klein, Robert J, Chung, Charles C, Oh, In-Jae, Chen, Kuan-Yu, Berndt, Sonja I, Wu, Wei, Chang, Jiang, Zhang, Xu-Chao, Huang, Ming-Shyan, Zheng, Hong, Wang, Junwen, Zhao, Xueying, Li, Yuqing, Choi, Jin Eun, Su, Wu-Chou, Park, Kyong Hwa, Sung, Sook Whan, Chen, Yuh-Min, Liu, Li, Kang, Chang Hyun, Hu, Lingmin, Chen, Chung-Hsing, Pao, William, Kim, Young-Chul, Yang, Tsung-Ying, Xu, Jun, Guan, Peng, Tan, Wen, Su, Jian, Wang, Chih-Liang, Li, Haixin, Sihoe, Alan Dart Loon, Zhao, Zhenhong, Chen, Ying, Choi, Yi Young, Hung, Jen-Yu, Kim, Jun Suk, Yoon, Ho-Il, Cai, Qiuyin, Lin, Chien-Chung, Park, In Kyu, Xu, Ping, Dong, Jing, Kim, Christopher, He, Qincheng, Perng, Reury-Perng, Kohno, Takashi, Kweon, Sun-Seog, Chen, Chih-Yi, Vermeulen, Roel C H, Wu, Junjie, Lim, Wei-Yen, Chen, Kun-Chieh, Chow, Wong-Ho, Ji, Bu-Tian, Chan, John K C, Chu, Minjie, Li, Yao-Jen, Yokota, Jun, Li, Jihua, Chen, Hongyan, Xiang, Yong-Bing, Yu, Chong-Jen, Kunitoh, Hideo, Wu, Guoping, Jin, Li, Lo, Yen-Li, Shiraishi, Kouya, Chen, Ying-Hsiang, Lin, Hsien-Chih, Wu, Tangchun, Wong, Maria Pik, Wu, Yi-Long, Yang, Pan-Chyr, Zhou, Baosen, Shin, Min-Ho, Fraumeni, Joseph F, Zheng, Wei, Lin, Dongxin, Chanock, Stephen J, Rothman, Nathaniel, Lan, Qing, Risk Assessment, Infection & Immunity, dIRAS RA-2, dIRAS RA-I&I RA, and LS IRAS EEPI GRA (Gezh.risico-analyse)

Subjects
Adult, Asian Continental Ancestry Group, China, Singapore, Lung Neoplasms, Smoking, Taiwan, Telomere Homeostasis, Middle Aged, Telomere, Polymorphism, Single Nucleotide, Japan, Risk Factors, Republic of Korea, Odds Ratio, Hong Kong, Humans, Female, Genetic Predisposition to Disease, Prospective Studies, Aged, Genome-Wide Association Study
Abstract

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.

Published
2015

11. Characterization of large structural genetic mosaicism in human autosomes

Author

Machiela, Mitchell J, Zhou, Weiyin, Sampson, Joshua N, Dean, Michael C, Jacobs, Kevin B, Black, Amanda, Brinton, Louise A, Chang, I-Shou, Chen, Chu, Chen, Constance, Chen, Kexin, Cook, Linda S, Crous Bou, Marta, De Vivo, Immaculata, Doherty, Jennifer, Friedenreich, Christine M, Gaudet, Mia M, Haiman, Christopher A, Hankinson, Susan E, Hartge, Patricia, Henderson, Brian E, Hong, Yun-Chul, Hosgood, H Dean, Hsiung, Chao A, Hu, Wei, Hunter, David J, Jessop, Lea, Kim, Hee Nam, Kim, Yeul Hong, Kim, Young Tae, Klein, Robert, Kraft, Peter, Lan, Qing, Lin, Dongxin, Liu, Jianjun, Le Marchand, Loic, Liang, Xiaolin, Lissowska, Jolanta, Lu, Lingeng, Magliocco, Anthony M, Matsuo, Keitaro, Olson, Sara H, Orlow, Irene, Park, Jae Yong, Pooler, Loreall, Prescott, Jennifer, Rastogi, Radhai, Risch, Harvey A, Schumacher, Fredrick, Seow, Adeline, Setiawan, Veronica Wendy, Shen, Hongbing, Sheng, Xin, Shin, Min-Ho, Shu, Xiao-Ou, VanDen Berg, David, Wang, Jiu-Cun, Wentzensen, Nicolas, Wong, Maria Pik, Wu, Chen, Wu, Tangchun, Wu, Yi-Long, Xia, Lucy, Yang, Hannah P, Yang, Pan-Chyr, Zheng, Wei, Zhou, Baosen, Abnet, Christian C, Albanes, Demetrius, Aldrich, Melinda C, Amos, Christopher, Amundadottir, Laufey T, Berndt, Sonja I, Blot, William J, Bock, Cathryn H, Bracci, Paige M, Burdett, Laurie, Buring, Julie E, Butler, Mary A, Carreón, Tania, Chatterjee, Nilanjan, Chung, Charles C, Cook, Michael B, Cullen, Michael, Davis, Faith G, Ding, Ti, Duell, Eric J, Epstein, Caroline G, Fan, Jin-Hu, Figueroa, Jonine D, Fraumeni, Joseph F, Freedman, Neal D, Fuchs, Charles S, Gao, Yu-Tang, Gapstur, Susan M, Patiño-Garcia, Ana, Garcia-Closas, Montserrat, Gaziano, J Michael, Giles, Graham G, and Gillanders, Elizabeth M

Subjects
Chromosome Aberrations, Male, Genetics & Heredity, Medical And Health Sciences, Genome, Genotype, Mosaicism, Human Genome, Middle Aged, Biological Sciences, Clinical Research, Neoplasms, Genetics, 2.1 Biological and endogenous factors, Humans, Female, Aetiology, Human, Aged, Genome-Wide Association Study
Abstract

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Published
2015

12. A genome-wide association study of marginal zone lymphoma shows association to the HLA region

Author

Vijai, Joseph, Wang, Zhaoming, Berndt, Sonja I, Skibola, Christine F, Slager, Susan L, de Sanjose, Silvia, Melbye, Mads, Glimelius, Bengt, Bracci, Paige M, Conde, Lucia, Birmann, Brenda M, Wang, Sophia S, Brooks-Wilson, Angela R, Lan, Qing, de Bakker, Paul IW, Vermeulen, Roel CH, Portlock, Carol, Ansell, Stephen M, Link, Brian K, Riby, Jacques, North, Kari E, Gu, Jian, Hjalgrim, Henrik, Cozen, Wendy, Becker, Nikolaus, Teras, Lauren R, Spinelli, John J, Turner, Jenny, Zhang, Yawei, Purdue, Mark P, Giles, Graham G, Kelly, Rachel S, Zeleniuch-Jacquotte, Anne, Ennas, Maria Grazia, Monnereau, Alain, Bertrand, Kimberly A, Albanes, Demetrius, Lightfoot, Tracy, Yeager, Meredith, Chung, Charles C, Burdett, Laurie, Hutchinson, Amy, Lawrence, Charles, Montalvan, Rebecca, Liang, Liming, Huang, Jinyan, Ma, Baoshan, Villano, Danylo J, Maria, Ann, Corines, Marina, Thomas, Tinu, Novak, Anne J, Dogan, Ahmet, Liebow, Mark, Thompson, Carrie A, Witzig, Thomas E, Habermann, Thomas M, Weiner, George J, Smith, Martyn T, Holly, Elizabeth A, Jackson, Rebecca D, Tinker, Lesley F, Ye, Yuanqing, Adami, Hans-Olov, Smedby, Karin E, De Roos, Anneclaire J, Hartge, Patricia, Morton, Lindsay M, Severson, Richard K, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, Diver, W Ryan, Vajdic, Claire M, Armstrong, Bruce K, Kricker, Anne, Zheng, Tongzhang, Holford, Theodore R, Severi, Gianluca, Vineis, Paolo, Ferri, Giovanni M, Ricco, Rosalia, Miligi, Lucia, Clavel, Jacqueline, Giovannucci, Edward, Kraft, Peter, Virtamo, Jarmo, Smith, Alex, Kane, Eleanor, Roman, Eve, Chiu, Brian CH, Fraumeni, Joseph F, Wu, Xifeng, Cerhan, James R, Offit, Kenneth, and Chanock, Stephen J

Subjects
Membrane Glycoproteins, Genotype, Lymphoma, Butyrophilins, European Continental Ancestry Group, Human Genome, B-Cell, Computational Biology, Marginal Zone, Single Nucleotide, Hematology, White People, Major Histocompatibility Complex, Rare Diseases, Genetics, Humans, 2.1 Biological and endogenous factors, Polymorphism, Aetiology, Genome-Wide Association Study, Cancer
Abstract

Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10(-15)) and HLA-B (rs2922994, P=2.43 × 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.

Published
2015

13. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types

Author

Sampson, Joshua N. Wheeler, William A. Yeager, Meredith and Panagiotou, Orestis Wang, Zhaoming Berndt, Sonja I. Lan, Qing Abnet, Christian C. Amundadottir, Laufey T. Figueroa, Jonine D. Landi, Maria Teresa Mirabello, Lisa Savage, Sharon A. Taylor, Philip R. De Vivo, Immaculata McGlynn, Katherine A. Purdue, Mark P. Rajaraman, Preetha Adami, Hans-Olov and Ahlbom, Anders Albanes, Demetrius Amary, Maria Fernanda An, She-Juan Andersson, Ulrika Andriole, Jr., Gerald Andrulis, Irene L. Angelucci, Emanuele Ansell, Stephen M. Arici, Cecilia Armstrong, Bruce K. Arslan, Alan A. Austin, Melissa A. Baris, Dalsu Barkauskas, Donald A. Bassig, Bryan A. and Becker, Nikolaus Benavente, Yolanda Benhamou, Simone Berg, Christine Van Den Berg, David Bernstein, Leslie Bertrand, Kimberly A. Birmann, Brenda M. Black, Amanda Boeing, Heiner and Boffetta, Paolo Boutron-Ruault, Marie-Christine Bracci, Paige M. Brinton, Louise Brooks-Wilson, Angela R. and Bueno-de-Mesquita, H. Bas Burdett, Laurie Buring, Julie and Butler, Mary Ann Cai, Qiuyin Cancel-Tassin, Geraldine and Canzian, Federico Carrato, Alfredo Carreon, Tania Carta, Angela Chan, John K. C. Chang, Ellen T. Chang, Gee-Chen and Chang, I-Shou Chang, Jiang Chang-Claude, Jenny Chen, Chien-Jen Chen, Chih-Yi Chen, Chu Chen, Chung-Hsing and Chen, Constance Chen, Hongyan Chen, Kexin Chen, Kuan-Yu and Chen, Kun-Chieh Chen, Ying Chen, Ying-Hsiang Chen, Yi-Song and Chen, Yuh-Min Chien, Li-Hsin Chirlaque, Maria-Dolores and Choi, Jin Eun Choi, Yi Young Chow, Wong-Ho Chung, Charles C. and Clavel, Jacqueline Clavel-Chapelon, Franoise Cocco, Pierluigi Colt, Joanne S. Comperat, Eva Conde, Lucia and Connors, Joseph M. Conti, David Cortessis, Victoria K. and Cotterchio, Michelle Cozen, Wendy Crouch, Simon Crous-Bou, Marta Cussenot, Olivier Davis, Faith G. Ding, Ti Diver, W. Ryan Dorronsoro, Miren Dossus, Laure Duell, Eric J. and Ennas, Maria Grazia Erickson, Ralph L. Feychting, Maria and Flanagan, Adrienne M. Foretova, Lenka Fraumeni, Jr., Joseph F. and Freedman, Neal D. Freeman, Laura E. Beane Fuchs, Charles and Gago-Dominguez, Manuela Gallinger, Steven Gao, Yu-Tang and Gapstur, Susan M. Garcia-Closas, Montserrat Garcia-Closas, Reina and Gascoyne, Randy D. Gastier-Foster, Julie Gaudet, Mia M. and Gaziano, J. Michael Giffen, Carol Giles, Graham G. and Giovannucci, Edward Glimelius, Bengt Goggins, Michael and Gokgoz, Nalan Goldstein, Alisa M. Gorlick, Richard Gross, Myron Grubb, III, Robert Gu, Jian Guan, Peng Gunter, Marc Guo, Huan Habermann, Thomas M. Haiman, Christopher A. and Halai, Dina Hallmans, Goran Hassan, Manal Hattinger, Claudia He, Qincheng He, Xingzhou Helzlsouer, Kathy and Henderson, Brian Henriksson, Roger Hjalgrim, Henrik and Hoffman-Bolton, Judith Hohensee, Chancellor Holford, Theodore R. and Holly, Elizabeth A. Hong, Yun-Chul Hoover, Robert N. and Horn-Ross, Pamela L. Hosain, G. M. Monawar Hosgood, III, H. Dean and Hsiao, Chin-Fu Hu, Nan Hu, Wei Hu, Zhibin Huang, Ming-Shyan Huerta, Jose-Maria Hung, Jen-Yu Hutchinson, Amy and Inskip, Peter D. Jackson, Rebecca D. Jacobs, Eric J. and Jenab, Mazda Jeon, Hyo-Sung Ji, Bu-Tian Jin, Guangfu and Jin, Li Johansen, Christoffer Johnson, Alison Jung, Yoo Jin and Kaaks, Rudolph Kamineni, Aruna Kane, Eleanor Kang, Chang Hyun Karagas, Margaret R. Kelly, Rachel S. Khaw, Kay-Tee and Kim, Christopher Kim, Hee Nam Kim, Jin Hee Kim, Jun Suk and Kim, Yeul Hong Kim, Young Tae Kim, Young-Chul Kitahara, Cari M. Klein, Alison P. Klein, Robert J. Kogevinas, Manolis and Kohno, Takashi Kolonel, Laurence N. Kooperberg, Charles and Kricker, Anne Krogh, Vittorio Kunitoh, Hideo Kurtz, Robert C. Kweon, Sun-Seog LaCroix, Andrea Lawrence, Charles and Lecanda, Fernando Lee, Victor Ho Fun Li, Donghui Li, Haixin and Li, Jihua Li, Yao-Jen Li, Yuqing Liao, Linda M. and Liebow, Mark Lightfoot, Tracy Lim, Wei-Yen Lin, Chien-Chung and Lin, Dongxin Lindstrom, Sara Linet, Martha S. Link, Brian K. Liu, Chenwei Liu, Jianjun Liu, Li Ljungberg, Boerje Lloreta, Josep Di Lollo, Simonetta Lu, Daru Lund, Eiluv Malats, Nuria Mannisto, Satu Le Marchand, Loic and Marina, Neyssa Masala, Giovanna Mastrangelo, Giuseppe and Matsuo, Keitaro Maynadie, Marc Mckay, James McKean-Cowdin, Roberta Melbye, Mads Melin, Beatrice S. Michaud, Dominique S. Mitsudomi, Tetsuya Monnereau, Alain Montalvan, Rebecca and Moore, Lee E. Mortensen, Lotte Maxild Nieters, Alexandra and North, Kari E. Novak, Anne J. Oberg, Ann L. Offit, Kenneth and Oh, In-Jae Olson, Sara H. Palli, Domenico Pao, William and Park, In Kyu Park, Jae Yong Park, Kyong Hwa and Patino-Garcia, Ana Pavanello, Sofia Peeters, Petra H. M. and Perng, Reury-Perng Peters, Ulrike Petersen, Gloria M. Picci, Piero Pike, Malcolm C. Porru, Stefano Prescott, Jennifer and Prokunina-Olsson, Ludmila Qian, Biyun Qiao, You-Lin Rais, Marco Riboli, Elio Riby, Jacques Risch, Harvey A. and Rizzato, Cosmeri Rodabough, Rebecca Roman, Eve Roupret, Morgan Ruder, Avima M. de Sanjose, Silvia Scelo, Ghislaine and Schned, Alan Schumacher, Fredrick Schwartz, Kendra and Schwenn, Molly Scotlandi, Katia Seow, Adeline Serra, Consol and Serra, Massimo Sesso, Howard D. Setiawan, Veronica Wendy and Severi, Gianluca Severson, Richard K. Shanafelt, Tait D. and Shen, Hongbing Shen, Wei Shin, Min-Ho Shiraishi, Kouya and Shu, Xiao-Ou Siddiq, Afshan Sierrasesumaga, Luis Sihoe, Alan Dart Loon Skibola, Christine F. Smith, Alex Smith, Martyn T. and Southey, Melissa C. Spinelli, John J. Staines, Anthony and Stampfer, Meir Stern, Marianna C. Stevens, Victoria L. and Stolzenberg-Solomon, Rachael S. Su, Jian Su, Wu-Chou Sund, Malin Sung, Jae Sook Sung, Sook Whan Tan, Wen Tang, Wei and Tardon, Adonina Thomas, David Thompson, Carrie A. and Tinker, Lesley F. Tirabosco, Roberto Tjonneland, Anne and Travis, Ruth C. Trichopoulos, Dimitrios Tsai, Fang-Yu Tsai, Ying-Huang Tucker, Margaret Turner, Jenny Vajdic, Claire M. and Vermeulen, Roel C. H. Villano, Danylo J. Vineis, Paolo and Virtamo, Jarmo Visvanathan, Kala Wactawski-Wende, Jean Wang, Chaoyu Wang, Chih-Liang Wang, Jiu-Cun Wang, Junwen Wei, Fusheng Weiderpass, Elisabete Weiner, George J. Weinstein, Stephanie Wentzensen, Nicolas White, Emily Witzig, Thomas E. and Wolpin, Brian M. Wong, Maria Pik Wu, Chen Wu, Guoping and Wu, Junjie Wu, Tangchun Wu, Wei Wu, Xifeng Wu, Yi-Long Wunder, Jay S. Xiang, Yong-Bing Xu, Jun Xu, Ping and Yang, Pan-Chyr Yang, Tsung-Ying Ye, Yuanqing Yin, Zhihua and Yokota, Jun Yoon, Ho-Il Yu, Chong-Jen Yu, Herbert and Yu, Kai Yuan, Jian-Min Zelenetz, Andrew Zeleniuch-Jacquotte, Anne Zhang, Xu-Chao Zhang, Yawei Zhao, Xueying Zhao, Zhenhong Zheng, Hong Zheng, Tongzhang Zheng, Wei Zhou, Baosen Zhu, Meng Zucca, Mariagrazia Boca, Simina M. and Cerhan, James R. Ferri, Giovanni M. Hartge, Patricia Hsiung, Chao Agnes Magnani, Corrado Miligi, Lucia Morton, Lindsay M. and Smedby, Karin E. Teras, Lauren R. Vijai, Joseph Wang, Sophia S. Brennan, Paul Caporaso, Neil E. Hunter, David J. and Kraft, Peter Rothman, Nathaniel Silverman, Debra T. and Slager, Susan L. Chanock, Stephen J. Chatterjee, Nilanjan

Abstract

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Published
2015

14. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Author

Cerhan, James R, Berndt, Sonja I, Vijai, Joseph, Ghesquières, Hervé, McKay, James, Wang, Sophia S, Wang, Zhaoming, Yeager, Meredith, Conde, Lucia, de Bakker, Paul IW, Nieters, Alexandra, Cox, David, Burdett, Laurie, Monnereau, Alain, Flowers, Christopher R, De Roos, Anneclaire J, Brooks-Wilson, Angela R, Lan, Qing, Severi, Gianluca, Melbye, Mads, Gu, Jian, Jackson, Rebecca D, Kane, Eleanor, Teras, Lauren R, Purdue, Mark P, Vajdic, Claire M, Spinelli, John J, Giles, Graham G, Albanes, Demetrius, Kelly, Rachel S, Zucca, Mariagrazia, Bertrand, Kimberly A, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Hutchinson, Amy, Zhi, Degui, Habermann, Thomas M, Link, Brian K, Novak, Anne J, Dogan, Ahmet, Asmann, Yan W, Liebow, Mark, Thompson, Carrie A, Ansell, Stephen M, Witzig, Thomas E, Weiner, George J, Veron, Amelie S, Zelenika, Diana, Tilly, Hervé, Haioun, Corinne, Molina, Thierry Jo, Hjalgrim, Henrik, Glimelius, Bengt, Adami, Hans-Olov, Bracci, Paige M, Riby, Jacques, Smith, Martyn T, Holly, Elizabeth A, Cozen, Wendy, Hartge, Patricia, Morton, Lindsay M, Severson, Richard K, Tinker, Lesley F, North, Kari E, Becker, Nikolaus, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, Lightfoot, Tracy, Crouch, Simon, Smith, Alex, Roman, Eve, Diver, W Ryan, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J, Villano, Danylo J, Zheng, Tongzhang, Zhang, Yawei, Holford, Theodore R, Kricker, Anne, Turner, Jenny, Southey, Melissa C, Clavel, Jacqueline, Virtamo, Jarmo, Weinstein, Stephanie, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Trichopoulos, Dimitrios, Vermeulen, Roel CH, Boeing, Heiner, Tjonneland, Anne, Angelucci, Emanuele, Di Lollo, Simonetta, Rais, Marco, and Birmann, Brenda M

Subjects
Likelihood Functions, Genotype, Lymphoma, Quantitative Trait Loci, Human Genome, Chromosome Mapping, Computational Biology, Single Nucleotide, Hematology, Biological Sciences, Diffuse, Medical and Health Sciences, White People, Rare Diseases, Genetic Loci, Large B-Cell, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Genome-Wide Association Study, Cancer, Developmental Biology
Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

Published
2014

15. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Author

Cerhan, James R, Berndt, Sonja I, Vijai, Joseph, Ghesquières, Hervé, McKay, James, Wang, Sophia S, Wang, Zhaoming, Yeager, Meredith, Conde, Lucia, de Bakker, Paul IW, Nieters, Alexandra, Cox, David, Burdett, Laurie, Monnereau, Alain, Flowers, Christopher R, De Roos, Anneclaire J, Brooks-Wilson, Angela R, Lan, Qing, Severi, Gianluca, Melbye, Mads, Gu, Jian, Jackson, Rebecca D, Kane, Eleanor, Teras, Lauren R, Purdue, Mark P, Vajdic, Claire M, Spinelli, John J, Giles, Graham G, Albanes, Demetrius, Kelly, Rachel S, Zucca, Mariagrazia, Bertrand, Kimberly A, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Hutchinson, Amy, Zhi, Degui, Habermann, Thomas M, Link, Brian K, Novak, Anne J, Dogan, Ahmet, Asmann, Yan W, Liebow, Mark, Thompson, Carrie A, Ansell, Stephen M, Witzig, Thomas E, Weiner, George J, Veron, Amelie S, Zelenika, Diana, Tilly, Hervé, Haioun, Corinne, Molina, Thierry Jo, Hjalgrim, Henrik, Glimelius, Bengt, Adami, Hans-Olov, Bracci, Paige M, Riby, Jacques, Smith, Martyn T, Holly, Elizabeth A, Cozen, Wendy, Hartge, Patricia, Morton, Lindsay M, Severson, Richard K, Tinker, Lesley F, North, Kari E, Becker, Nikolaus, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, Lightfoot, Tracy, Crouch, Simon, Smith, Alex, Roman, Eve, Diver, W Ryan, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J, Villano, Danylo J, Zheng, Tongzhang, Zhang, Yawei, Holford, Theodore R, Kricker, Anne, Turner, Jenny, Southey, Melissa C, Clavel, Jacqueline, Virtamo, Jarmo, Weinstein, Stephanie, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Trichopoulos, Dimitrios, Vermeulen, Roel CH, Boeing, Heiner, Tjonneland, Anne, Angelucci, Emanuele, Di Lollo, Simonetta, Rais, Marco, and Birmann, Brenda M

Subjects
Likelihood Functions, Genotype, Lymphoma, Quantitative Trait Loci, European Continental Ancestry Group, Chromosome Mapping, Computational Biology, Single Nucleotide, Biological Sciences, Diffuse, Medical and Health Sciences, Genetic Loci, Large B-Cell, Humans, Genetic Predisposition to Disease, Polymorphism, Genome-Wide Association Study, Developmental Biology
Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

Published
2014

16. Genome-wide Association Study Identifies Five Susceptibility Loci for Follicular Lymphoma outside the HLA Region

Author

Skibola, Christine F., Berndt, Sonja I., Vijai, Joseph, Conde, Lucia, Wang, Zhaoming, Yeager, Meredith, de Bakker, Paul I. W., Birmann, Brenda M., Vajdic, Claire M., Foo, Jia-Nee, Bracci, Paige M., Vermeulen, Roel C. H., Slager, Susan L., de Sanjose, Silvia, Wang, Sophia S., Linet, Martha S., Salles, Gilles, Lan, Qing, Severi, Gianluca, Hjalgrim, Henrik, Lightfoot, Tracy, Melbye, Mads, Gu, Jian, Ghesquieres, Herve, Link, Brian K., Morton, Lindsay M., Holly, Elizabeth A., Smith, Alex, Tinker, Lesley F., Teras, Lauren R., Kricker, Anne, Becker, Nikolaus, Purdue, Mark P., Spinelli, John J., Zhang, Yawei, Giles, Graham G., Vineis, Paolo, Monnereau, Alain, Bertrand, Kimberly A., Albanes, Demetrius, Zeleniuch-Jacquotte, Anne, Gabbas, Attilio, Chung, Charles C., Burdett, Laurie, Hutchinson, Amy, Lawrence, Charles, Montalvan, Rebecca, Liang, Liming, Huang, Jinyan, Ma, Baoshan, Liu, Jianjun, Adami, Hans-Olov, Glimelius, Bengt, Ye, Yuanqing, Nowakowski, Grzegorz S., Dogan, Ahmet, Thompson, Carrie A., Habermann, Thomas M., Novak, Anne J., Liebow, Mark, Witzig, Thomas E., Weiner, George J., Schenk, Maryjean, Hartge, Patricia, De Roos, Anneclaire J., Cozen, Wendy, Zhi, Degui, Akers, Nicholas K., Riby, Jacques, Smith, Martyn T., Lacher, Mortimer, Villano, Danylo J., Maria, Ann, Roman, Eve, Kane, Eleanor, Jackson, Rebecca D., North, Kari E., Diver, W. Ryan, Turner, Jenny, Armstrong, Bruce K., Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, McKay, James, Brooks-Wilson, Angela R., Zheng, Tongzhang, Holford, Theodore R., Chamosa, Saioa, Kaaks, Rudolph, Kelly, Rachel S., Ohlsson, Bodil, Travis, Ruth C., Weiderpass, Elisabete, Clave, Jacqueline, Giovannucci, Edward, Kraft, Peter, Virtamo, Jarmo, Mazza, Patrizio, Cocco, Pierluigi, Ennas, Maria Grazia, Chiu, Brian C. H., Fraumeni, Joseph R., Nieters, Alexandra, Offit, Kenneth, Wu, Xifeng, Cerhan, James R., Smedby, Karin E., Chanock, Stephen J., Rothman, Nathaniel, LS IRAS EEPI GRA (Gezh.risico-analyse), Risk Assessment of Toxic and Immunomodulatory Agents, and IRAS RATIA-SIB

Subjects
EXPRESSION, RISK, CLASS-I, RESOURCE, TOOL, UNIVERSITY, PEPTIDE, VARIANTS, SET, SNPS
Abstract

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 x 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 x 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 x 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 x 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 x 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DR beta 1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (P-omnibus = 4.20 x 10(-67) to 2.67 x 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 x 10(-16)) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 x 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

Published
2014

17. Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region

Author

Skibola, Christine F, Berndt, Sonja I, Vijai, Joseph, Conde, Lucia, Wang, Zhaoming, Yeager, Meredith, de Bakker, Paul IW, Birmann, Brenda M, Vajdic, Claire M, Foo, Jia-Nee, Bracci, Paige M, Vermeulen, Roel CH, Slager, Susan L, de Sanjose, Silvia, Wang, Sophia S, Linet, Martha S, Salles, Gilles, Lan, Qing, Severi, Gianluca, Hjalgrim, Henrik, Lightfoot, Tracy, Melbye, Mads, Gu, Jian, Ghesquières, Hervé, Link, Brian K, Morton, Lindsay M, Holly, Elizabeth A, Smith, Alex, Tinker, Lesley F, Teras, Lauren R, Kricker, Anne, Becker, Nikolaus, Purdue, Mark P, Spinelli, John J, Zhang, Yawei, Giles, Graham G, Vineis, Paolo, Monnereau, Alain, Bertrand, Kimberly A, Albanes, Demetrius, Zeleniuch-Jacquotte, Anne, Gabbas, Attilio, Chung, Charles C, Burdett, Laurie, Hutchinson, Amy, Lawrence, Charles, Montalvan, Rebecca, Liang, Liming, Huang, Jinyan, Ma, Baoshan, Liu, Jianjun, Adami, Hans-Olov, Glimelius, Bengt, Ye, Yuanqing, Nowakowski, Grzegorz S, Dogan, Ahmet, Thompson, Carrie A, Habermann, Thomas M, Novak, Anne J, Liebow, Mark, Witzig, Thomas E, Weiner, George J, Schenk, Maryjean, Hartge, Patricia, De Roos, Anneclaire J, Cozen, Wendy, Zhi, Degui, Akers, Nicholas K, Riby, Jacques, Smith, Martyn T, Lacher, Mortimer, Villano, Danylo J, Maria, Ann, Roman, Eve, Kane, Eleanor, Jackson, Rebecca D, North, Kari E, Diver, W Ryan, Turner, Jenny, Armstrong, Bruce K, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, McKay, James, Brooks-Wilson, Angela R, Zheng, Tongzhang, Holford, Theodore R, Chamosa, Saioa, Kaaks, Rudolph, Kelly, Rachel S, Ohlsson, Bodil, Travis, Ruth C, Weiderpass, Elisabete, Clavel, Jacqueline, Giovannucci, Edward, Kraft, Peter, and Virtamo, Jarmo

Subjects
Lymphoma, Medical and Health Sciences, Chromosomes, Rare Diseases, HLA Antigens, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Alleles, Cancer, Genetics & Heredity, Tumor, Human Genome, Follicular, Single Nucleotide, Hematology, Biological Sciences, Haplotypes, Case-Control Studies, Biomarkers, Human, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

Published
2014

18. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Author

Cerhan, James R., Berndt, Sonja I., Vijai, Joseph, Ghesquières, Hervé, McKay, James, Wang, Sophia S., Wang, Zhaoming, Yeager, Meredith, Conde, Lucia, De Bakker, Paul I W, Nieters, Alexandra, Cox, David, Burdett, Laurie, Monnereau, Alain, Flowers, Christopher R., De Roos, Anneclaire J., Brooks-Wilson, Angela R., Lan, Qing, Severi, Gianluca, Melbye, Mads, Gu, Jian, Jackson, Rebecca D., Kane, Eleanor, Teras, Lauren R., Purdue, Mark P., Vajdic, Claire M., Spinelli, John J., Giles, Graham G., Albanes, Demetrius, Kelly, Rachel S., Zucca, Mariagrazia, Bertrand, Kimberly A., Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Hutchinson, Amy, Zhi, Degui, Habermann, Thomas M., Link, Brian K., Novak, Anne J., Dogan, Ahmet, Asmann, Yan W., Liebow, Mark, Thompson, Carrie A., Ansell, Stephen M., Witzig, Thomas E., Weiner, George J., Veron, Amelie S., Zelenika, Diana, Tilly, Hervé, Haioun, Corinne, Molina, Thierry Jo, Hjalgrim, Henrik, Glimelius, Bengt, Adami, Hans Olov, Bracci, Paige M., Riby, Jacques, Smith, Martyn T., Holly, Elizabeth A., Cozen, Wendy, Hartge, Patricia, Morton, Lindsay M., Severson, Richard K., Tinker, Lesley F., North, Kari E., Becker, Nikolaus, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, Lightfoot, Tracy, Crouch, Simon, Smith, Alex, Roman, Eve, Diver, W. Ryan, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J., Villano, Danylo J., Zheng, Tongzhang, Zhang, Yawei, Holford, Theodore R., Kricker, Anne, Turner, Jenny, Southey, Melissa C., Clavel, Jacqueline, Virtamo, Jarmo, Weinstein, Stephanie, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Trichopoulos, Dimitrios, Vermeulen, Roel C H, Boeing, Heiner, Tjonneland, Anne, Angelucci, Emanuele, Di Lollo, Simonetta, Rais, Marco, Birmann, Brenda M., Laden, Francine, Giovannucci, Edward, Kraft, Peter, Huang, Jinyan, Ma, Baoshan, Ye, Yuanqing, Chiu, Brian C H, Sampson, Joshua, Liang, Liming, Park, Ju Hyun, Chung, Charles C., Weisenburger, Dennis D., Chatterjee, Nilanjan, Fraumeni, Joseph F., Slager, Susan L., Wu, Xifeng, De Sanjose, Silvia, Smedby, Karin E., Salles, Gilles, Skibola, Christine F., Rothman, Nathaniel, Chanock, Stephen J., LS IRAS EEPI GRA (Gezh.risico-analyse), Risk Assessment of Toxic and Immunomodulatory Agents, and IRAS RATIA-SIB

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10 '21), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10 '10), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10 '8) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10 '13 and 3.63 × 10 '11, respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

Published
2014

19. Genetic variants in Fas signaling pathway genes and risk of gastric cancer

Author

Hyland, Paula L., Lin, Shih-Wen, Hu, Nan, Zhang, Han, Wang, Lemin, Su, Hua, Wang, Chaoyu, Ding, Ti, Tang, Ze-Zhong, Fan, Jin-Hu, Qiao, You-Lin, Xiong, Xiaoqin, Wheeler, William, Giffen, Carol, Yu, Kai, Yuenger, Jeff, Burdett, Laurie, Wang, Zhaoming, Chanock, Stephen J., Tucker, Margaret A., Dawsey, Sanford M., Freedman, Neal D., Goldstein, Alisa M., Abnet, Christian C., and Taylor, Philip R

Subjects
Male, China, Genotype, Stomach, Adenocarcinoma, Middle Aged, Prognosis, Polymorphism, Single Nucleotide, Article, Asian People, Gastric Mucosa, Risk Factors, Stomach Neoplasms, Case-Control Studies, Biomarkers, Tumor, Humans, Female, Genetic Predisposition to Disease, Prospective Studies, fas Receptor, Genome-Wide Association Study, Signal Transduction
Abstract

Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (P = 5.5E-04) and GCA (P = 6.3E-03), but not GNCA (P = 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal P < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal P < 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations.

Published
2013

20. Common Genetic Polymorphisms Modify the Effect of Smoking on Absolute Risk of Bladder Cancer

Author

Garcia-Closas, Montserrat Rothman, Nathaniel Figueroa, Jonine D. and Prokunina-Olsson, Ludmila Han, Summer S. Baris, Dalsu and Jacobs, Eric J. Malats, Nuria De Vivo, Immaculata Albanes, Demetrius Purdue, Mark P. Sharma, Sapna Fu, Yi-Ping and Kogevinas, Manolis Wang, Zhaoming Tang, Wei Tardon, Adonina and Serra, Consol Carrato, Alfredo Garcia-Closas, Reina and Lloreta, Josep Johnson, Alison Schwenn, Molly Karagas, Margaret R. Schned, Alan Andriole, Jr., Gerald Grubb, III, Robert Black, Amanda Gapstur, Susan M. Thun, Michael and Diver, William Ryan Weinstein, Stephanie J. Virtamo, Jarmo and Hunter, David J. Caporaso, Neil Landi, Maria Teresa and Hutchinson, Amy Burdett, Laurie Jacobs, Kevin B. Yeager, Meredith Fraumeni, Jr., Joseph F. Chanock, Stephen J. and Silverman, Debra T. Chatterjee, Nilanjan

Abstract

Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P = 7 x 10(-4)) and UGT1A6 (P = 8 x 10(-4)). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (P-additive = 1 x 10(-4)). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made. Cancer Res; 73(7); 2211-20. (C)2012 AACR.

Published
2013

21. Detectable clonal mosaicism and its relationship to aging and cancer

Author

Jacobs, Kevin B. Yeager, Meredith Zhou, Weiyin Wacholder, Sholom Wang, Zhaoming Rodriguez-Santiago, Benjamin and Hutchinson, Amy Deng, Xiang Liu, Chenwei Horner, Marie-Josephe Cullen, Michael Epstein, Caroline G. Burdett, Laurie Dean, Michael C. Chatterjee, Nilanjan Sampson, Joshua and Chung, Charles C. Kovaks, Joseph Gapstur, Susan M. and Stevens, Victoria L. Teras, Lauren T. Gaudet, Mia M. and Albanes, Demetrius Weinstein, Stephanie J. Virtamo, Jarmo and Taylor, Philip R. Freedman, Neal D. Abnet, Christian C. and Goldstein, Alisa M. Hu, Nan Yu, Kai Yuan, Jian-Min Liao, Linda Ding, Ti Qiao, You-Lin Gao, Yu-Tang Koh, Woon-Puay and Xiang, Yong-Bing Tang, Ze-Zhong Fan, Jin-Hu Aldrich, Melinda C. Amos, Christopher Blot, William J. Bock, Cathryn H. Gillanders, Elizabeth M. Harris, Curtis C. Haiman, Christopher A. Henderson, Brian E. Kolonel, Laurence N. Le Marchand, Loic McNeill, Lorna H. Rybicki, Benjamin A. and Schwartz, Ann G. Signorello, Lisa B. Spitz, Margaret R. and Wiencke, John K. Wrensch, Margaret Wu, Xifeng Zanetti, Krista A. Ziegler, Regina G. Figueroa, Jonine D. and Garcia-Closas, Montserrat Malats, Nuria Marenne, Gaelle and Prokunina-Olsson, Ludmila Baris, Dalsu Schwenn, Molly and Johnson, Alison Landi, Maria Teresa Goldin, Lynn Consonni, Dario Bertazzi, Pier Alberto Rotunno, Melissa Rajaraman, Preetha Andersson, Ulrika Freeman, Laura E. Beane Berg, Christine D. Buring, Julie E. Butler, Mary A. Carreon, Tania and Feychting, Maria Ahlbom, Anders Gaziano, J. Michael and Giles, Graham G. Hallmans, Goran Hankinson, Susan E. Hartge, Patricia Henriksson, Roger Inskip, Peter D. Johansen, Christoffer Landgren, Annelie McKean-Cowdin, Roberta and Michaud, Dominique S. Melin, Beatrice S. Peters, Ulrike and Ruder, Avima M. Sesso, Howard D. Severi, Gianluca Shu, Xiao-Ou Visvanathan, Kala White, Emily Wolk, Alicja and Zeleniuch-Jacquotte, Anne Zheng, Wei Silverman, Debra T. and Kogevinas, Manolis Gonzalez, Juan R. Villa, Olaya Li, Donghui Duell, Eric J. Risch, Harvey A. Olson, Sara H. and Kooperberg, Charles Wolpin, Brian M. Jiao, Li Hassan, Manal and Wheeler, William Arslan, Alan A. Bueno-de-Mesquita, H. Bas and Fuchs, Charles S. Gallinger, Steven Gross, Myron D. and Holly, Elizabeth A. Klein, Alison P. LaCroix, Andrea and Mandelson, Margaret T. Petersen, Gloria Boutron-Ruault, Marie-Christine Bracci, Paige M. Canzian, Federico Chang, Kenneth Cotterchio, Michelle Giovannucci, Edward L. Goggins, Michael Bolton, Judith A. Hoffman Jenab, Mazda Khaw, Kay-Tee and Krogh, Vittorio Kurtz, Robert C. McWilliams, Robert R. and Mendelsohn, Julie B. Rabe, Kari G. Riboli, Elio Tjonneland, Anne Tobias, Geoffrey S. Trichopoulos, Dimitrios Elena, Joanne W. Yu, Herbert Amundadottir, Laufey and Stolzenberg-Solomon, Rachael Z. Kraft, Peter Schumacher, Fredrick Stram, Daniel Savage, Sharon A. Mirabello, Lisa and Andrulis, Irene L. Wunder, Jay S. Patino Garcia, Ana and Sierrasesumaga, Luis Barkauskas, Donald A. Gorlick, Richard G. and Purdue, Mark Chow, Wong-Ho Moore, Lee E. Schwartz, Kendra L. Davis, Faith G. Hsing, Ann W. Berndt, Sonja I. and Black, Amanda Wentzensen, Nicolas Brinton, Louise A. and Lissowska, Jolanta Peplonska, Beata McGlynn, Katherine A. and Cook, Michael B. Graubard, Barry I. Kratz, Christian P. and Greene, Mark H. Erickson, Ralph L. Hunter, David J. Thomas, Gilles Hoover, Robert N. Real, Francisco X. Fraumeni, Jr., Joseph F. Caporaso, Neil E. Tucker, Margaret Rothman, Nathaniel Perez-Jurado, Luis A. Chanock, Stephen J.

Abstract

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of > 2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

Published
2012

22. Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer

Author

Tang, Wei Fu, Yi-Ping Figueroa, Jonine D. Malats, Nuria and Garcia-Closas, Montserrat Chatterjee, Nilanjan Kogevinas, Manolis Baris, Dalsu Thun, Michael Hall, Jennifer L. De Vivo, Immaculata Albanes, Demetrius Porter-Gill, Patricia and Purdue, Mark P. Burdett, Laurie Liu, Luyang Hutchinson, Amy and Myers, Timothy Tardon, Adonina Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Lloreta, Josep Johnson, Alison and Schwenn, Molly Karagas, Margaret R. Schned, Alan Black, Amanda Jacobs, Eric J. Diver, W. Ryan Gapstur, Susan M. and Virtamo, Jarmo Hunter, David J. Fraumeni, Jr., Joseph F. and Chanock, Stephen J. Silverman, Debra T. Rothman, Nathaniel and Prokunina-Olsson, Ludmila

Abstract

A recent genome-wide association study of bladder cancer identified the UGT1A gene cluster on chromosome 2q37.1 as a novel susceptibility locus. The UGT1A cluster encodes a family of UDP-glucuronosyltransferases (UGTs), which facilitate cellular detoxification and removal of aromatic amines. Bioactivated forms of aromatic amines found in tobacco smoke and industrial chemicals are the main risk factors for bladder cancer. The association within the UGT1A locus was detected by a single nucleotide polymorphism (SNP) rs11892031. Now, we performed detailed resequencing, imputation and genotyping in this region. We clarified the original genetic association detected by rs11892031 and identified an uncommon SNP rs17863783 that explained and strengthened the association in this region (allele frequency 0.014 in 4035 cases and 0.025 in 5284 controls, OR 0.55, 95CI 0.440.69, P 3.3 10(7)). Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest that rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease, such as bladder cancer.

Published
2012

23. A genome-wide association study of bladder cancer identifies a new susceptibility locus within SLC14A1, a urea transporter gene on chromosome 18q12.3

Author

Garcia-Closas, Montserrat Ye, Yuanqing Rothman, Nathaniel and Figueroa, Jonine D. Malats, Nuria Dinney, Colin P. and Chatterjee, Nilanjan Prokunina-Olsson, Ludmila Wang, Zhaoming and Lin, Jie Real, Francisco X. Jacobs, Kevin B. Baris, Dalsu Thun, Michael De Vivo, Immaculata Albanes, Demetrius and Purdue, Mark P. Kogevinas, Manolis Kamat, Ashish M. and Lerner, Seth P. Grossman, H. Barton Gu, Jian Pu, Xia and Hutchinson, Amy Fu, Yi-Ping Burdett, Laurie Yeager, Meredith and Tang, Wei Tardon, Adonina Serra, Consol Carrato, Alfredo and Garcia-Closas, Reina Lloreta, Josep Johnson, Alison and Schwenn, Molly Karagas, Margaret R. Schned, Alan Andriole, Jr., Gerald Grubb, III, Robert Black, Amanda Jacobs, Eric J. and Diver, W. Ryan Gapstur, Susan M. Weinstein, Stephanie J. and Virtamo, Jarmo Hunter, David J. Caporaso, Neil Landi, Maria Teresa Fraumeni, Jr., Joseph F. Silverman, Debra T. Chanock, Stephen J. Wu, Xifeng

Abstract

Genome-wide and candidate-gene association studies of bladder cancer have identified 10 susceptibility loci thus far. We conducted a meta-analysis of two previously published genome-wide scans (4501 cases and 6076 controls of European background) and followed up the most significant association signals [17 single nucleotide polymorphisms (SNPs) in 10 genomic regions] in 1382 cases and 2201 controls from four studies. A combined analysis adjusted for study center, age, sex, and smoking status identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 x 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2) = 1.00; P = 8.9 x 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22). The signal localizes to the solute carrier family 14 member 1 gene, SLC14A1, a urea transporter that regulates cellular osmotic pressure. In the kidney, SLC14A1 regulates urine volume and concentration whereas in erythrocytes it determines the Kidd blood groups. Our findings suggest that genetic variation in SLC14A1 could provide new etiological insights into bladder carcinogenesis.

Published
2011

24. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

Author

Rothman, Nathaniel Garcia-Closas, Montserrat Chatterjee, Nilanjan Malats, Nuria Wu, Xifeng Figueroa, Jonine D. and Real, Francisco X. Van den Berg, David Matullo, Giuseppe and Baris, Dalsu Thun, Michael Kiemeney, Lambertus A. Vineis, Paolo De Vivo, Immaculata Albanes, Demetrius Purdue, Mark P. and Rafnar, Thorunn Hildebrandt, Michelle A. T. Kiltie, Anne E. and Cussenot, Olivier Golka, Klaus Kumar, Rajiv Taylor, Jack A. Mayordomo, Jose I. Jacobs, Kevin B. Kogevinas, Manolis and Hutchinson, Amy Wang, Zhaoming Fu, Yi-Ping and Prokunina-Olsson, Ludmila Burdett, Laurie Yeager, Meredith and Wheeler, William Tardon, Adonina Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Lloreta, Josep Johnson, Alison and Schwenn, Molly Karagas, Margaret R. Schned, Alan and Andriole, Jr., Gerald Grubb, III, Robert Black, Amanda and Jacobs, Eric J. Diver, W. Ryan Gapstur, Susan M. Weinstein, Stephanie J. Virtamo, Jarmo Cortessis, Victoria K. and Gago-Dominguez, Manuela Pike, Malcolm C. Stern, Mariana C. and Yuan, Jian-Min Hunter, David J. McGrath, Monica Dinney, Colin P. Czerniak, Bogdan Chen, Meng Yang, Hushan and Vermeulen, Sita H. Aben, Katja K. Witjes, J. Alfred and Makkinje, Remco R. Sulem, Patrick Besenbacher, Soren and Stefansson, Kari Riboli, Elio Brennan, Paul Panico, Salvatore Navarro, Carmen Allen, Naomi E. Bueno-de-Mesquita, H. Bas Trichopoulos, Dimitrios Caporaso, Neil Landi, Maria Teresa Canzian, Federico Ljungberg, Borje Tjonneland, Anne and Clavel-Chapelon, Francoise Bishop, David T. Teo, Mark T. W. and Knowles, Margaret A. Guarrera, Simonetta Polidoro, Silvia and Ricceri, Fulvio Sacerdote, Carlotta Allione, Alessandra and Cancel-Tassin, Geraldine Selinski, Silvia Hengstler, Jan G. and Dietrich, Holger Fletcher, Tony Rudnai, Peter Gurzau, Eugen and Koppova, Kvetoslava Bolick, Sophia C. E. Godfrey, Ashley and Xu, Zongli Sanz-Velez, Jose I. Garcia-Prats, Maria D. and Sanchez, Manuel Valdivia, Gabriel Porru, Stefano Benhamou, Simone Hoover, Robert N. Fraumeni, Jr., Joseph F. Silverman, Debra T. Chanock, Stephen J.

Abstract

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 x 10(-12)) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 x 10(-11)) on 19q12 maps to CCNE1 and rs11892031 (P = 1 x 10(-7)) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 x 10(-11)) and a tag SNP for NAT2 acetylation status (P = 4 x 10(-11)), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.

Published
2010

25. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

Author

Glimelius, Bengt, Machado, Moara, Allmer, Cristine, Benavente, Yolanda, Turner, Jenny, Spinelli, John J., Kricker, Anne, Wu, Xifeng, Maynadie, Marc, Liebow, Mark, Chanock, Stephen J., Kaaks, Rudolph, McKay, James, Cozen, Wendy, Weiner, George J., Vajdic, Claire M., Chang, Ellen T., Chaffee, Kari G., Camp, Nicola J., Chirlaque, Maria-Dolores, Severson, Richard K., Weinstein, Stephanie, Shanafelt, Tait D., Ferri, Giovanni M., Gu, Jian, Ennas, Maria Grazia, Diver, W. Ryan, Zhi, Degui, Snowden, John A., Park, Ju-Hyun, Hjalgrim, Henrik, Foretova, Lenka, Becker, Nikolaus, Kelly, Rachel S., Connors, Joseph M., Morton, Lindsay M., Wang, Sophia S., Link, Brian K., Brennan, Paul, Vachon, Celine M., Clavel, Jacqueline, Ma, Baoshan, Virtamo, Jarmo, De Roos, Anneclaire J., Glenn, Martha, Vineis, Paolo, Cunningham, Julie M., Strom, Sara S., Achenbach, Sara J., Tinker, Lesley F., Holford, Theodore R., Rothman, Nathaniel, Offit, Kenneth, Lawrence, Charles, Cannon-Albright, Lisa A., Curtin, Karen, Miligi, Lucia, Burdett, Laurie, Skibola, Christine F., Kraft, Peter, Boffetta, Paolo, Arnett, Donna K., Wright, Josh, Kay, Neil E., Bracci, Paige M., Riboli, Elio, Monnereau, Alain, Southey, Melissa C., Teras, Lauren R., Ye, Yuanqing, Casabonne, Delphine, Chatterjee, Nilanjan, Goldin, Lynn R., Smedby, Karin E., Nieters, Alexandra, Vijai, Joseph, Purdue, Mark P., Gascoyne, Randy D., Weiderpass, Elisabete, Caporaso, Neil E., Zeleniuch-Jacquotte, Anne, Slager, Susan L., Zheng, Tongzhang, De Sanjose, Silvia, Call, Timothy G., Hartge, Patricia, Montalvan, Rebecca, Hutchinson, Amy, Travis, Ruth C., Leis, Jose F., Melbye, Mads, Novak, Anne J., Masala, Giovanna, Yeager, Meredith, Fraumeni, Joseph F., Leach, Justin M., Huang, Jinyan, Cocco, Pierluigi, Sala, Nuria, Giles, Graham G., Brooks-Wilson, Angela R., Cerhan, James R., Wang, Zhaoming, Milne, Roger L., Giovannucci, Edward, Maria, Ann, Albanes, Demetrius, Birmann, Brenda M., Bertrand, Kimberly A., Weinberg, J. Brice, Berndt, Sonja I., North, Kari E., Cox, Angela, Villano, Danylo J., Crouch, Simon, Jackson, Rebecca D., Adami, Hans-Olov, Holly, Elizabeth A., Zhang, Yawei, Staines, Anthony, Vermeulen, Roel C.H., Liang, Liming, Lan, Qing, Norman, Aaron D., Riby, Jacques, and Conde, Lucia

Subjects
3. Good health
Abstract

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P

26. Detectable clonal mosaicism and its relationship to aging and cancer

Author

Jacobs, Kevin B., Yeager, Meredith, Zhou, Weiyin, Wacholder, Sholom, Wang, Zhaoming, Rodriguez-Santiago, Benjamin, Hutchinson, Amy, Deng, Xiang, Liu, Chenwei, Horner, Marie-Josephe, Cullen, Michael, Liao, Linda, Schwartz, Ann G., McNeill, Lorna H., Schwenn, Molly, Figueroa, Jonine D., Henderson, Brian E., Shu, Xiao-Ou, Zeleniuch-Jacquotte, Anne, Wiencke, John K., Gonzalez, Juan R., Gallinger, Steven, Fan, Jin-Hu, Thomas, Gilles, Wrensch, Margaret, Savage, Sharon A., Silverman, Debra T., Amos, Christopher I., Tang, Ze-Zhong, Sierrasesúmaga, Luis, Consonni, Dario, Albanes, Demetrius, Trichopoulos, Dimitrios, Olson, Sara H., Chow, Wong-Ho, Krogh, Vittorio, Beane Freeman, Laura, Kratz, Christian P., Holly, Elizabeth A., Blot, William J., Hallmans, Göran, Peters, Ulrike, Duell, Eric J., Brinton, Louise A., Yu, Herbert, Hoover, Robert N., Caporaso, Neil E ., Bertazzi, Pier Alberto, Chanock, Stephen J., Erickson, Ralph L., Elena, Joanne W., Visvanathan, Kala, Tobias, Geoffrey S., Rothman, Nathaniel, Gross, Myron D., Hassan, Manal, Chang, Kenneth, Cotterchio, Michelle, Johnson, Alison, Moore, Lee E., Rajaraman, Preetha, Purdue, Mark, Klein, Alison P., Wheeler, William, Wentzensen, Nicolas, Tjønneland, Anne, Arslan, Alan A., Petersen, Gloria, Chatterjee, Nilanjan, Canzian, Federico, Goggins, Michael, Landi, Maria Teresa, Kurtz, Robert C., Graubard, Barry I., Kovaks, Joseph, Marenne, Gaelle, Dean, Michael C., Giovannucci, Edward L., Wunder, Jay S., Andrulis, Irene L., Butler, Mary A., Jenab, Mazda, Bueno de Mesquita, H. Bas, Marchand, Loic Le, Carreon, Tania, Goldin, Lynn, Virtamo, Jarmo, Ruder, Avima M., Peplonska, Beata, Burdett, Laurie, Sampson, Joshua, Gorlick, Richard G., Fuchs, Charles S., Chung, Charles C., Barkauskas, Donald A., Taylor, Philip R., Haiman, Christopher A., Hunter, David J., Gapstur, Susan M., Giles, Graham G., White, Emily, Mendelsohn, Julie B., Zheng, Wei, Lissowska, Jolanta, Amundadottir, Laufey, Andersson, Ulrika, Davis, Faith G., Freedman, Neal D., Boutron-Ruault, Marie-Christine, LaCroix, Andrea, Rabe, Kari G., Hankinson, Susan E., Bracci, Paige M., McKean-Cowdin, Roberta, Weinstein, Stephanie J., Mandelson, Margaret T., Gao, Yu-Tang, Kolonel, Laurence N., Harris, Curtis C., Teras, Lauren T., Fraumeni Jr., Joseph F., Greene, Mark H., Sesso, Howard D., Mirabello, Lisa, Schwartz, Kendra L., Risch, Harvey A., Abnet, Christian C., Prokunina-Olsson, Ludmila, Garcia Closas, Montserrat, Michaud, Dominique S., Stevens, Victoria L., Signorello, Lisa B., Tucker, Margaret, Ding, Ti, Aldrich, Melinda C., Stram, Daniel, Kraft, Peter, Pérez Jurado, Luis A., Berg, Christine D., Hoffman Bolton, Judith A., Koh, Woon-Puay, Buring, Julie E., Ziegler, Regina G., Bock, Cathryn H., McWilliams, Robert R., Feychting, Maria, Goldstein, Alisa M., Hartge, Patricia, Johansen, Christoffer, Hu, Nan, Patiño García, Ana, Rotunno, Melissa, Gillanders, Elizabeth M., Rybicki, Benjamin A., Spitz, Margaret R., Riboli, Elio, Gaziano, J. Michael, Epstein, Caroline G., Khaw, Kay-Tee, Inskip, Peter D., Melin, Beatrice S., Severi, Gianluca, McGlynn, Katherine A., Wolpin, Brian M., Henriksson, Roger, Stolzenberg-Solomon, Rachael Z., Qiao, You-Lin, Gaudet, Mia M., Wu, Xifeng, Berndt, Sonja I., Yu, Kai, Hsing, Ann W., Landgren, Annelie, Wolk, Alicja, Xiang, Yong-Bing, Ahlbom, Anders, Cook, Michael B., Black, Amanda, Baris, Dalsu, Yuan, Jian-Min, Li, Donghui, Malats, Núria, Jiao, Li, Kogevinas, Manolis, Kooperberg, Charles, Villa, Olaya, Real, Francisco X., Zanetti, Krista A., and Schumacher, Fredrick

Subjects
Aging, Envelliment, Càncer, Cancer
Abstract

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of > 2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

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