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51. Risk and Prognosis of Hepatocellular Carcinoma in Mexican Americans with Type 2 Diabetes Mellitus.

Author

Hatia, Rikita I, Hwang, Lu-Yu, Li, Ruosha, Troisi, Catherine, Jalal, Prasun K, Amos, Christopher I, Gomez, Henry F, Chun, Yun Shin, Rashid, Asif, Kaseb, Ahmed O, Scheet, Paul A, and Hassan, Manal M

Subjects
TYPE 2 diabetes, MEXICAN Americans, LOGISTIC regression analysis, CANCER prognosis, VIRAL hepatitis
Abstract

Introduction: Hepatocellular carcinoma (HCC) disproportionately affects Hispanic persons with higher age-specific incidence and increased mortality rates compared to non-Hispanic Whites. These high rates of incidence and mortality may be explained by the variation in risk factors. Given the high prevalence of type 2 diabetes mellitus (DM) among the Hispanic population, we aimed to assess the risk and prognosis of HCC in Mexican Americans with type 2 DM with consideration of treatment for DM. Methods: A case-control study of 241 Mexican American HCC patients and 500 healthy controls in Texas was conducted. Multivariable logistic regression analysis was performed to determine the association between type 2 DM and HCC risk while adjusting for other risk factors. Also, a restricted analysis of patients with type 2 DM was conducted to determine the effects of age at onset and duration of DM on HCC risk. Interactions among DM, heavy alcohol consumption, and viral hepatitis infection were examined. Overall survival was examined, and multivariable Cox proportional hazards regression analysis was performed for HCC patients with type 2 DM. Results: The adjusted odds ratio (AOR) for DM was 2.74 (P < 0.01). Compared with patients who had DM for 2– 10 years, those who had it for at least 20 years had an AOR of 4.60 (P = 0.04). Metformin use was associated with a reduced risk of death in HCC cases with type 2 DM, with a hazard ratio of 0.72 (P = 0.01) as compared with non-users. Conclusion: Our results demonstrate that type 2 DM was independently associated with increased risk of HCC among Mexican Americans. Metformin use was associated with improved survival among HCC patients with type 2 DM. Type 2 DM significantly increased the risk of HCC alone and in conjunction with other parameters of metabolic syndrome in the Mexican American population after adjusting for other risk factors. [ABSTRACT FROM AUTHOR]

Published
2025
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56. Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Author

Schmit, Stephanie L, Edlund, Christopher K, Schumacher, Fredrick R, Gong, Jian, Harrison, Tabitha A, Huyghe, Jeroen R, Qu, Chenxu, Melas, Marilena, Van Den Berg, David J, Wang, Hansong, Tring, Stephanie, Plummer, Sarah J, Albanes, Demetrius, Alonso, M Henar, Amos, Christopher I, Anton, Kristen, Aragaki, Aaron K, Arndt, Volker, Barry, Elizabeth L, Berndt, Sonja I, Bezieau, Stéphane, Bien, Stephanie, Bloomer, Amanda, Boehm, Juergen, Boutron-Ruault, Marie-Christine, Brenner, Hermann, Brezina, Stefanie, Buchanan, Daniel D, Butterbach, Katja, Caan, Bette J, Campbell, Peter T, Carlson, Christopher S, Castelao, Jose E, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Cheng, Iona, Cheng, Ya-Wen, Chin, Lee Soo, Church, James M, Church, Timothy, Coetzee, Gerhard A, Cotterchio, Michelle, Correa, Marcia Cruz, Curtis, Keith R, Duggan, David, Easton, Douglas F, English, Dallas, Feskens, Edith JM, Fischer, Rocky, FitzGerald, Liesel M, Fortini, Barbara K, Fritsche, Lars G, Fuchs, Charles S, Gago-Dominguez, Manuela, Gala, Manish, Gallinger, Steven J, Gauderman, W James, Giles, Graham G, Giovannucci, Edward L, Gogarten, Stephanie M, Gonzalez-Villalpando, Clicerio, Gonzalez-Villalpando, Elena M, Grady, William M, Greenson, Joel K, Gsur, Andrea, Gunter, Marc, Haiman, Christopher A, Hampe, Jochen, Harlid, Sophia, Harju, John F, Hayes, Richard B, Hofer, Philipp, Hoffmeister, Michael, Hopper, John L, Huang, Shu-Chen, Huerta, Jose Maria, Hudson, Thomas J, Hunter, David J, Idos, Gregory E, Iwasaki, Motoki, Jackson, Rebecca D, Jacobs, Eric J, Jee, Sun Ha, Jenkins, Mark A, Jia, Wei-Hua, Jiao, Shuo, Joshi, Amit D, Kolonel, Laurence N, Kono, Suminori, Kooperberg, Charles, Krogh, Vittorio, Kuehn, Tilman, Küry, Sébastien, LaCroix, Andrea, Laurie, Cecelia A, Lejbkowicz, Flavio, Lemire, Mathieu, Lenz, Heinz-Josef, and Levine, David

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Human Genome, Prevention, Colo-Rectal Cancer, Clinical Research, Genetics, Cancer, 2.1 Biological and endogenous factors, Case-Control Studies, Colorectal Neoplasms, Ethnicity, Follow-Up Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Prognosis, United States, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundPrevious genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.MethodsWe conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.ResultsThe discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.ConclusionsThis study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Published
2019

57. Age‐specific genome‐wide association study in glioblastoma identifies increased proportion of ‘lower grade glioma’‐like features associated with younger age

Author

Ostrom, Quinn T, Kinnersley, Ben, Armstrong, Georgina, Rice, Terri, Chen, Yanwen, Wiencke, John K, McCoy, Lucie S, Hansen, Helen M, Amos, Christopher I, Bernstein, Jonine L, Claus, Elizabeth B, Eckel‐Passow, Jeanette E, Il'yasova, Dora, Johansen, Christoffer, Lachance, Daniel H, Lai, Rose K, Merrell, Ryan T, Olson, Sara H, Sadetzki, Siegal, Schildkraut, Joellen M, Shete, Sanjay, Rubin, Joshua B, Andersson, Ulrika, Rajaraman, Preetha, Chanock, Stephen J, Linet, Martha S, Wang, Zhaoming, Yeager, Meredith, consortium, on behalf of the GliomaScan, Houlston, Richard S, Jenkins, Robert B, Wrensch, Margaret R, Melin, Beatrice, Bondy, Melissa L, and Barnholtz‐Sloan, Jill S

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Neurosciences, Human Genome, Cancer, Cancer Genomics, Brain Cancer, Brain Disorders, Genetics, 2.1 Biological and endogenous factors, Adolescent, Adult, Age Factors, Aged, Brain Neoplasms, Case-Control Studies, Female, Genome-Wide Association Study, Glioblastoma, Humans, Male, Middle Aged, Neoplasm Grading, Polymorphism, Single Nucleotide, Young Adult, glioma, brain tumors, age, GliomaScan consortium, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54-63 = 1.50x10-9 , OR54-63 = 1.28, 95%CI54-63 = 1.18-1.39; p64+ = 2.14x10-11 , OR64+ = 1.32, 95%CI64+ = 1.21-1.43] and rs11979158 [p54-63 = 6.13x10-8 , OR54-63 = 1.35, 95%CI54-63 = 1.21-1.50; p64+ = 2.18x10-10 , OR64+ = 1.42, 95%CI64+ = 1.27-1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p18-53 = 9.30 × 10-11 , OR18-53 = 1.76, 95%CI18-53 = 1.49-2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'-like tumor characteristics in GBM samples in those 18-53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54-63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.'

Published
2018

58. Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21.

Author

Ostrom, Quinn T, Kinnersley, Ben, Wrensch, Margaret R, Eckel-Passow, Jeanette E, Armstrong, Georgina, Rice, Terri, Chen, Yanwen, Wiencke, John K, McCoy, Lucie S, Hansen, Helen M, Amos, Christopher I, Bernstein, Jonine L, Claus, Elizabeth B, Il'yasova, Dora, Johansen, Christoffer, Lachance, Daniel H, Lai, Rose K, Merrell, Ryan T, Olson, Sara H, Sadetzki, Siegal, Schildkraut, Joellen M, Shete, Sanjay, Rubin, Joshua B, Lathia, Justin D, Berens, Michael E, Andersson, Ulrika, Rajaraman, Preetha, Chanock, Stephen J, Linet, Martha S, Wang, Zhaoming, Yeager, Meredith, GliomaScan consortium, Houlston, Richard S, Jenkins, Robert B, Melin, Beatrice, Bondy, Melissa L, and Barnholtz-Sloan, Jill S

Subjects
GliomaScan consortium, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 7, Chromosomes, Human, Pair 8, Humans, Glioma, Brain Neoplasms, Genetic Predisposition to Disease, Logistic Models, Odds Ratio, Risk Factors, Case-Control Studies, Sex Factors, Genotype, Polymorphism, Single Nucleotide, Alleles, Adult, Middle Aged, Female, Male, Genome-Wide Association Study, Neurosciences, Human Genome, Genetics, Prevention, Rare Diseases, Brain Cancer, Cancer, Brain Disorders
Abstract

Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

Published
2018

62. Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications

Author

Murdock, David R., Venner, Eric, Muzny, Donna M., Metcalf, Ginger A., Murugan, Mullai, Hadley, Trevor D., Chander, Varuna, de Vries, Paul S., Jia, Xiaoming, Hussain, Aliza, Agha, Ali M., Sabo, Aniko, Li, Shoudong, Meng, Qingchang, Hu, Jianhong, Tian, Xia, Cohen, Michelle, Yi, Victoria, Kovar, Christie L., Gingras, Marie-Claude, Korchina, Viktoriya, Howard, Chad, Riconda, Daniel L., Pereira, Stacey, Smith, Hadley S., Huda, Zohra A., Buentello, Alexandria, Marino, Patricia R., Leiber, Lee, Balasubramanyam, Ashok, Amos, Christopher I., Civitello, Andrew B., Chelu, Mihail G., Maag, Ronald, McGuire, Amy L., Boerwinkle, Eric, Wehrens, Xander H.T., Ballantyne, Christie M., and Gibbs, Richard A.

Published
2021
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64. Deciphering associations between three RNA splicing-related genetic variants and lung cancer risk

Author

Yang, Wenjun, Liu, Hongliang, Zhang, Ruoxin, Freedman, Jennifer A., Han, Younghun, Hung, Rayjean J., Brhane, Yonathan, McLaughlin, John, Brennan, Paul, Bickeboeller, Heike, Rosenberger, Albert, Houlston, Richard S., Caporaso, Neil E., Landi, Maria Teresa, Brueske, Irene, Risch, Angela, Christiani, David C., Amos, Christopher I., Chen, Xiaoxin, Patierno, Steven R., and Wei, Qingyi

Published
2022
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66. Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis

Author

Bouras, Emmanouil, Karhunen, Ville, Gill, Dipender, Huang, Jian, Haycock, Philip C., Gunter, Marc J., Johansson, Mattias, Brennan, Paul, Key, Tim, Lewis, Sarah J., Martin, Richard M., Murphy, Neil, Platz, Elizabeth A., Travis, Ruth, Yarmolinsky, James, Zuber, Verena, Martin, Paul, Katsoulis, Michail, Freisling, Heinz, Nøst, Therese Haugdahl, Schulze, Matthias B., Dossus, Laure, Hung, Rayjean J., Amos, Christopher I., Ahola-Olli, Ari, Palaniswamy, Saranya, Männikkö, Minna, Auvinen, Juha, Herzig, Karl-Heinz, Keinänen-Kiukaanniemi, Sirkka, Lehtimäki, Terho, Salomaa, Veikko, Raitakari, Olli, Salmi, Marko, Jalkanen, Sirpa, Jarvelin, Marjo-Riitta, Dehghan, Abbas, and Tsilidis, Konstantinos K.

Published
2022
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67. Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

Author

Rosenberger, Albert, Muttray, Nils, Hung, Rayjean J., Christiani, David C., Caporaso, Neil E., Liu, Geoffrey, Bojesen, Stig E., Le Marchand, Loic, Albanes, Demetrios, Aldrich, Melinda C., Tardon, Adonina, Fernández-Tardón, Guillermo, Rennert, Gad, Field, John K., Davies, Michael P. A., Liloglou, Triantafillos, Kiemeney, Lambertus A., Lazarus, Philip, Wendel, Bernadette, Haugen, Aage, Zienolddiny, Shanbeh, Lam, Stephen, Schabath, Matthew B., Andrew, Angeline S., Duell, Eric J., Arnold, Susanne M., Goodman, Gary E., Chen, Chu, Doherty, Jennifer A., Taylor, Fiona, Cox, Angela, Woll, Penella J., Risch, Angela, Muley, Thomas R., Johansson, Mikael, Brennan, Paul, Landi, Maria Teresa, Shete, Sanjay S., Amos, Christopher I., and Bickeböller, Heike

Published
2022
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70. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author

Siminovitch, Katherine A., Hirschfield, Gideon M., Mason, Andrew, Vincent, Catherine, Xie, Gang, Zhang, Jinyi, Tang, Ruqi, Ma, Xiong, Li, Zhiqiang, Shi, Yongyong, Affronti, Andrea, Almasio, Piero L., Alvaro, Domenico, Andreone, Pietro, Andriulli, Angelo, Azzaroli, Francesco, Battezzati, Pier Maria, Benedetti, Antonio, Bragazzi, MariaConsiglia, Brunetto, Maurizia, Bruno, Savino, Calvaruso, Vincenza, Cardinale, Vincenzo, Casella, Giovanni, Cazzagon, Nora, Ciaccio, Antonio, Coco, Barbara, Colli, Agostino, Colloredo, Guido, Colombo, Massimo, Colombo, Silvia, Cristoferi, Laura, Cursaro, Carmela, Crocè, Lory Saveria, Crosignani, Andrea, D’Amato, Daphne, Donato, Francesca, Elia, Gianfranco, Fabris, Luca, Fagiuoli, Stefano, Ferrari, Carlo, Floreani, Annarosa, Galli, Andrea, Giannini, Edoardo, Grattagliano, Ignazio, Lampertico, Pietro, Lleo, Ana, Malinverno, Federica, Mancuso, Clara, Marra, Fabio, Marzioni, Marco, Massironi, Sara, Mattalia, Alberto, Miele, Luca, Milani, Chiara, Morini, Lorenzo, Morisco, Filomena, Muratori, Luigi, Muratori, Paolo, Niro, Grazia A., O’Donnell, Sarah, Picciotto, Antonio, Portincasa, Piero, Rigamonti, Cristina, Ronca, Vincenzo, Rosina, Floriano, Spinzi, Giancarlo, Strazzabosco, Mario, Tarocchi, Mirko, Tiribelli, Claudio, Toniutto, Pierluigi, Valenti, Luca, Vinci, Maria, Zuin, Massimo, Nakamura, Hitomi, Abiru, Seigo, Nagaoka, Shinya, Komori, Atsumasa, Yatsuhashi, Hiroshi, Ishibashi, Hiromi, Ito, Masahiro, Migita, Kiyoshi, Ohira, Hiromasa, Katsushima, Shinji, Naganuma, Atsushi, Sugi, Kazuhiro, Komatsu, Tatsuji, Mannami, Tomohiko, Matsushita, Kouki, Yoshizawa, Kaname, Makita, Fujio, Nikami, Toshiki, Nishimura, Hideo, Kouno, Hiroshi, Kouno, Hirotaka, Ota, Hajime, Komura, Takuya, Nakamura, Yoko, Shimada, Masaaki, Hirashima, Noboru, Komeda, Toshiki, Ario, Keisuke, Nakamuta, Makoto, Yamashita, Tsutomu, Furuta, Kiyoshi, Kikuchi, Masahiro, Naeshiro, Noriaki, Takahashi, Hironao, Mano, Yutaka, Tsunematsu, Seiji, Yabuuchi, Iwao, Shimada, Yusuke, Yamauchi, Kazuhiko, Sugimoto, Rie, Sakai, Hironori, Mita, Eiji, Koda, Masaharu, Tsuruta, Satoru, Kamitsukasa, Hiroshi, Sato, Takeaki, Masaki, Naohiko, Kobata, Tatsuro, Fukushima, Nobuyoshi, Ohara, Yukio, Muro, Toyokichi, Takesaki, Eiichi, Takaki, Hitoshi, Yamamoto, Tetsuo, Kato, Michio, Nagaoki, Yuko, Hayashi, Shigeki, Ishida, Jinya, Watanabe, Yukio, Kobayashi, Masakazu, Koga, Michiaki, Saoshiro, Takeo, Yagura, Michiyasu, Hirata, Keisuke, Tanaka, Atsushu, Takikawa, Hajime, Zeniya, Mikio, Abe, Masanori, Onji, Morikazu, Kaneko, Shuichi, Honda, Masao, Arai, Kuniaki, Arinaga-Hino, Teruko, Hashimoto, Etsuko, Taniai, Makiko, Umemura, Takeji, Joshita, Satoru, Nakao, Kazuhiko, Ichikawa, Tatsuki, Shibata, Hidetaka, Yamagiwa, Satoshi, Seike, Masataka, Honda, Koichi, Sakisaka, Shotaro, Takeyama, Yasuaki, Harada, Masaru, Senju, Michio, Yokosuka, Osamu, Kanda, Tatsuo, Ueno, Yoshiyuki, Kikuchi, Kentaro, Ebinuma, Hirotoshi, Himoto, Takashi, Yasunami, Michio, Murata, Kazumoto, Mizokami, Masashi, Kawata, Kazuhito, Shimoda, Shinji, Miyake, Yasuhiro, Takaki, Akinobu, Yamamoto, Kazuhide, Hirano, Katsuji, Ichida, Takafumi, Ido, Akio, Tsubouchi, Hirohito, Chayama, Kazuaki, Harada, Kenichi, Nakanuma, Yasuni, Maehara, Yoshihiko, Taketomi, Akinobu, Shirabe, Ken, Soejima, Yuji, Mori, Akira, Yagi, Shintaro, Uemoto, Shinji, H, Egawa, Tanaka, Tomohiro, Yamashiki, Noriyo, Tamura, Sumito, Sugawara, Yasuhiro, Kokudo, Norihiro, Juran, Brian D., Atkinson, Elizabeth J., Cheung, Angela, de Andrade, Mariza, Lazaridis, Konstantinos N., Chalasani, Naga, Luketic, Vel, Odin, Joseph, Chopra, Kapil, Baras, Aris, Horowitz, Julie, Abecasis, Goncalo, Cantor, Michael, Coppola, Giovanni, Economides, Aris, Lotta, Luca A., Overton, John D., Reid, Jeffrey G., Shuldiner, Alan, Beechert, Christina, Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Lattari, Michael, Lopez, Alexander, Schleicher, Thomas D., Padilla, Maria Sotiropoulos, Toledo, Karina, Widom, Louis, Wolf, Sarah E., Pradhan, Manasi, Manoochehri, Kia, Ulloa, Ricardo H., Bai, Xiaodong, Balasubramanian, Suganthi, Barnard, Leland, Blumenfeld, Andrew, Eom, Gisu, Habegger, Lukas, Hawes, Alicia, Khalid, Shareef, Maxwell, Evan K., Salerno, William, Staples, Jeffrey C., Jones, Marcus B., Mitnaul, Lyndon J., Sturgess, Richard, Healey, Christopher, Yeoman, Andrew, Gunasekera, Anton VJ., Kooner, Paul, Kapur, Kapil, Sathyanarayana, V., Kallis, Yiannis, Subhani, Javaid, Harvey, Rory, McCorry, Roger, Rooney, Paul, Ramanaden, David, Evans, Richard, Mathialahan, Thiriloganathan, Gasem, Jaber, Shorrock, Christopher, Bhalme, Mahesh, Southern, Paul, Tibble, Jeremy A., Gorard, David A., Jones, Susan, Mells, George, Mulcahy, Victoria, Srivastava, Brijesh, Foxton, Matthew R., Collins, Carole E., Elphick, David, Karmo, Mazn, Porras-Perez, Francisco, Mendall, Michael, Yapp, Tom, Patel, Minesh, Ede, Roland, Sayer, Joanne, Jupp, James, Fisher, Neil, Carter, Martyn J., Koss, Konrad, Shah, Jayshri, Piotrowicz, Andrzej, Scott, Glyn, Grimley, Charles, Gooding, Ian R., Williams, Simon, Tidbury, Judith, Lim, Guan, Cheent, Kuldeep, Levi, Sass, Mansour, Dina, Beckley, Matilda, Hollywood, Coral, Wong, Terry, Marley, Richard, Ramage, John, Gordon, Harriet M., Ridpath, Jo, Ngatchu, Theodore, Bob Grover, Vijay Paul, Shidrawi, Ray G., Abouda, George, Corless, L., Narain, Mark, Rees, Ian, Brown, Ashley, Taylor-Robinson, Simon, Wilkins, Joy, Grellier, Leonie, Banim, Paul, Das, Debasish, Heneghan, Michael A., Curtis, Howard, Matthews, Helen C., Mohammed, Faiyaz, Aldersley, Mark, Srirajaskanthan, Raj, Walker, Giles, McNair, Alistair, Sharif, Amar, Sen, Sambit, Bird, George, Prince, Martin I., Prasad, Geeta, Kitchen, Paul, Barnardo, Adrian, Oza, Chirag, Sivaramakrishnan, Nurani N., Gupta, Prakash, Shah, Amir, Evans, Chris DJ., Saha, Subrata, Pollock, Katharine, Bramley, Peter, Mukhopadhya, Ashis, Barclay, Stephen T., McDonald, Natasha, Bathgate, Andrew J., Palmer, Kelvin, Dillon, John F., Rushbrook, Simon M., Przemioslo, Robert, McDonald, Chris, Millar, Andrew, Tai, Cheh, Mitchell, Stephen, Metcalf, Jane, Shaukat, Syed, Ninkovic, Mary, Shmueli, Udi, Davis, Andrew, Naqvi, Asifabbas, Lee, Tom JW., Ryder, Stephen, Collier, Jane, Klass, Howard, Cramp, Matthew E., Sharer, Nichols, Aspinall, Richard, Ghosh, Deb, Douds, Andrew C., Booth, Jonathan, Williams, Earl, Hussaini, Hyder, Christie, John, Mann, Steven, Thorburn, Douglas, Marshall, Aileen, Patanwala, Imran, Ala, Aftab, Maltby, Julia, Matthew, Ray, Corbett, Chris, Vyas, Sam, Singhal, Saket, Gleeson, Dermot, Misra, Sharat, Butterworth, Jeff, George, Keith, Harding, Tim, Douglass, Andrew, Mitchison, Harriet, Panter, Simon, Shearman, Jeremy, Bray, Gary, Roberts, Michael, Butcher, Graham, Forton, Daniel, Mahmood, Zahid, Cowan, Matthew, Das, Debashis, Ch’ng, Chin Lye, Rahman, Mesbah, Whatley, Gregory C.A., Wesley, Emma, Mandal, Aditya, Jain, Sanjiv, Pereira, Stephen P., Wright, Mark, Trivedi, Palak, Gordon, Fiona H., Unitt, Esther, Palejwala, Altaf, Austin, Andrew, Vemala, Vishwaraj, Grant, Allister, Higham, Andrew D., Brind, Alison, Mathew, Ray, Cox, Mark, Ramakrishnan, Subramaniam, King, Alistair, Whalley, Simon, Fraser, Jocelyn, Thomson, S.J., Bell, Andrew, Wong, Voi Shim, Kia, Richard, Gee, Ian, Keld, Richard, Ransford, Rupert, Gotto, James, Millson, Charles, Cordell, Heather J., Fryett, James J., Ueno, Kazuko, Darlay, Rebecca, Aiba, Yoshihiro, Hitomi, Yuki, Kawashima, Minae, Nishida, Nao, Khor, Seik-Soon, Gervais, Olivier, Kawai, Yosuke, Nagasaki, Masao, Tokunaga, Katsushi, Gerussi, Alessio, Carbone, Marco, Asselta, Rosanna, Ferreira, Manuel A.R., Sun, Dylan, Jones, David E., Flack, Steven, Spicer, Ann, Mulcahy, Victoria L., Byan, Jinyoung, Han, Younghun, Sandford, Richard N., Amos, Christopher I., Seldin, Michael F., Invernizzi, Pietro, Nakamura, Minoru, and Mells, George F.

Published
2021
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71. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Author

Chen, Hongjie, Majumdar, Arunabha, Wang, Lu, Kar, Siddhartha, Brown, Kevin M., Feng, Helian, Turman, Constance, Dennis, Joe, Easton, Douglas, Michailidou, Kyriaki, Simard, Jacques, Bishop, Timothy, Cheng, Iona C., Huyghe, Jeroen R., Schmit, Stephanie L., O’Mara, Tracy A., Spurdle, Amanda B., Gharahkhani, Puya, Schumacher, Johannes, Jankowski, Janusz, Gockel, Ines, Bondy, Melissa L., Houlston, Richard S., Jenkins, Robert B., Melin, Beatrice, Lesseur, Corina, Ness, Andy R., Diergaarde, Brenda, Olshan, Andrew F., Amos, Christopher I., Christiani, David C., Landi, Maria T., McKay, James D., Brossard, Myriam, Iles, Mark M., Law, Matthew H., MacGregor, Stuart, Beesley, Jonathan, Jones, Michelle R., Tyrer, Jonathan, Winham, Stacey J., Klein, Alison P., Petersen, Gloria, Li, Donghui, Wolpin, Brian M., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Brennan, Paul, Chanock, Stephen J., Gaborieau, Valerie, Purdue, Mark P., Pharoah, Paul, Hung, Rayjean J., Amundadottir, Laufey T., Kraft, Peter, Pasaniuc, Bogdan, and Lindström, Sara

Published
2021
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73. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Author

Milne, Roger L, Kuchenbaecker, Karoline B, Michailidou, Kyriaki, Beesley, Jonathan, Kar, Siddhartha, Lindström, Sara, Hui, Shirley, Lemaçon, Audrey, Soucy, Penny, Dennis, Joe, Jiang, Xia, Rostamianfar, Asha, Finucane, Hilary, Bolla, Manjeet K, McGuffog, Lesley, Wang, Qin, Aalfs, Cora M, Adams, Marcia, Adlard, Julian, Agata, Simona, Ahmed, Shahana, Ahsan, Habibul, Aittomäki, Kristiina, Al-Ejeh, Fares, Allen, Jamie, Ambrosone, Christine B, Amos, Christopher I, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Auber, Bernd, Auer, Paul L, Ausems, Margreet GEM, Azzollini, Jacopo, Bacot, François, Balmaña, Judith, Barile, Monica, Barjhoux, Laure, Barkardottir, Rosa B, Barrdahl, Myrto, Barnes, Daniel, Barrowdale, Daniel, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Bignon, Yves-Jean, Blazer, Kathleen R, Blok, Marinus J, Blomqvist, Carl, Blot, William, Bobolis, Kristie, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Anders, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Bozsik, Aniko, Bradbury, Angela R, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Bressac-de Paillerets, Brigitte, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Brunet, Joan, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byun, Jinyoung, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canzian, Federico, Caron, Olivier, Carracedo, Angel, Carter, Brian D, Castelao, J Esteban, Castera, Laurent, Caux-Moncoutier, Virginie, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Xiaoqing, Cheng, Ting-Yuan David, Chiquette, Jocelyne, Christiansen, Hans, Claes, Kathleen BM, Clarke, Christine L, Conner, Thomas, Conroy, Don M, and Cook, Jackie

Subjects
Biological Sciences, Genetics, Cancer, Human Genome, Estrogen, Prevention, Clinical Research, Cancer Genomics, Women's Health, Breast Cancer, 2.1 Biological and endogenous factors, BRCA1 Protein, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk Factors, White People, ABCTB Investigators, EMBRACE, GEMO Study Collaborators, HEBON, kConFab/AOCS Investigators, NBSC Collaborators, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Published
2017

74. Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors

Author

Melin, Beatrice S, Barnholtz-Sloan, Jill S, Wrensch, Margaret R, Johansen, Christoffer, Il'yasova, Dora, Kinnersley, Ben, Ostrom, Quinn T, Labreche, Karim, Chen, Yanwen, Armstrong, Georgina, Liu, Yanhong, Eckel-Passow, Jeanette E, Decker, Paul A, Labussière, Marianne, Idbaih, Ahmed, Hoang-Xuan, Khe, Di Stefano, Anna-Luisa, Mokhtari, Karima, Delattre, Jean-Yves, Broderick, Peter, Galan, Pilar, Gousias, Konstantinos, Schramm, Johannes, Schoemaker, Minouk J, Fleming, Sarah J, Herms, Stefan, Heilmann, Stefanie, Nöthen, Markus M, Wichmann, Heinz-Erich, Schreiber, Stefan, Swerdlow, Anthony, Lathrop, Mark, Simon, Matthias, Sanson, Marc, Andersson, Ulrika, Rajaraman, Preetha, Chanock, Stephen, Linet, Martha, Wang, Zhaoming, Yeager, Meredith, Wiencke, John K, Hansen, Helen, McCoy, Lucie, Rice, Terri, Kosel, Matthew L, Sicotte, Hugues, Amos, Christopher I, Bernstein, Jonine L, Davis, Faith, Lachance, Dan, Lau, Ching, Merrell, Ryan T, Shildkraut, Joellen, Ali-Osman, Francis, Sadetzki, Siegal, Scheurer, Michael, Shete, Sanjay, Lai, Rose K, Claus, Elizabeth B, Olson, Sara H, Jenkins, Robert B, Houlston, Richard S, and Bondy, Melissa L

Subjects
Biological Sciences, Genetics, Prevention, Cancer Genomics, Rare Diseases, Human Genome, Neurosciences, Brain Cancer, Brain Disorders, Cancer, 2.1 Biological and endogenous factors, Alleles, Brain Neoplasms, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glioblastoma, Glioma, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, GliomaScan Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Published
2017

75. Tobacco Smoking and Risk of Second Primary Lung Cancer

Author

Aredo, Jacqueline V., Luo, Sophia J., Gardner, Rebecca M., Sanyal, Nilotpal, Choi, Eunji, Hickey, Thomas P., Riley, Thomas L., Huang, Wen-Yi, Kurian, Allison W., Leung, Ann N., Wilkens, Lynne R., Robbins, Hilary A., Riboli, Elio, Kaaks, Rudolf, Tjønneland, Anne, Vermeulen, Roel C.H., Panico, Salvatore, Le Marchand, Loïc, Amos, Christopher I., Hung, Rayjean J., Freedman, Neal D., Johansson, Mattias, Cheng, Iona, Wakelee, Heather A., and Han, Summer S.

Published
2021
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78. Prognostic stratification in DLBCL patients with aberrant MYC gene.

Author

Li, Jian‐Rong, Shaw, Vikram R., Parthasarathy, Abi, Li, Yong, Amos, Christopher I., and Cheng, Chao

Subjects
MYC oncogenes, GENE expression profiling, TREATMENT effectiveness, OVERTREATMENT, BIOMARKERS
Abstract

Summary: Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disease characterized by a subset of patients who exhibit treatment resistance and poor prognoses. Genomic assays have been widely employed to identify high‐risk individuals characterized by rearrangements in the MYC, BCL2 and BCL6 genes. These patients typically undergo more aggressive therapeutic treatments; however, there remains a significant variation in their treatment outcomes. This study introduces an MYC signature score (MYCSS) derived from gene expression profiles, specifically designed to evaluate MYC overactivation in DLBCL patients. MYCSS was validated across several independent cohorts to assess its ability to stratify patients based on MYC‐related genetic and molecular aberrations, enhancing the accuracy of prognostic evaluations compared to conventional MYC biomarkers. Our results indicate that MYCSS significantly refines prognostic accuracy beyond that of conventional MYC biomarkers focused on genetic aberrations. More importantly, we found that nearly 50% of patients identified as high risk by traditional MYC metrics actually share similar survival prospects with those having no MYC aberrations. These patients may benefit from standard GCB‐based therapies rather than more aggressive treatments. MYCSS provides a robust signature that identifies high‐risk patients, aiding in the precision treatment of DLBCL, and minimizing the potential for overtreatment. [ABSTRACT FROM AUTHOR]

Published
2024
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82. Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

Author

Carreras-Torres, Robert, Johansson, Mattias, Haycock, Philip C, Wade, Kaitlin H, Relton, Caroline L, Martin, Richard M, Smith, George Davey, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline, Arnold, Susanne M, Bickeböller, Heike, Bojesen, Stig E, Brunnström, Hans, Manjer, Jonas, Brüske, Irene, Caporaso, Neil E, Chen, Chu, Christiani, David C, Christian, W Jay, Doherty, Jennifer A, Duell, Eric J, Field, John K, Davies, Michael PA, Marcus, Michael W, Goodman, Gary E, Grankvist, Kjell, Haugen, Aage, Hong, Yun-Chul, Kiemeney, Lambertus A, van der Heijden, Erik HFM, Kraft, Peter, Johansson, Mikael B, Lam, Stephen, Landi, Maria Teresa, Lazarus, Philip, Le Marchand, Loïc, Liu, Geoffrey, Melander, Olle, Park, Sungshim L, Rennert, Gad, Risch, Angela, Haura, Eric B, Scelo, Ghislaine, Zaridze, David, Mukeriya, Anush, Savić, Milan, Lissowska, Jolanta, Swiatkowska, Beata, Janout, Vladimir, Holcatova, Ivana, Mates, Dana, Schabath, Matthew B, Shen, Hongbing, Tardon, Adonina, Teare, M Dawn, Woll, Penella, Tsao, Ming-Sound, Wu, Xifeng, Yuan, Jian-Min, Hung, Rayjean J, Amos, Christopher I, McKay, James, and Brennan, Paul

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Genetics, Lung, Nutrition, Tobacco Smoke and Health, Prevention, Cancer, Tobacco, Obesity, Clinical Research, Lung Cancer, Aetiology, 2.1 Biological and endogenous factors, Body Mass Index, Fasting, Humans, Insulin, Insulin Resistance, Likelihood Functions, Lipids, Lung Neoplasms, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, General Science & Technology
Abstract

BackgroundAssessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer.Methods and findingsWe identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results.ConclusionsOur results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

Published
2017

85. Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

Author

Qin, Na, Li, Yuancheng, Wang, Cheng, Zhu, Meng, Dai, Juncheng, Hong, Tongtong, Albanes, Demetrius, Lam, Stephen, Tardon, Adonina, Chen, Chu, Goodman, Gary, Bojesen, Stig E., Landi, Maria Teresa, Johansson, Mattias, Risch, Angela, Wichmann, H-Erich, Bickeboller, Heike, Rennert, Gadi, Arnold, Susanne, Brennan, Paul, Field, John K., Shete, Sanjay, Le Marchand, Loic, Melander, Olle, Brunnstrom, Hans, Liu, Geoffrey, Hung, Rayjean J., Andrew, Angeline, Kiemeney, Lambertus A., Zienolddiny, Shan, Grankvist, Kjell, Johansson, Mikael, Caporaso, Neil, Woll, Penella, Lazarus, Philip, Schabath, Matthew B., Aldrich, Melinda C., Stevens, Victoria L., Jin, Guangfu, Christiani, David C., Hu, Zhibin, Amos, Christopher I., Ma, Hongxia, and Shen, Hongbing

Published
2021
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86. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer

Author

Lesseur, Corina, Diergaarde, Brenda, Olshan, Andrew F, Wünsch-Filho, Victor, Ness, Andrew R, Liu, Geoffrey, Lacko, Martin, Eluf-Neto, José, Franceschi, Silvia, Lagiou, Pagona, Macfarlane, Gary J, Richiardi, Lorenzo, Boccia, Stefania, Polesel, Jerry, Kjaerheim, Kristina, Zaridze, David, Johansson, Mattias, Menezes, Ana M, Curado, Maria Paula, Robinson, Max, Ahrens, Wolfgang, Canova, Cristina, Znaor, Ariana, Castellsagué, Xavier, Conway, David I, Holcátová, Ivana, Mates, Dana, Vilensky, Marta, Healy, Claire M, Szeszenia-Dąbrowska, Neonila, Fabiánová, Eleonóra, Lissowska, Jolanta, Grandis, Jennifer R, Weissler, Mark C, Tajara, Eloiza H, Nunes, Fabio D, de Carvalho, Marcos B, Thomas, Steve, Hung, Rayjean J, Peters, Wilbert HM, Herrero, Rolando, Cadoni, Gabriella, Bueno-de-Mesquita, H Bas, Steffen, Annika, Agudo, Antonio, Shangina, Oxana, Xiao, Xiangjun, Gaborieau, Valérie, Chabrier, Amélie, Anantharaman, Devasena, Boffetta, Paolo, Amos, Christopher I, McKay, James D, and Brennan, Paul

Subjects
Biological Sciences, Genetics, Human Genome, Cancer, Cancer Genomics, Women's Health, Dental/Oral and Craniofacial Disease, Digestive Diseases, 2.1 Biological and endogenous factors, Aged, Case-Control Studies, Female, Genetic Markers, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, HLA Antigens, Haplotypes, Humans, Male, Middle Aged, Mouth, Mouth Neoplasms, Papillomaviridae, Papillomavirus Infections, Pharyngeal Neoplasms, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10-8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10-9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10-6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

Published
2016

87. FastPop: a rapid principal component derived method to infer intercontinental ancestry using genetic data

Author

Li, Yafang, Byun, Jinyoung, Cai, Guoshuai, Xiao, Xiangjun, Han, Younghun, Cornelis, Olivier, Dinulos, James E, Dennis, Joe, Easton, Douglas, Gorlov, Ivan, Seldin, Michael F, and Amos, Christopher I

Subjects
Mathematical Sciences, Biological Sciences, Statistics, Genetics, Algorithms, Bayes Theorem, Ethnicity, Genetics, Population, Genome-Wide Association Study, Genotype, HapMap Project, Humans, Polymorphism, Single Nucleotide, Principal Component Analysis, Racial Groups, Software, Population structure, Principal component, Ancestry, Genome-wide association study, Information and Computing Sciences, Bioinformatics, Biological sciences, Information and computing sciences, Mathematical sciences
Abstract

BackgroundIdentifying subpopulations within a study and inferring intercontinental ancestry of the samples are important steps in genome wide association studies. Two software packages are widely used in analysis of substructure: Structure and Eigenstrat. Structure assigns each individual to a population by using a Bayesian method with multiple tuning parameters. It requires considerable computational time when dealing with thousands of samples and lacks the ability to create scores that could be used as covariates. Eigenstrat uses a principal component analysis method to model all sources of sampling variation. However, it does not readily provide information directly relevant to ancestral origin; the eigenvectors generated by Eigenstrat are sample specific and thus cannot be generalized to other individuals.ResultsWe developed FastPop, an efficient R package that fills the gap between Structure and Eigenstrat. It can: 1, generate PCA scores that identify ancestral origins and can be used for multiple studies; 2, infer ancestry information for data arising from two or more intercontinental origins. We demonstrate the use of FastPop using 2318 SNP markers selected from the genome based on high variability among European, Asian and West African (African) populations. We conducted an analysis of 505 Hapmap samples with European, African or Asian ancestry along with 19661 additional samples of unknown ancestry. The results from FastPop are highly consistent with those obtained by Structure across the 19661 samples we studied. The correlations of the results between FastPop and Structure are 0.99, 0.97 and 0.99 for European, African and Asian ancestry scores, respectively. Compared with Structure, FastPop is more efficient as it finished ancestry inference for 19661 samples in 16 min compared with 21-24 h required by Structure. FastPop also provided scores based on SNP weights so the scores of reference population can be applied to other studies provided the same set of markers are used. We also present application of the method for studying four continental populations (European, Asian, African, and Native American).ConclusionsWe developed an algorithm that can infer ancestries on data involving two or more intercontinental origins. It is efficient for analyzing large datasets. Additionally the PCA derived scores can be applied to multiple data sets to ensure the same ancestry analysis is applied to all studies.

Published
2016

88. Pleiotropic Analysis of Lung Cancer and Blood Triglycerides

Author

Zuber, Verena, Marconett, Crystal N, Shi, Jianxin, Hua, Xing, Wheeler, William, Yang, Chenchen, Song, Lei, Dale, Anders M, Laplana, Marina, Risch, Angela, Witoelar, Aree, Thompson, Wesley K, Schork, Andrew J, Bettella, Francesco, Wang, Yunpeng, Djurovic, Srdjan, Zhou, Beiyun, Borok, Zea, van der Heijden, Henricus FM, de Graaf, Jacqueline, Swinkels, Dorine, Aben, Katja K, McKay, James, Hung, Rayjean J, Bikeböller, Heike, Stevens, Victoria L, Albanes, Demetrius, Caporaso, Neil E, Han, Younghun, Wei, Yongyue, Panadero, Maria Angeles, Mayordomo, Jose I, Christiani, David C, Kiemeney, Lambertus, Andreassen, Ole A, Houlston, Richard, Amos, Christopher I, Chatterjee, Nilanjan, Laird-Offringa, Ite A, Mills, Ian G, and Landi, Maria Teresa

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Human Genome, Prevention, Cancer, Lung Cancer, Genetics, Tobacco, Tobacco Smoke and Health, Lung, 2.1 Biological and endogenous factors, Cardiovascular Diseases, Case-Control Studies, Chromosomes, Human, Pair 6, Genetic Pleiotropy, Genome-Wide Association Study, Humans, Lung Neoplasms, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Risk Factors, Triglycerides, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10(-4)) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21 ,: Pcombined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer.

Published
2016

89. The causal relevance of body mass index in different histological types of lung cancer: A Mendelian randomization study.

Author

Carreras-Torres, Robert, Haycock, Philip C, Relton, Caroline L, Martin, Richard M, Smith, George Davey, Kraft, Peter, Gao, Chi, Tworoger, Shelley, Le Marchand, Loïc, Wilkens, Lynne R, Park, Sungshim L, Haiman, Christopher, Field, John K, Davies, Michael, Marcus, Michael, Liu, Geoffrey, Caporaso, Neil E, Christiani, David C, Wei, Yongyue, Chen, Chu, Doherty, Jennifer A, Severi, Gianluca, Goodman, Gary E, Hung, Rayjean J, Amos, Christopher I, McKay, James, Johansson, Mattias, and Brennan, Paul

Subjects
Humans, Lung Neoplasms, Body Mass Index, Risk Factors, Case-Control Studies, Smoking, Female, Male, Mendelian Randomization Analysis
Abstract

Body mass index (BMI) is inversely associated with lung cancer risk in observational studies, even though it increases the risk of several other cancers, which could indicate confounding by tobacco smoking or reverse causality. We used the two-sample Mendelian randomization (MR) approach to circumvent these limitations of observational epidemiology by constructing a genetic instrument for BMI, based on results from the GIANT consortium, which was evaluated in relation to lung cancer risk using GWAS results on 16,572 lung cancer cases and 21,480 controls. Results were stratified by histological subtype, smoking status and sex. An increase of one standard deviation (SD) in BMI (4.65 Kg/m(2)) raised the risk for lung cancer overall (OR = 1.13; P = 0.10). This was driven by associations with squamous cell (SQ) carcinoma (OR = 1.45; P = 1.2 × 10(-3)) and small cell (SC) carcinoma (OR = 1.81; P = 0.01). An inverse trend was seen for adenocarcinoma (AD) (OR = 0.82; P = 0.06). In stratified analyses, a 1 SD increase in BMI was inversely associated with overall lung cancer in never smokers (OR = 0.50; P = 0.02). These results indicate that higher BMI may increase the risk of certain types of lung cancer, in particular SQ and SC carcinoma.

Published
2016

90. Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population

Author

Zanetti, Krista A, Wang, Zhaoming, Aldrich, Melinda, Amos, Christopher I, Blot, William J, Bowman, Elise D, Burdette, Laurie, Cai, Qiuyin, Caporaso, Neil, Chung, Charles C, Gillanders, Elizabeth M, Haiman, Christopher A, Hansen, Helen M, Henderson, Brian E, Kolonel, Laurence N, Le Marchand, Loic, Li, Shengchao, McNeill, Lorna Haughton, Ryan, Bríd M, Schwartz, Ann G, Sison, Jennette D, Spitz, Margaret R, Tucker, Margaret, Wenzlaff, Angela S, Wiencke, John K, Wilkens, Lynne, Wrensch, Margaret R, Wu, Xifeng, Zheng, Wei, Zhou, Weiyin, Christiani, David, Palmer, Julie R, Penning, Trevor M, Rieber, Alyssa G, Rosenberg, Lynn, Ruiz-Narvaez, Edward A, Su, Li, Vachani, Anil, Wei, Yongyue, Whitehead, Alexander S, Chanock, Stephen J, and Harris, Curtis C

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Women's Health, Human Genome, Prevention, Cancer, Genetics, Clinical Research, Lung Cancer, Lung, 2.1 Biological and endogenous factors, Respiratory, Black or African American, Case-Control Studies, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 5, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lung Neoplasms, Polymorphism, Single Nucleotide, Population Surveillance, Quantitative Trait Loci, Genome-wide association study, Lung neoplasms, Smoking, African Americans, Telomerase, Receptors, Cholinergic, Clinical Sciences, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

ObjectivesGenome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping.Materials and methodsWe genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p

Published
2016

92. Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans

Author

David, Sean P, Wang, Ange, Kapphahn, Kristopher, Hedlin, Haley, Desai, Manisha, Henderson, Michael, Yang, Lingyao, Walsh, Kyle M, Schwartz, Ann G, Wiencke, John K, Spitz, Margaret R, Wenzlaff, Angela S, Wrensch, Margaret R, Eaton, Charles B, Furberg, Helena, Brown, W Mark, Goldstein, Benjamin A, Assimes, Themistocles, Tang, Hua, Kooperberg, Charles L, Quesenberry, Charles P, Tindle, Hilary, Patel, Manali I, Amos, Christopher I, Bergen, Andrew W, Swan, Gary E, and Stefanick, Marcia L

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Clinical Research, Lung, Tobacco Smoke and Health, Genetics, Human Genome, Tobacco, Lung Cancer, Women's Health, Cancer, Cancer Genomics, Prevention, Good Health and Well Being, Black or African American, Case-Control Studies, Chromosomes, Human, Pair 15, Female, Gene-Environment Interaction, Genes, Modifier, Humans, Lung Neoplasms, Male, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Receptors, Nicotinic, Smoking, African-Americans, Environment, rs2036527, Single Nucleotide Polymorphisms, Clinical Sciences, Public Health and Health Services, Clinical sciences
Abstract

BackgroundGenome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene-environment interactions is not well understood.MethodsWe analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case-control study of African-American females and males (1078 lung cancer cases and 822 controls).FindingsNine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10(-5)). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = - 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.InterpretationThese results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.

Published
2016

93. The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium

Author

Amirian, E Susan, Armstrong, Georgina N, Zhou, Renke, Lau, Ching C, Claus, Elizabeth B, Barnholtz-Sloan, Jill S, Il'yasova, Dora, Schildkraut, Joellen, Ali-Osman, Francis, Sadetzki, Siegal, Johansen, Christoffer, Houlston, Richard S, Jenkins, Robert B, Lachance, Daniel, Olson, Sara H, Bernstein, Jonine L, Merrell, Ryan T, Wrensch, Margaret R, Davis, Faith G, Lai, Rose, Shete, Sanjay, Amos, Christopher I, Scheurer, Michael E, Aldape, Kenneth, Alafuzoff, Irina, Brännström, Thomas, Broholm, Helle, Collins, Peter, Giannini, Caterina, Rosenblum, Marc, Tihan, Tarik, Melin, Beatrice S, and Bondy, Melissa L

Subjects
Epidemiology, Health Sciences, Brain Cancer, Cancer, Genetics, Brain Disorders, Clinical Research, Rare Diseases, Neurosciences, Human Genome, 2.1 Biological and endogenous factors, 6.1 Pharmaceuticals, 2.2 Factors relating to the physical environment, Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Glioma, Humans, Incidence, International Cooperation, Male, Middle Aged, Molecular Epidemiology, Retrospective Studies, Risk Factors, Young Adult, cancer, case-control studies, glioblastoma, glioma, methodology, study profile, Mathematical Sciences, Medical and Health Sciences
Abstract

Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions.

Published
2016

94. Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci

Author

Kachuri, Linda, Amos, Christopher I, McKay, James D, Johansson, Mattias, Vineis, Paolo, Bueno-de-Mesquita, H Bas, Boutron-Ruault, Marie-Christine, Johansson, Mikael, Quirós, J Ramón, Sieri, Sabina, Travis, Ruth C, Weiderpass, Elisabete, Le Marchand, Loic, Henderson, Brian E, Wilkens, Lynne, Goodman, Gary E, Chen, Chu, Doherty, Jennifer A, Christiani, David C, Wei, Yongyue, Su, Li, Tworoger, Shelley, Zhang, Xuehong, Kraft, Peter, Zaridze, David, Field, John K, Marcus, Michael W, Davies, Michael PA, Hyde, Russell, Caporaso, Neil E, Landi, Maria Teresa, Severi, Gianluca, Giles, Graham G, Liu, Geoffrey, McLaughlin, John R, Li, Yafang, Xiao, Xiangjun, Fehringer, Gord, Zong, Xuchen, Denroche, Robert E, Zuzarte, Philip C, McPherson, John D, Brennan, Paul, and Hung, Rayjean J

Subjects
Lung, Human Genome, Genetics, Cancer, Prevention, Lung Cancer, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 5, Female, Genetic Loci, Genetic Predisposition to Disease, Genotyping Techniques, Humans, Lung Neoplasms, Male, Middle Aged, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000×) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73×10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64×10(-6)), rs112290073 (OR = 1.85, P = 1.27×10(-5)), rs138895564 (OR = 2.16, P = 2.06×10(-5); among young cases, OR = 3.77, P = 8.41×10(-4)). In addition, we found that rs139852726 (P = 1.44×10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84×10(-7)) and lung cancer (P = 2.37×10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.

Published
2016

95. A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer

Author

Scarbrough, Peter M, Weber, Rachel Palmieri, Iversen, Edwin S, Brhane, Yonathan, Amos, Christopher I, Kraft, Peter, Hung, Rayjean J, Sellers, Thomas A, Witte, John S, Pharoah, Paul, Henderson, Brian E, Gruber, Stephen B, Hunter, David J, Garber, Judy E, Joshi, Amit D, McDonnell, Kevin, Easton, Doug F, Eeles, Ros, Kote-Jarai, Zsofia, Muir, Kenneth, Doherty, Jennifer A, and Schildkraut, Joellen M

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Human Genome, Colo-Rectal Cancer, Prevention, Genetics, Breast Cancer, Aging, Digestive Diseases, Genetic Testing, Cancer, Aetiology, 2.1 Biological and endogenous factors, BRCA2 Protein, Biomarkers, Tumor, Breast Neoplasms, Cell Cycle Proteins, Colorectal Neoplasms, DNA Damage, DNA Repair, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Humans, Lung Neoplasms, Male, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk Factors, Signal Transduction, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundDNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility.MethodsWe conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling.ResultsWe identified three susceptibility DNA repair genes, RAD51B (P < 5.09 × 10(-6)), MSH5 (P < 5.09 × 10(-6)), and BRCA2 (P = 5.70 × 10(-6)). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways.ConclusionsOnly three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways.ImpactResults suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria.

Published
2016

96. Lung Cancer in Ever- and Never-Smokers:Findings from Multi-Population GWAS Studies

Author

Li, Yafang, Xiao, Xiangjun, Li, Jianrong, Han, Younghun, Cheng, Chao, Fernandes, Gail F., Slewitzke, Shannon E., Rosenberg, Susan M., Zhu, Meng, Byun, Jinyoung, Bosse, Yohan, McKay, James D., Albanes, Demetrios, Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E., Landi, Maria T., Johansson, Mattias, Risch, Angela, Bickeböller, Heike, Wichmann, H. Erich, Christiani, David C., Rennert, Gad, Arnold, Susanne M., Goodman, Gary E., Field, John K., Davies, Michael P.A., Shete, Sanjay, Le Marchand, Loïc, Liu, Geoffrey, Hung, Rayjean J., Andrew, Angeline S., Kiemeney, Lambertus A., Sun, Ryan, Zienolddiny, Shanbeh, Grankvist, Kjell, Johansson, Mikael, Caporaso, Neil E., Cox, Angela, Hong, Yun Chul, Lazarus, Philip, Schabath, Matthew B., Aldrich, Melinda C., Schwartz, Ann G., Gorlov, Ivan, Purrington, Kristen S., Yang, Ping, Liu, Yanhong, Bailey-Wilson, Joan E., Pinney, Susan M., Mandal, Diptasri, Willey, James C., Gaba, Colette, Brennan, Paul, Xia, Jun, Shen, Hongbing, Amos, Christopher I., Li, Yafang, Xiao, Xiangjun, Li, Jianrong, Han, Younghun, Cheng, Chao, Fernandes, Gail F., Slewitzke, Shannon E., Rosenberg, Susan M., Zhu, Meng, Byun, Jinyoung, Bosse, Yohan, McKay, James D., Albanes, Demetrios, Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E., Landi, Maria T., Johansson, Mattias, Risch, Angela, Bickeböller, Heike, Wichmann, H. Erich, Christiani, David C., Rennert, Gad, Arnold, Susanne M., Goodman, Gary E., Field, John K., Davies, Michael P.A., Shete, Sanjay, Le Marchand, Loïc, Liu, Geoffrey, Hung, Rayjean J., Andrew, Angeline S., Kiemeney, Lambertus A., Sun, Ryan, Zienolddiny, Shanbeh, Grankvist, Kjell, Johansson, Mikael, Caporaso, Neil E., Cox, Angela, Hong, Yun Chul, Lazarus, Philip, Schabath, Matthew B., Aldrich, Melinda C., Schwartz, Ann G., Gorlov, Ivan, Purrington, Kristen S., Yang, Ping, Liu, Yanhong, Bailey-Wilson, Joan E., Pinney, Susan M., Mandal, Diptasri, Willey, James C., Gaba, Colette, Brennan, Paul, Xia, Jun, Shen, Hongbing, and Amos, Christopher I.

Abstract

Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44, 823 ever-smokers and 20, 074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. Results: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 ͯ 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. Conclusions: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. Impact: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.

Published
2024

97. CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility

Author

Du, Mulong, Xin, Junyi, Zheng, Rui, Yuan, Qianyu, Wang, Zhihui, Liu, Hongliang, Liu, Hanting, Cai, Guoshuai, Albanes, Demetrius, Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E., Landi, Maria Teresa, Johansson, Mattias, Risch, Angela, Bickeboller, Heike, Wichmann, H. Erich, Rennert, Gad, Arnold, Susanne, Brennan, Paul, Field, John K., Shete, Sanjay S., Le Marchand, Loïc, Liu, Geoffrey, Andrew, Angeline S., Kiemeney, Lambertus A., Zienolddiny, Shan, Grankvist, Kjell, Johansson, Mikael, Caporaso, Neil E., Cox, Angela, Hong, Yun Chul, Yuan, Jian Min, Schabath, Matthew B., Aldrich, Melinda C., Wang, Meilin, Shen, Hongbing, Chen, Feng, Zhang, Zhengdong, Hung, Rayjean J., Amos, Christopher I., Wei, Qingyi, Lazarus, Philip, Christiani, David C., Du, Mulong, Xin, Junyi, Zheng, Rui, Yuan, Qianyu, Wang, Zhihui, Liu, Hongliang, Liu, Hanting, Cai, Guoshuai, Albanes, Demetrius, Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E., Landi, Maria Teresa, Johansson, Mattias, Risch, Angela, Bickeboller, Heike, Wichmann, H. Erich, Rennert, Gad, Arnold, Susanne, Brennan, Paul, Field, John K., Shete, Sanjay S., Le Marchand, Loïc, Liu, Geoffrey, Andrew, Angeline S., Kiemeney, Lambertus A., Zienolddiny, Shan, Grankvist, Kjell, Johansson, Mikael, Caporaso, Neil E., Cox, Angela, Hong, Yun Chul, Yuan, Jian Min, Schabath, Matthew B., Aldrich, Melinda C., Wang, Meilin, Shen, Hongbing, Chen, Feng, Zhang, Zhengdong, Hung, Rayjean J., Amos, Christopher I., Wei, Qingyi, Lazarus, Philip, and Christiani, David C.

Abstract

Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen–metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke–exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85–0.91, P = 2.18 X 10-16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis.

Published
2024

98. Lung cancer in ever- and never-smokers : findings from multi-population GWAS studies

Author

Li, Yafang, Xiao, Xiangjun, Li, Jianrong, Han, Younghun, Cheng, Chao, Fernandes, Gail F., Slewitzke, Shannon E., Rosenberg, Susan M., Zhu, Meng, Byun, Jinyoung, Bossé, Yohan, McKay, James D., Albanes, Demetrios, Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E., Landi, Maria T., Johansson, Mattias, Risch, Angela, Bickeböller, Heike, Wichmann, H-Erich, Christiani, David C., Rennert, Gad, Arnold, Susanne M., Goodman, Gary E., Field, John K., Davies, Michael P A, Shete, Sanjay, Marchand, Loïc Le, Liu, Geoffrey, Hung, Rayjean J., Andrew, Angeline S., Kiemeney, Lambertus A., Sun, Ryan, Zienolddiny, Shanbeh, Grankvist, Kjell, Johansson, Mikael, Caporaso, Neil E., Cox, Angela, Hong, Yun-Chul, Lazarus, Philip, Schabath, Matthew B., Aldrich, Melinda C., Schwartz, Ann G., Gorlov, Ivan, Purrington, Kristen S., Yang, Ping, Liu, Yanhong, Bailey-Wilson, Joan E., Pinney, Susan M., Mandal, Diptasri, Willey, James C., Gaba, Colette, Brennan, Paul, Xia, Jun, Shen, Hongbing, Amos, Christopher I., Li, Yafang, Xiao, Xiangjun, Li, Jianrong, Han, Younghun, Cheng, Chao, Fernandes, Gail F., Slewitzke, Shannon E., Rosenberg, Susan M., Zhu, Meng, Byun, Jinyoung, Bossé, Yohan, McKay, James D., Albanes, Demetrios, Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E., Landi, Maria T., Johansson, Mattias, Risch, Angela, Bickeböller, Heike, Wichmann, H-Erich, Christiani, David C., Rennert, Gad, Arnold, Susanne M., Goodman, Gary E., Field, John K., Davies, Michael P A, Shete, Sanjay, Marchand, Loïc Le, Liu, Geoffrey, Hung, Rayjean J., Andrew, Angeline S., Kiemeney, Lambertus A., Sun, Ryan, Zienolddiny, Shanbeh, Grankvist, Kjell, Johansson, Mikael, Caporaso, Neil E., Cox, Angela, Hong, Yun-Chul, Lazarus, Philip, Schabath, Matthew B., Aldrich, Melinda C., Schwartz, Ann G., Gorlov, Ivan, Purrington, Kristen S., Yang, Ping, Liu, Yanhong, Bailey-Wilson, Joan E., Pinney, Susan M., Mandal, Diptasri, Willey, James C., Gaba, Colette, Brennan, Paul, Xia, Jun, Shen, Hongbing, and Amos, Christopher I.

Abstract

BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. RESULTS: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. CONCLUSIONS: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. IMPACT: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.

Published
2024
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99. Discovery of new myositis genetic associations through leveraging other immune-mediated diseases

Author

Lab Reumatologie/Klinische Immunologie, Reales, Guillermo, Amos, Christopher I., Benveniste, Olivier, Chinoy, Hector, De Bleecker, Jan, De Paepe, Boel, Doria, Andrea, Gregersen, Peter K., Lamb, Janine A., Limaye, Vidya, Lundberg, Ingrid E., Machado, Pedro M., Maurer, Britta, Miller, Frederick W., Molberg, Øyvind, Pachman, Lauren M., Padyukov, Leonid, Radstake, Timothy R., Reed, Ann M., Rider, Lisa G., Rothwell, Simon, Selva-O'Callaghan, Albert, Vencovský, Jiri, Wedderburn, Lucy R., Wallace, Chris, Myositis Genetics Consortium, Lab Reumatologie/Klinische Immunologie, Reales, Guillermo, Amos, Christopher I., Benveniste, Olivier, Chinoy, Hector, De Bleecker, Jan, De Paepe, Boel, Doria, Andrea, Gregersen, Peter K., Lamb, Janine A., Limaye, Vidya, Lundberg, Ingrid E., Machado, Pedro M., Maurer, Britta, Miller, Frederick W., Molberg, Øyvind, Pachman, Lauren M., Padyukov, Leonid, Radstake, Timothy R., Reed, Ann M., Rider, Lisa G., Rothwell, Simon, Selva-O'Callaghan, Albert, Vencovský, Jiri, Wedderburn, Lucy R., Wallace, Chris, and Myositis Genetics Consortium

Published
2024

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