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1. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author: Klein, Alison P., Wolpin, Brian M., Risch, Harvey A., Stolzenberg-Solomon, Rachael Z., Mocci, Evelina, Zhang, Mingfeng, Canzian, Federico, Childs, Erica J., Hoskins, Jason W., Jermusyk, Ashley, Zhong, Jun, Chen, Fei, Albanes, Demetrius, Andreotti, Gabriella, Arslan, Alan A., Babic, Ana, Bamlet, William R., Beane-Freeman, Laura, Berndt, Sonja I., Blackford, Amanda, Borges, Michael, Borgida, Ayelet, Bracci, Paige M., Brais, Lauren, Brennan, Paul, Brenner, Hermann, Bueno-de-Mesquita, Bas, Campa, Daniele, Capurso, Gabriele, Cavestro, Giulia Martina, Chaffee, Kari G., Chung, Charles C., Cleary, Sean, Cotterchio, Michelle, Dijk, Frederike, Duell, Eric J., Foretova, Lenka, Fuchs, Charles, Funel, Niccola, Gallinger, Steven, M. Gaziano, J. Michael, Gazouli, Maria, Giles, Graham G., Giovannucci, Edward, Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Hegyi, Peter, Helzlsouer, Kathy J., Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A., Hoover, Robert, Hung, Rayjean J., Jacobs, Eric J., Jamroziak, Krzysztof, Janout, Vladimir, Kaaks, Rudolf, Khaw, Kay-Tee, Klein, Eric A., Kogevinas, Manolis, Kooperberg, Charles, Kulke, Matthew H., Kupcinskas, Juozas, Kurtz, Robert J., Laheru, Daniel, Landi, Stefano, Lawlor, Rita T., Lee, I.-Min, LeMarchand, Loic, Lu, Lingeng, Malats, Núria, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L., Mohelníková-Duchoňová, Beatrice, Neale, Rachel E., Neoptolemos, John P., Oberg, Ann L., Olson, Sara H., Orlow, Irene, Pasquali, Claudio, Patel, Alpa V., Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Scelo, Ghislaine, Severi, Gianluca, Shu, Xiao-Ou, Silverman, Debra, Smith, Jill P., Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Tavano, Francesca, Thornquist, Mark D., Tobias, Geoffrey S., Van Den Eeden, Stephen K., Vashist, Yogesh, Visvanathan, Kala, Vodicka, Pavel, Wactawski-Wende, Jean, Wang, Zhaoming, Wentzensen, Nicolas, White, Emily, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Li, Donghui, Chanock, Stephen, Obazee, Ofure, Petersen, Gloria M., Amundadottir, Laufey T., Buring, Julie, Sesso, Howard, and Kraft, Phillip
Abstract: In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10−8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10−14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10−10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10−8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10−8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene., Version of Record
Published: 2018
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2. Socioeconomic status and the 25 × 25 risk factors as determinants of premature mortality: a multicohort study and meta-analysis of 1·7 million men and women

Author: Stringhini, Silvia, Carmeli, Cristian, Jokela, Markus, Avendaño, Mauricio, Muennig, Peter, Guida, Florence, Ricceri, Fulvio, d'Errico, Angelo, Barros, Henrique, Bochud, Murielle, Chadeau-Hyam, Marc, Clavel-Chapelon, Françoise, Costa, Giuseppe, Delpierre, Cyrille, Fraga, Silvia, Goldberg, Marcel, Giles, Graham G., Krogh, Vittorio, Kelly-Irving, Michelle, Layte, Richard, Lasserre, Aurélie M., Marmot, Michael G., Preisig, Martin, Shipley, Martin J., Vollenweider, Peter, Zins, Marie, Kawachi, Ichiro, Steptoe, Andrew, Mackenbach, Johan P., Vineis, Paolo, Kivimäki, Mika, Alenius, Harri, Avendano, Mauricio, Carra, Luca, Castagné, Raphaele, Courtin, Emilie, D'Errico, Angelo, Dugué, Pierre-Antoine, Elliott, Paul, Gares, Valérie, Giles, Graham, Greco, Dario, Hodge, Allison, Irving, Michelle Kelly, Karisola, Piia, Lang, Thierry, Lepage, Benoit, Mackenbach, Johan, Marmot, Michael, McCrory, Cathal, Milne, Roger, Nusselder, Wilma, Panico, Salvatore, Petrovic, Dusan, Polidoro, Silvia, Raitakari, Olli, Ribeiro, Ana Isabel, Robinson, Oliver, Valverde, Jose Rubio, Sacerdote, Carlotta, Satolli, Roberto, Severi, Gianluca, and Tumino, Rosario
Abstract: Background In 2011, WHO member states signed up to the 25 x 25 initiative, a plan to cut mortality due to noncommunicable diseases by 25% by 2025. However, socioeconomic factors influencing non-communicable diseases have not been included in the plan. In this study, we aimed to compare the contribution of socioeconomic status to mortality and years-of-life-lost with that of the 25 x 25 conventional risk factors.Methods We did a multicohort study and meta-analysis with individual-level data from 48 independent prospective cohort studies with information about socioeconomic status, indexed by occupational position, 25 x 25 risk factors (high alcohol intake, physical inactivity, current smoking, hypertension, diabetes, and obesity), and mortality, for a total population of 1 751 479 (54% women) from seven high-income WHO member countries. We estimated the association of socioeconomic status and the 25 x 25 risk factors with all-cause mortality and cause-specific mortality by calculating minimally adjusted and mutually adjusted hazard ratios [HR] and 95% CIs. We also estimated the population attributable fraction and the years of life lost due to suboptimal risk factors.Findings During 26.6 million person-years at risk (mean follow-up 13.3 years [SD 6.4 years]), 310 277 participants died. HR for the 25 x 25 risk factors and mortality varied between 1.04 (95% CI 0.98-1.11) for obesity in men and 2.17 (2.06-2.29) for current smoking in men. Participants with low socioeconomic status had greater mortality compared with those with high socioeconomic status (HR 1.42, 95% CI 1.38-1.45 for men; 1.34, 1.28-1.39 for women); this association remained significant in mutually adjusted models that included the 25 x 25 factors (HR 1.26, 1.21-1.32, men and women combined). The population attributable fraction was highest for smoking, followed by physical inactivity then socioeconomic status. Low socioeconomic status was associated with a 2.1-year reduction in life expectancy between ages 40 and 85 years, the corresponding years-of-life-lost were 0.5 years for high alcohol intake, 0.7 years for obesity, 3.9 years for diabetes, 1.6 years for hypertension, 2.4 years for physical inactivity, and 4.8 years for current smoking.Interpretation Socioeconomic circumstances, in addition to the 25 x 25 factors, should be targeted by local and global health strategies and health risk surveillance to reduce mortality., Version of Record
Published: 2017

3. Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma

Author: Bernatsky, Sasha, Velásquez García, Héctor A, Spinelli, John J, Gaffney, Patrick, Smedby, Karin E, Ramsey-Goldman, Rosalind, Wang, Sophia S, Albanes, Demetrius, Angelucci, Emanuele, Ansell, Stephen M, Asmann, Yan W, Becker, Nikolaus, Benavente, Yolanda, Berndt, Sonja I, Bertrand, Kimberly A, Boeing, Heiner, Boffetta, Paolo, Bracci, Paige M, Brennan, Paul, Brooks-Wilson, Angela R, Cerhan, James R, Chanock, Stephen J, Clavel, Jacqueline, Conde, Lucia, Cotenbader, Karen H, Cox, David G, Cozen, Wendy, Crouch, Simon, De Roos, Anneclaire J, de Sanjose, Silvia, Di Lollo, Simonetta, Diver, W Ryan, Dogan, Ahmet, Foretova, Lenka, Ghesquières, Hervé, Giles, Graham G, Glimelius, Bengt, Habermann, Thomas M, Haioun, Corinne, Hartge, Patricia, Hjalgrim, Henrik, Holford, Theodore R, Holly, Elizabeth A, Jackson, Rebecca D, Kaaks, Rudolph, Kane, Eleanor, Klein, Robert J, Kricker, Anne, Lan, Qing, Lawrence, Charles, Liebow, Mark, Lightfoot, Tracy, Link, Brian K, Maynadie, Marc, McKay, James, Melbye, Mads, Molina, Thierry J, Monnereau, Alain, Morton, Lindsay M, Nieters, Alexandra, North, Kari E, Novak, Anne J, Offit, Kenneth, Purdue, Mark P, Rais, Marco, Riby, Jacques, Roman, Eve, Rothman, Nathaniel, Salles, Gilles, Severi, Gianluca, Severson, Richard K, Skibola, Christine F, Slager, Susan L, Smith, Alex, Smith, Martyn T, Southey, Melissa C, Staines, Anthony, Teras, Lauren R, Thompson, Carrie A, Tilly, Hervé, Tinker, Lesley F, Tjonneland, Anne, Turner, Jenny, Vajdic, Claire M, Vermeulen, Roel C H, Vijai, Joseph, Vineis, Paolo, Virtamo, Jarmo, Wang, Zhaoming, Weinstein, Stephanie, Witzig, Thomas E, Zelenetz, Andrew, Zeleniuch-Jacquotte, Anne, Zhang, Yawei, Zheng, Tongzhang, Zucca, Mariagrazia, Clarke, Ann E, Adami, Hans-Olov, Birmann, Brenda, Kelly, Rachel, and Kraft, Phillip
Subjects: lymphoma, Systemic lupus, malignancy
Abstract: Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE., Version of Record
Published: 2017
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4. Circulating concentrations of biomarkers and metabolites related to vitamin status, one-carbon and the kynurenine pathways in US, Nordic, Asian, and Australian populations123

Author: Midttun, Øivind, Theofylaktopoulou, Despoina, McCann, Adrian, Fanidi, Anouar, Muller, David C, Meyer, Klaus, Ulvik, Arve, Zheng, Wei, Shu, Xiao-Ou, Xiang, Yong-Bing, Prentice, Ross, Thomson, Cynthia A, Pettinger, Mary, Giles, Graham G, Hodge, Allison, Cai, Qiuyin, Blot, William J, Wu, Jie, Johansson, Mikael, Hultdin, Johan, Grankvist, Kjell, Stevens, Victoria L, McCullough, Marjorie L, Weinstein, Stephanie J, Albanes, Demetrius, Langhammer, Arnulf, Hveem, Kristian, Næss, Marit, Gaziano, J Michael, Buring, Julie E, Lee, I-Min, Severi, Gianluca, Han, Jiali, Zeleniuch-Jacquotte, Anne, le Marchand, Loic, Yuan, Jian-Min, Butler, Lesley M, Koh, Woon-Puay, Wang, Renwei, Gao, Yu-Tang, Ericson, Ulrika, Sonestedt, Emily, Ziegler, Regina G, Freedman, Neal D, Visvanathan, Kala, Jones, Miranda R, Relton, Caroline, Brennan, Paul, Johansson, Mattias, Ueland, Per M, Sesso, Howard, Zhang, Xuehong, Stampfer, Meir, and Smith-Warner, Stephanie
Subjects: biomarker, Lung Cancer Cohort Consortium, one-carbon metabolism, tryptophan metabolism, vitamin status
Abstract: Background: Circulating concentrations of biomarkers that are related to vitamin status vary by factors such as diet, fortification, and supplement use. Published biomarker concentrations have also been influenced by the variation across laboratories, which complicates a comparison of results from different studies. Objective: We robustly and comprehensively assessed differences in biomarkers that are related to vitamin status across geographic regions. Design: The trial was a cross-sectional study in which we investigated 38 biomarkers that are related to vitamin status and one-carbon and tryptophan metabolism in serum and plasma from 5314 healthy control subjects representing 20 cohorts recruited from the United States, Nordic countries, Asia, and Australia, participating in the Lung Cancer Cohort Consortium. All samples were analyzed in a centralized laboratory. Results: Circulating concentrations of riboflavin, pyridoxal 5′-phosphate, folate, vitamin B-12, all-trans retinol, 25-hydroxyvitamin D, and α-tocopherol as well as combined vitamin scores that were based on these nutrients showed that the general B-vitamin concentration was highest in the United States and that the B vitamins and lipid soluble vitamins were low in Asians. Conversely, circulating concentrations of metabolites that are inversely related to B vitamins involved in the one-carbon and kynurenine pathways were high in Asians. The high B-vitamin concentration in the United States appears to be driven mainly by multivitamin-supplement users. Conclusions: The observed differences likely reflect the variation in intake of vitamins and, in particular, the widespread multivitamin-supplement use in the United States. The results provide valuable information about the differences in biomarker concentrations in populations across continents., Version of Record
Published: 2017
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5. Genome-wide association study identifies multiple risk loci for renal cell carcinoma

Author: Scelo, Ghislaine, Purdue, Mark P., Brown, Kevin M., Johansson, Mattias, Wang, Zhaoming, Eckel-Passow, Jeanette E., Ye, Yuanqing, Hofmann, Jonathan N., Choi, Jiyeon, Foll, Matthieu, Gaborieau, Valerie, Machiela, Mitchell J., Colli, Leandro M., Li, Peng, Sampson, Joshua N., Abedi-Ardekani, Behnoush, Besse, Celine, Blanche, Helene, Boland, Anne, Burdette, Laurie, Chabrier, Amelie, Durand, Geoffroy, Le Calvez-Kelm, Florence, Prokhortchouk, Egor, Robinot, Nivonirina, Skryabin, Konstantin G., Wozniak, Magdalena B., Yeager, Meredith, Basta-Jovanovic, Gordana, Dzamic, Zoran, Foretova, Lenka, Holcatova, Ivana, Janout, Vladimir, Mates, Dana, Mukeriya, Anush, Rascu, Stefan, Zaridze, David, Bencko, Vladimir, Cybulski, Cezary, Fabianova, Eleonora, Jinga, Viorel, Lissowska, Jolanta, Lubinski, Jan, Navratilova, Marie, Rudnai, Peter, Szeszenia-Dabrowska, Neonila, Benhamou, Simone, Cancel-Tassin, Geraldine, Cussenot, Olivier, Baglietto, Laura, Boeing, Heiner, Khaw, Kay-Tee, Weiderpass, Elisabete, Ljungberg, Borje, Sitaram, Raviprakash T., Bruinsma, Fiona, Jordan, Susan J., Severi, Gianluca, Winship, Ingrid, Hveem, Kristian, Vatten, Lars J., Fletcher, Tony, Koppova, Kvetoslava, Larsson, Susanna C., Wolk, Alicja, Banks, Rosamonde E., Selby, Peter J., Easton, Douglas F., Pharoah, Paul, Andreotti, Gabriella, Freeman, Laura E. Beane, Koutros, Stella, Albanes, Demetrius, Männistö, Satu, Weinstein, Stephanie, Clark, Peter E., Edwards, Todd L., Lipworth, Loren, Gapstur, Susan M., Stevens, Victoria L., Carol, Hallie, Freedman, Matthew L., Pomerantz, Mark M., Cho, Eunyoung, Kraft, Peter, Preston, Mark A., Michael Gaziano, J., Black, Amanda, Freedman, Neal D., Huang, Wen-Yi, Anema, John G., Kahnoski, Richard J., Lane, Brian R., Noyes, Sabrina L., Petillo, David, Teh, Bin Tean, Peters, Ulrike, White, Emily, Anderson, Garnet L., Johnson, Lisa, Luo, Juhua, Buring, Julie, Lee, I-Min, Chow, Wong-Ho, Moore, Lee E., Wood, Christopher, Eisen, Timothy, Henrion, Marc, Larkin, James, Barman, Poulami, Leibovich, Bradley C., Choueiri, Toni K., Mark Lathrop, G., Rothman, Nathaniel, Deleuze, Jean-Francois, McKay, James D., Parker, Alexander S., Wu, Xifeng, Houlston, Richard S., Brennan, Paul, Chanock, Stephen J., Wilson, Kathryn, and Sesso, Howard
Abstract: Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10−10), 3p22.1 (rs67311347, P=2.5 × 10−8), 3q26.2 (rs10936602, P=8.8 × 10−9), 8p21.3 (rs2241261, P=5.8 × 10−9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10−8), 11q22.3 (rs74911261, P=2.1 × 10−10) and 14q24.2 (rs4903064, P=2.2 × 10−24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility., Version of Record
Published: 2017
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6. Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort

Author: Fortner, Renée T., Vitonis, Allison F., Schock, Helena, Hüsing, Anika, Johnson, Theron, Fashemi, Titilayo, Yamamoto, Hidemi S., Tjønneland, Anne, Hansen, Louise, Overvad, Kim, Boutron-Ruault, Marie-Christine, Kvaskoff, Marina, Severi, Gianluca, Boeing, Heiner, Trichopoulou, Antonia, Benetou, Vassiliki, La Vecchia, Carlo, Palli, Domenico, Sieri, Sabina, Tumino, Rosario, Matullo, Giuseppe, Mattiello, Amalia, Onland-Moret, N. Charlotte, Peeters, Petra H., Weiderpass, Elisabete, Gram, Inger Torhild, Jareid, Mie, Quirós, J. Ramón, Duell, Eric J., Sánchez, Maria-Jose, Chirlaque, María Dolores, Ardanaz, Eva, Larrañaga, Nerea, Nodin, Björn, Brändstedt, Jenny, Idahl, Annika, Khaw, Kay-Tee, Allen, Naomi, Gunter, Marc, Johansson, Mattias, Dossus, Laure, Merritt, Melissa A., Riboli, Elio, Kaaks, Rudolf, Fichorova, Raina, Cramer, Daniel, and Terry, Kathryn
Subjects: Ovarian cancer, Early detection markers, CA125, CA15.3, HE4
Abstract: Background: Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening. Methods: We evaluated cross-sectional relationships between lifestyle and reproductive factors and these markers among controls (n = 1910) from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Improvements in discrimination of prediction models adjusting for correlates of the markers were evaluated among postmenopausal women in the nested case-control study (n = 590 cases). Generalized linear models were used to calculate geometric means of CA125, CA15.3, and HE4. CA72.4 above vs. below limit of detection was evaluated using logistic regression. Early detection prediction was modeled using conditional logistic regression. Results: CA125 concentrations were lower, and CA15.3 higher, in post- vs. premenopausal women (p ≤ 0.02). Among postmenopausal women, CA125 was higher among women with higher parity and older age at menopause (ptrend ≤ 0.02), but lower among women reporting oophorectomy, hysterectomy, ever use of estrogen-only hormone therapy, or current smoking (p < 0.01). CA15.3 concentrations were higher among heavier women and in former smokers (p ≤ 0.03). HE4 was higher with older age at blood collection and in current smokers, and inversely associated with OC use duration, parity, and older age at menopause (≤ 0.02). No associations were observed with CA72.4. Adjusting for correlates of the markers in prediction models did not improve the discrimination. Conclusions: This study provides insights into sources of variation in ovarian cancer early detection markers in healthy women and informs about the utility of individualizing marker cutpoints based on epidemiologic factors. Electronic supplementary material The online version of this article (doi:10.1186/s13048-017-0315-6) contains supplementary material, which is available to authorized users., Version of Record
Published: 2017
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7. Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study

Author: Fedirko, Veronika, Tran, Hao Quang, Gewirtz, Andrew T., Stepien, Magdalena, Trichopoulou, Antonia, Aleksandrova, Krasimira, Olsen, Anja, Tjønneland, Anne, Overvad, Kim, Carbonnel, Franck, Boutron-Ruault, Marie-Christine, Severi, Gianluca, Kühn, Tilman, Kaaks, Rudolf, Boeing, Heiner, Bamia, Christina, Grioni, Sara, Panico, Salvatore, Palli, Domenico, Tumino, Rosario, Naccarati, Alessio, Peeters, Petra H., Bueno-de-Mesquita, H. B., Weiderpass, Elisabete, Castaño, José María Huerta, Barricarte, Aurelio, Sánchez, María-José, Dorronsoro, Miren, Quirós, J. Ramón, Agudo, Antonio, Sjöberg, Klas, Ohlsson, Bodil, Hemmingsson, Oskar, Werner, Mårten, Bradbury, Kathryn E., Khaw, Kay-Tee, Wareham, Nick, Tsilidis, Konstantinos K., Aune, Dagfinn, Scalbert, Augustin, Romieu, Isabelle, Riboli, Elio, Jenab, Mazda, and Lagiou, Pagona
Subjects: Hepatocellular carcinoma, Lipopolysaccharide, Flagellin, Endotoxins, Prospective studies
Abstract: Background: Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking. Methods: We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression. Results: Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70–81.40; P trend = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses. Conclusions: These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0830-8) contains supplementary material, which is available to authorized users., Version of Record
Published: 2017
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8. A meta-analysis of individual participant data reveals an association between circulating levels of IGF-I and prostate cancer risk

Author: Travis, Ruth, Appleby, Paul, Martin, Richard, Holly, Jeff M. P., Albanes, Demetrius, Black, Amanda, Bueno-de-Mesquita, H. B., Chan, June, Chen, Chu, Chirlaque, Maria-Dolores, Cook, Michael, Deschasaux, Mélanie, Donovan, Jenny, Ferrucci, Luigi, Galan, Pilar, Giles, Graham, Giovannucci, Edward, Gunter, Marc, Habel, Laurel, Hamdy, Freddie, Helzlsouer, Kathy, Hercberg, Serge, Hoover, Robert, Janssen, Joseph A. M. J. L., Kaaks, Rudolf, Kubo, Tatsuhiko, Le Marchand, Loic, Metter, E. Jeffrey, Mikami, Kazuya, Morris, Joan, Neal, David, Neuhouser, Marian, Ozasa, Kotaro, Palli, Domenico, Platz, Elizabeth, Pollak, Michael, Price, Alison, Roobol, Monique, Schaefer, Catherine, Schenk, Jeannette, Severi, Gianluca, Stampfer, Meir, Pär Stattin, Tamakoshi, Akiko, Tangen, Catherine, Touvier, Mathilde, Wald, Nicholas, Weiss, Noel, Ziegler, Regina, Key, Timothy, and Allen, Naomi
Abstract: The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (P-trend all <= 0.005), and IGFBP-1 was inversely associated weakly with risk (P-trend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (P-heterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, P-heterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development., Accepted Manuscript
Published: 2016

9. 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, Le Marchand, Loïc, Wilkens, Lynne R., Park, Sungshim L., Haiman, Christopher, Field, John K., Davies, Michael, Marcus, Michael, Liu, Geoffrey, Caporaso, Neil E., Wei, Yongyue, Chen, Chu, Doherty, Jennifer A., Severi, Gianluca, Goodman, Gary E., Hung, Rayjean J., Amos, Christopher I., McKay, James, Johansson, Mattias, Brennan, Paul, Kraft, Phillip, Gao, Chi, Tworoger, Shelley, and Christiani, David
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/m2) 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., Version of Record
Published: 2016
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10. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author: Hollestelle, Antoinette, van der Baan, Frederieke H., Berchuck, Andrew, Johnatty, Sharon E., Aben, Katja K., Agnarsson, Bjarni A., Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Antoniou, Antonis C., Apicella, Carmel, Arndt, Volker, Arnold, Norbert, Arun, Banu K., Arver, Brita, Ashworth, Alan, Baglietto, Laura, Balleine, Rosemary, Bandera, Elisa V., Barrowdale, Daniel, Bean, Yukie T., Beckmann, Lars, Beckmann, Matthias W., Benitez, Javier, Berger, Andreas, Berger, Raanan, Beuselinck, Benoit, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Anders, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Brüning, Thomas, Budzilowska, Agnieszka, Bunker, Clareann H., Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S., Caligo, Maria A., Campbell, Ian, Carter, Jonathan, Chang-Claude, Jenny, Chanock, Stephen J., Claes, Kathleen B.M., Collée, J. Margriet, Cook, Linda S., Couch, Fergus J., Cox, Angela, Cramer, Daniel, Cross, Simon S., Cunningham, Julie M., Cybulski, Cezary, Czene, Kamila, Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, de la Hoya, Miguel, deFazio, Anna, Dennis, Joseph, Devilee, Peter, Dicks, Ed M., Diez, Orland, Doherty, Jennifer A., Domchek, Susan M., Dorfling, Cecilia M., Dörk, Thilo, Silva, Isabel Dos Santos, du Bois, Andreas, Dumont, Martine, Dunning, Alison M., Duran, Mercedes, Easton, Douglas F., Eccles, Diana, Edwards, Robert P., Ehrencrona, Hans, Ejlertsen, Bent, Ekici, Arif B., Ellis, Steve D., Engel, Christoph, Eriksson, Mikael, Fasching, Peter A., Feliubadalo, Lidia, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Fontaine, Annette, Fortuzzi, Stefano, Fostira, Florentia, Fridley, Brooke L., Friebel, Tara, Friedman, Eitan, Friel, Grace, Frost, Debra, Garber, Judy, García-Closas, Montserrat, Gayther, Simon A., Gentry-Maharaj, Aleksandra, Gerdes, Anne-Marie, Giles, Graham G., Glasspool, Rosalind, Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Gore, Martin, Greene, Mark H., Grip, Mervi, Gronwald, Jacek, Gschwantler Kaulich, Daphne, Guénel, Pascal, Guzman, Starr R., Haeberle, Lothar, Haiman, Christopher A., Hall, Per, Halverson, Sandra L., Hamann, Ute, Hansen, Thomas V.O., Harter, Philipp, Hartikainen, Jaana M., Healey, Sue, Hein, Alexander, Heitz, Florian, Henderson, Brian E., Herzog, Josef, T Hildebrandt, Michelle A., Høgdall, Claus K., Høgdall, Estrid, Hogervorst, Frans B.L., Hopper, John L., Humphreys, Keith, Huzarski, Tomasz, Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, Janavicius, Ramunas, Jaworska, Katarzyna, Jensen, Allan, Jensen, Uffe Birk, Johnson, Nichola, Jukkola-Vuorinen, Arja, Kabisch, Maria, Karlan, Beth Y., Kataja, Vesa, Kauff, Noah, Kelemen, Linda E., Kerin, Michael J., Kiemeney, Lambertus A., Kjaer, Susanne K., Knight, Julia A., Knol-Bout, Jacoba P., Konstantopoulou, Irene, Kosma, Veli-Matti, Krakstad, Camilla, Kristensen, Vessela, Kuchenbaecker, Karoline B., Kupryjanczyk, Jolanta, Laitman, Yael, Lambrechts, Diether, Lambrechts, Sandrina, Larson, Melissa C., Lasa, Adriana, Laurent-Puig, Pierre, Lazaro, Conxi, Le, Nhu D., Le Marchand, Loic, Leminen, Arto, Lester, Jenny, Levine, Douglas A., Li, Jingmei, Liang, Dong, Lindblom, Annika, Lindor, Noralane, Lissowska, Jolanta, Long, Jirong, Lu, Karen H., Lubinski, Jan, Lundvall, Lene, Lurie, Galina, Mai, Phuong L., Mannermaa, Arto, Margolin, Sara, Mariette, Frederique, Marme, Frederik, Martens, John W.M., Massuger, Leon F.A.G., Maugard, Christine, Mazoyer, Sylvie, McGuffog, Lesley, McGuire, Valerie, McLean, Catriona, McNeish, Iain, Meindl, Alfons, Menegaux, Florence, Menéndez, Primitiva, Menkiszak, Janusz, Menon, Usha, Mensenkamp, Arjen R., Miller, Nicola, Milne, Roger L., Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Müller, Heiko, Mulligan, Anna Marie, Muranen, Taru A., Narod, Steven A., Nathanson, Katherine L., Ness, Roberta B., Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Nielsen, Finn C., Nielsen, Sune F., Nordestgaard, Børge G., Nussbaum, Robert L., Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olson, Janet E., Olson, Sara H., Oosterwijk, Jan C., Orlow, Irene, Orr, Nick, Orsulic, Sandra, Osorio, Ana, Ottini, Laura, Paul, James, Pearce, Celeste L., Pedersen, Inge Sokilde, Peissel, Bernard, Pejovic, Tanja, Pelttari, Liisa M., Perkins, Jo, Permuth-Wey, Jenny, Peterlongo, Paolo, Peto, Julian, Phelan, Catherine M., Phillips, Kelly-Anne, Piedmonte, Marion, Pike, Malcolm C., Platte, Radka, Plisiecka-Halasa, Joanna, Poole, Elizabeth M., Poppe, Bruce, Pylkäs, Katri, Radice, Paolo, Ramus, Susan J., Rebbeck, Timothy, Reed, Malcolm W.R., Rennert, Gad, Risch, Harvey A., Robson, Mark, Rodriguez, Gustavo C., Romero, Atocha, Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo, Salani, Ritu, Salvesen, Helga B., Sawyer, Elinor J., Schildkraut, Joellen M., Schmidt, Marjanka K., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schrauder, Michael G., Schumacher, Fredrick, Schwaab, Ira, Scuvera, Giulietta, Sellers, Thomas A., Severi, Gianluca, Seynaeve, Caroline M., Shah, Mitul, Shrubsole, Martha, Siddiqui, Nadeem, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sinilnikova, Olga M., Smeets, Dominiek, Sohn, Christof, Soller, Maria, Song, Honglin, Soucy, Penny, Southey, Melissa C., Stegmaier, Christa, Stoppa-Lyonnet, Dominique, Sucheston, Lara, Swerdlow, Anthony, Tangen, Ingvild L., Tea, Muy-Kheng, Teixeira, Manuel R., Terry, Kathryn, Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J., Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda Ewart, Tollenaar, Rob A.E.M., Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Tsimiklis, Helen, Tung, Nadine, Tworoger, Shelley, Tyrer, Jonathan P., Vachon, Celine M., Van, Laura J., van Altena, Anne M., Van Asperen, C.J., van den Berg, David, van den Ouweland, Ans M.W., van Doorn, Helena C., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vergote, Ignace, Verhoef, Senno, Vierkant, Robert A., Vijai, Joseph, Vitonis, Allison F., von Wachenfeldt, Anna, Walsh, Christine, Wang, Qin, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weischer, Maren, Weitzel, Jeffrey N., Weltens, Caroline, Wentzensen, Nicolas, Whittemore, Alice S., Wilkens, Lynne R., Winqvist, Robert, Wu, Anna H., Wu, Xifeng, Yang, Hannah P., Zaffaroni, Daniela, Pilar Zamora, M., Zheng, Wei, Ziogas, Argyrios, Chenevix-Trench, Georgia, Pharoah, Paul D.P., Rookus, Matti A., Hooning, Maartje J., and Goode, Ellen L.
Subjects: KRAS variant, Breast cancer, Ovarian cancer, Genetic association, Clinical outcome
Abstract: OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). RESULTS: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., Other Research Unit, Accepted Manuscript
Published: 2016
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11. 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, Carreón, Tania, Chaffee, Kari G., Chang, I-Shou, Chatterjee, Nilanjan, Chen, Chu, Chen, Constance, Chen, Kexin, Chung, Charles C., Cook, Linda S., Cullen, Michael, Davis, Faith G., Ding, Ti, Doherty, Jennifer, Duell, Eric J., Epstein, Caroline G., Fan, Jin-Hu, Figueroa, Jonine D., Fraumeni, Joseph F., Friedenreich, Christine M., Gallinger, Steven, Gao, Yu-Tang, Gapstur, Susan M., Garcia-Closas, Montserrat, Gaudet, Mia M., Giles, Graham G., Gillanders, Elizabeth M., Goldin, Lynn, Goldstein, Alisa M., Haiman, Christopher A., Hallmans, Goran, Harris, Curtis C., Henriksson, Roger, Holly, Elizabeth A., Hong, Yun-Chul, Hoover, Robert N., Hsiung, Chao A., Hu, Nan, Hu, Wei, 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, Krogh, Vittorio, Kurtz, Robert C., LaCroix, Andrea, Lan, Qing, Landi, Maria Teresa, Marchand, Loic Le, Li, Donghui, Liang, Xiaolin, Liao, Linda M., Lin, Dongxin, Liu, Jianjun, Lissowska, Jolanta, Lu, Lingeng, Magliocco, Anthony M., Malats, Nuria, Matsuo, Keitaro, McNeill, Lorna H., McWilliams, Robert R., Melin, Beatrice S., Mirabello, Lisa, Moore, Lee, Olson, Sara H., Orlow, Irene, Park, Jae Yong, Patiño-Garcia, Ana, Peplonska, Beata, Peters, Ulrike, Petersen, Gloria M., Pooler, Loreall, Prescott, Jennifer, Prokunina-Olsson, Ludmila, Purdue, Mark P., Qiao, You-Lin, Rajaraman, Preetha, Real, Francisco X., Riboli, Elio, Risch, Harvey A., Rodriguez-Santiago, Benjamin, Ruder, Avima M., Savage, Sharon A., Schumacher, Fredrick, Schwartz, Ann G., Schwartz, Kendra L., Seow, Adeline, Wendy Setiawan, Veronica, Severi, Gianluca, Shen, Hongbing, Sheng, Xin, Shin, Min-Ho, Shu, Xiao-Ou, Silverman, Debra T., Spitz, Margaret R., Stevens, Victoria L., Stolzenberg-Solomon, Rachael, Stram, Daniel, Tang, Ze-Zhong, Taylor, Philip R., Teras, Lauren R., Tobias, Geoffrey S., Van Den Berg, David, Visvanathan, Kala, Wacholder, Sholom, Wang, Jiu-Cun, Wang, Zhaoming, Wentzensen, Nicolas, Wheeler, William, White, Emily, Wiencke, John K., Wolpin, Brian M., Wong, Maria Pik, Wu, Chen, Wu, Tangchun, Wu, Xifeng, Wu, Yi-Long, Wunder, Jay S., Xia, Lucy, Yang, Hannah P., Yang, Pan-Chyr, Yu, Kai, Zanetti, Krista A., Zeleniuch-Jacquotte, Anne, Zheng, Wei, Zhou, Baosen, Ziegler, Regina G., Perez-Jurado, Luis A., Caporaso, Neil E., Rothman, Nathaniel, Tucker, Margaret, Dean, Michael C., Yeager, Meredith, Chanock, Stephen J., Crous Bou, Marta, De Vivo, Immaculata, Fuchs, Charles, Gaziano, John, Giovannucci, Edward, Hankinson, Susan, Hunter, David, and Kraft, Phillip
Abstract: To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases., Version of Record
Published: 2016
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12. Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data

Author: Wang, Zhaoming, Rajaraman, Preetha, Melin, Beatrice, Chung, Charles, Zhang, Weijia, McKean-Cowdin, Roberta, Michaud, Dominique, Yeager, Meredith, Ahlbom, Anders, Albanes, Demetrius, Andersson, Ulrika, Freeman, Laura E. Beane, Buring, Julie, Butler, Mary Ann, Carreón, Tania, Feychting, Maria, Gapstur, Susan, Gaziano, J. Michael, Giles, Graham, Hallmans, Goran, Henriksson, Roger, Hoffman-Bolton, Judith, Inskip, Peter, Kitahara, Cari, Le Marchand, Loic, Linet, Martha, Li, Shengchao, Peters, Ulrike, Purdue, Mark, Rothman, Nathaniel, Ruder, Avima, Sesso, Howard, Severi, Gianluca, Stampfer, Meir, Stevens, Victoria, Visvanathan, Kala, Wang, Sophia, White, Emily, Zeleniuch-Jacquotte, Anne, Hoover, Robert, Fraumeni, Joseph, Chatterjee, Nilanjan, Hartge, Patricia, and Chanock, Stephen
Abstract: We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 x 10(-11)), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with approximate to 3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele, Accepted Manuscript
Published: 2015

13. Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies

Author: Key, Timothy, Appleby, Paul, Travis, Ruth, Albanes, Demetrius, Alberg, Anthony, Barricarte, Aurelio, Black, Amanda, Boeing, Heiner, Bueno-de-Mesquita, H. Bas, Chan, June, Chen, Chu, Cook, Michael, Donovan, Jenny, Galan, Pilar, Gilbert, Rebecca, Giles, Graham, Giovannucci, Edward, Goodman, Gary, Goodman, Phyllis, Gunter, Marc, Hamdy, Freddie, Heliövaara, Markku, Helzlsouer, Kathy, Henderson, Brian, Hercberg, Serge, Hoffman-Bolton, Judy, Hoover, Robert, Johansson, Mattias, Khaw, Kay-Tee, King, Irena, Knekt, Paul, Kolonel, Laurence, Le Marchand, Loic, Männistö, Satu, Martin, Richard, Meyer, Haakon, Mondul, Alison, Moy, Kristin, Neal, David, Neuhouser, Marian, Palli, Domenico, Platz, Elizabeth, Pouchieu, Camille, Rissanen, Harri, Schenk, Jeannette, Severi, Gianluca, Stampfer, Meir, Tjønneland, Anne, Touvier, Mathilde, Trichopoulou, Antonia, Weinstein, Stephanie, Ziegler, Regina, Zhou, Cindy Ke, and Allen, Naomi
Abstract: Background: Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. Objective: The objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, alpha-tocopherol, and gamma-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors. Design: Principal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets. Results: Data were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For alpha-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). gamma-Tocopherol was not associated with risk. Conclusions: Overall prostate cancer risk was positively associated with retinol and inversely associated with alpha-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and alpha-tocopherol. Whether these associations reflect causal relations is unclear., Version of Record
Published: 2015

14. Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Author: Schumacher, Fredrick, Schmit, Stephanie, Jiao, Shuo, Edlund, Christopher, Wang, Hansong, Zhang, Ben, Hsu, Li, Huang, Shu-Chen, Fischer, Christopher, Harju, John, Idos, Gregory, Lejbkowicz, Flavio, Manion, Frank, McDonnell, Kevin, McNeil, Caroline, Melas, Marilena, Rennert, Hedy, Shi, Wei, Thomas, Duncan, Van Den Berg, David J., Hutter, Carolyn, Aragaki, Aaron, Butterbach, Katja, Caan, Bette, Carlson, Christopher, Chanock, Stephen, Curtis, Keith, Fuchs, Charles, Gala, Manish, Giovannucci, Edward, Gogarten, Stephanie, Hayes, Richard, Henderson, Brian, Hunter, David, Jackson, Rebecca, Kolonel, Laurence, Kooperberg, Charles, Sébastien Küry, LaCroix, Andrea, Laurie, Cathy, Laurie, Cecelia, Lemire, Mathieu, Levine, David, Ma, Jing, Makar, Karen, Qu, Conghui, Taverna, Darin, Ulrich, Cornelia, Wu, Kana, Kono, Suminori, West, Dee, Berndt, Sonja, Stéphane Bezieau, Brenner, Hermann, Campbell, Peter, Chan, Andrew, Chang-Claude, Jenny, Coetzee, Gerhard, Conti, David, Duggan, David, Figueiredo, Jane, Fortini, Barbara, Gallinger, Steven, Gauderman, W. James, Giles, Graham, Green, Roger, Haile, Robert, Harrison, Tabitha, Hoffmeister, Michael, Hopper, John, Hudson, Thomas, Jacobs, Eric, Iwasaki, Motoki, Jee, Sun Ha, Jenkins, Mark, Jia, Wei-Hua, Joshi, Amit, Li, Li, Lindor, Noralene, Matsuo, Keitaro, Moreno, Victor, Mukherjee, Bhramar, Newcomb, Polly, Potter, John, Raskin, Leon, Rennert, Gad, Rosse, Stephanie, Severi, Gianluca, Schoen, Robert, Seminara, Daniela, Shu, Xiao-Ou, Slattery, Martha, Tsugane, Shoichiro, White, Emily, Xiang, Yong-Bing, Zanke, Brent, Zheng, Wei, Le Marchand, Loic, Casey, Graham, and Gruber, Stephen
Abstract: Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E - 08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies., Accepted Manuscript
Published: 2015

15. Cerebral Circulation Time is Prolonged and Not Correlated with EDSS in Multiple Sclerosis Patients: A Study Using Digital Subtracted Angiography

Author: Monti, Lucia, Donati, Donatella, Menci, Elisabetta, Cioni, Samuele, Bellini, Matteo, Grazzini, Irene, Leonini, Sara, Galluzzi, Paolo, Severi, Sauro, Burroni, Luca, Casasco, Alfredo, Morbidelli, Lucia, Santarnecchi, Emiliano, and Piu, Pietro
Abstract: Literature has suggested that changes in brain flow circulation occur in patients with multiple sclerosis. In this study, digital subtraction angiography (DSA) was used to measure the absolute CCT value in MS patients and to correlate its value to age at disease onset and duration, and to expand disability status scale (EDSS). DSA assessment was performed on eighty MS patients and on a control group of forty-four age-matched patients. CCT in MS and control groups was calculated by analyzing the angiographic images. Lesion and brain volumes were calculated in a representative group of MS patients. Statistical correlations among CCT and disease duration, age at disease onset, lesion load, brain volumes and EDSS were considered. A significant difference between CCT in MS patients (mean = 4.9s; sd = 1.27s) and control group (mean = 2.8s; sd = 0.51s) was demonstrated. No significant statistical correlation was found between CCT and the other parameters in all MS patients. Significantly increased CCT value in MS patients suggests the presence of microvascular dysfunctions, which do not depend on clinical and MRI findings. Hemodynamic changes may not be exclusively the result of a late chronic inflammatory process., Version of Record
Published: 2015
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16. 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, Wang, Sophia S., Brooks-Wilson, Angela R., Lan, Qing, de Bakker, Paul I. W., Vermeulen, Roel C. H., 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, Albanes, Demetrius, Lightfoot, Tracy, Yeager, Meredith, Chung, Charles C., Burdett, Laurie, Hutchinson, Amy, Lawrence, Charles, Montalvan, Rebecca, 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, 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, Virtamo, Jarmo, Smith, Alex, Kane, Eleanor, Roman, Eve, Chiu, Brian C. H., Fraumeni, Joseph F., Wu, Xifeng, Cerhan, James R., Offit, Kenneth, Chanock, Stephen J., Rothman, Nathaniel, Nieters, Alexandra, Birmann, Brenda, Bertrand, Kimberly, Liang, Liming, Adami, Hans-Olov, Giovannucci, Edward, and Kraft, Phillip
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., Version of Record
Published: 2015
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17. Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort

Author: Fages, Anne, Duarte-Salles, Talita, Stepien, Magdalena, Ferrari, Pietro, Fedirko, Veronika, Pontoizeau, Clément, Trichopoulou, Antonia, Aleksandrova, Krasimira, Tjønneland, Anne, Olsen, Anja, Clavel-Chapelon, Françoise, Boutron-Ruault, Marie-Christine, Severi, Gianluca, Kaaks, Rudolf, Kuhn, Tilman, Floegel, Anna, Boeing, Heiner, Bamia, Christina, Trichopoulos, Dimitrios, Palli, Domenico, Pala, Valeria, Panico, Salvatore, Tumino, Rosario, Vineis, Paolo, Bueno-de-Mesquita, H. Bas, Peeters, Petra H., Weiderpass, Elisabete, Agudo, Antonio, Molina-Montes, Esther, Huerta, José María, Ardanaz, Eva, Dorronsoro, Miren, Sjöberg, Klas, Ohlsson, Bodil, Khaw, Kay-Tee, Wareham, Nick, Travis, Ruth C., Schmidt, Julie A., Cross, Amanda, Gunter, Marc, Riboli, Elio, Scalbert, Augustin, Romieu, Isabelle, Elena-Herrmann, Benedicte, Jenab, Mazda, and Lagiou, Pagona
Subjects: Epidemiology, European Prospective Investigation into Cancer and Nutrition, Hepatocellular carcinoma, Liver cancer, Metabolomics, Nuclear magnetic resonance
Abstract: Background: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers. Methods: To address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched controls (n = 222) identified from amongst the participants of a large European prospective cohort. Results: A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis. Conclusion: Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12916-015-0462-9) contains supplementary material, which is available to authorized users., Version of Record
Published: 2015
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18. Prostate Cancer (PCa) Risk Variants and Risk of Fatal PCa in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium

Author: Shui, Irene M., Lindström, Sara, Kibel, Adam S., Berndt, Sonja I., Campa, Daniele, Gerke, Travis, Penney, Kathryn L., Albanes, Demetrius, Berg, Christine, Bueno-de-Mesquita, H. Bas, Chanock, Stephen, Crawford, E. David, Diver, W. Ryan, Gapstur, Susan M., Gaziano, J. Michael, Giles, Graham G., Henderson, Brian, Hoover, Robert, Johansson, Mattias, Marchand, Loic Le, Ma, Jing, Navarro, Carmen, Overvad, Kim, Schumacher, Fredrick R., Severi, Gianluca, Siddiq, Afshan, Stampfer, Meir, Stevens, Victoria L., Travis, Ruth C., Trichopoulos, Dimitrios, Vineis, Paolo, Mucci, Lorelei A., Yeager, Meredith, Giovannucci, Edward, and Kraft, Peter
Abstract: Background: Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM). Objective: To examine the association of 47 established PCa risk single-nucleotide polymorphisms (SNPs) with PCSM. Design, setting, and participants: We included 10 487 men who had PCa and 11 024 controls, with a median follow-up of 8.3 yr, during which 1053 PCa deaths occurred.Outcome measurements and statistical analysis: The main outcome was PCSM. The risk allele was defined as the allele associated with an increased risk for PCa in the literature. We used Cox proportional hazards regression to calculate the hazard ratios of each SNP with time to progression to PCSM after diagnosis. We also used logistic regression to calculate odds ratios for each risk SNP, comparing fatal PCa cases to controls. Results and limitations: Among the cases, we found that 8 of the 47 SNPs were significantly associated (p < 0.05) with time to PCSM. The risk allele of rs11672691 (intergenic) was associated with an increased risk for PCSM, while 7 SNPs had risk alleles inversely associated (rs13385191 [C2orf43], rs17021918 [PDLIM5], rs10486567 [JAZF1], rs6465657 [LMTK2], rs7127900 (intergenic), rs2735839 [KLK3], rs10993994 [MSMB], rs13385191 [C2orf43]). In the case-control analysis, 22 SNPs were associated (p < 0.05) with the risk of fatal PCa, but most did not differentiate between fatal and nonfatal PCa. Rs11672691 and rs10993994 were associated with both fatal and nonfatal PCa, while rs6465657, rs7127900, rs2735839, and rs13385191 were associated with nonfatal PCa only. Conclusions: Eight established risk loci were associated with progression to PCSM after diagnosis. Twenty-two SNPs were associated with fatal PCa incidence, but most did not differentiate between fatal and nonfatal PCa. The relatively small magnitudes of the associations do not translate well into risk prediction, but these findings merit further follow-up, because they may yield important clues about the complex biology of fatal PCa.Patient summary: In this report, we assessed whether established PCa risk variants could predict PCSM. We found eight risk variants associated with PCSM: One predicted an increased risk of PCSM, while seven were associated with decreased risk. Larger studies that focus on fatal PCa are needed to identify more markers that could aid prediction., Accepted Manuscript
Published: 2014

19. Circulating Biomarkers of One-Carbon Metabolism in Relation to Renal Cell Carcinoma Incidence and Survival

Author: Johansson, Mattias, Fanidi, Anouar, Muller, David C., Bassett, Julie K., Midttun, Øivind, Vollset, Stein Emil, Travis, Ruth C., Palli, Domenico, Mattiello, Amalia, Sieri, Sabina, Trichopoulou, Antonia, Ljungberg, Börje, Hallmans, Göran, Weiderpass, Elisabete, Skeie, Guri, González, Carlos A., Dorronsoro, Miren, Peeters, Petra H., Bueno-de-Mesquita, H. B(as)., Ros, Martine M., Boutron Ruault, Marie-Christine, Fagherazzi, Guy, Clavel, Françoise, Sánchez, María-José, Gurrea, Aurelio Barricarte, Navarro, Carmen, Quiros, J. Ramon, Overvad, Kim, Tjønneland, Anne, Aleksandrova, Krassimira, Vineis, Paolo, Gunter, Marc J., Kaaks, Rudolf, Giles, Graham, Relton, Caroline, Riboli, Elio, Boeing, Heiner, Ueland, Per Magne, Severi, Gianluca, Brennan, Paul, Lagiou, Pagona, and Trichopoulos, Dimitrios
Abstract: Background: The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival. Methods: The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested within the Melbourne Collaborative Cohort Study (MCCS). Plasma concentrations of vitamin B2, vitamin B6, folate, vitamin B12, methionine and homocysteine were measured in prediagnostic samples and evaluated with respect to RCC risk using conditional and unconditional logistic regression models, and to all-cause mortality in RCC cases using Cox regression models. All statistical tests were two-sided. Results: EPIC participants with higher plasma concentrations of vitamin B6 had lower risk of RCC, the odds ratio comparing the 4th and 1st quartiles (OR4vs1) being 0.40 95% confidence interval [CI] = 0.28 to 0.57, P trend < .001. We found similar results after adjusting for potential confounders (adjusted P trend < .001). In survival analysis, the hazard ratio for all-cause mortality in RCC cases when comparing the 4th and 1st quartiles (HR4vs1) of vitamin B6 was 0.57 (95% CI = 0.37 to 0.87, P trend < .001). Subsequent replication of these associations within the MCCS yielded very similar results for both RCC risk (OR4vs1 = 0.47, 95% CI = 0.23 to 0.99, P trend = .07) and all-cause mortality (HR4vs1 = 0.56, 95% CI = 0.27 to 1.17, P trend = .02). No association was evident for the other measured biomarkers. Conclusion: Study participants with higher circulating concentrations of vitamin B6 had lower risk of RCC and improved survival following diagnosis in two independent cohorts., Version of Record
Published: 2014
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20. 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, 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, Zucca, Mariagrazia, Bertrand, Kimberly, 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, Laden, Francine, Giovannucci, Edward, Kraft, Phillip, 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 Jr, Joseph F., Slager, Susan L., Wu, Xifeng, de Sanjose, Silvia, Smedby, Karin E., Salles, Gilles, Skibola, Christine F., Rothman, Nathaniel, and Chanock, Stephen J.
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 three new genome-wide association studies (GWAS) and one prior scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of nine 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; \(P=2.33x10^{-21}\)), rs2523607 at 6p21.33 (HLA-B; \(2.40x10^{-10}\)), rs79480871 at 2p23.3 (NCOA1; \(P=4.23x10^{-8}\)), and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; \(P=9.98x10^{-13}\) and \(P=3.63x10^{-11}\), respectively). These data provide substantial new evidence for genetic susceptibility to this B-cell malignancy, and point towards pathways involved in immune recognition and immune function in the pathogenesis of DLBCL., Accepted Manuscript
Published: 2014
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21. Polymorphisms of an Innate Immune Gene, Toll-Like Receptor 4, and Aggressive Prostate Cancer Risk: A Systematic Review and Meta-Analysis

Author: Weng, Pei-Hsuan, Huang, Yi-Ling, Page, John H., Chen, Jen-Hau, Xu, Jianfeng, Koutros, Stella, Berndt, Sonja, Chanock, Stephen, Yeager, Meredith, Witte, John S., Eeles, Rosalind A., Easton, Douglas F., Neal, David E., Donovan, Jenny, Hamdy, Freddie C., Muir, Kenneth R., Giles, Graham, Severi, Gianluca, Smith, Jeffrey R., Balistreri, Carmela R., Chen, Yen-Ching, and Shui, Irene
Subjects: Biology and Life Sciences, Evolutionary Biology, Population Genetics, Genetic Polymorphism, Genetics, Cancer Genetics, Physical Sciences, Mathematics, Statistics (Mathematics), Statistical Methods, Meta-Analysis, Systematic Reviews
Abstract: Background: Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews. Methods: We performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls. Results: Using random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity. Conclusions: TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa., Version of Record
Published: 2014
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22. Circulating Fatty Acids and Prostate Cancer Risk: Individual Participant Meta-Analysis of Prospective Studies

Author: Crowe, Francesca L., Appleby, Paul N., Travis, Ruth C., Barnett, Matt, Brasky, Theodore M., Bueno-de-Mesquita, H. Bas, Chajes, Veronique, Chirlaque, Maria-Dolores, English, Dallas R., Gibson, Robert A., Giles, Graham G., Goodman, Gary E., Henning, Susanne M., Kaaks, Rudolf, King, Irena B., Kolonel, Lawrence N., Kristal, Alan R., Neuhouser, Marian L., Park, Song-Yi, Severi, Gianluca, Siddiq, Afshan, Stattin, Pär, Tangen, Catherine M., Tjønneland, Anne, Tumino, Rosario, Wilkens, Lynne R., Key, Timothy J., Allen, Naomi E., Chavarro, Jorge, Stampfer, Meir, and Trichopoulos, Dimitrios
Abstract: Background: Individual studies have suggested that some circulating fatty acids are associated with prostate cancer risk, but have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. Methods: Principal investigators of prospective studies on circulating fatty acids and prostate cancer were invited to collaborate. Investigators provided individual participant data on circulating fatty acids (weight percent) and other characteristics of prostate cancer cases and controls. Prostate cancer risk by study-specific fifths of 14 fatty acids was estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. Results: Five thousand and ninety-eight case patients and 6649 control patients from seven studies with an average follow-up of 5.1 (SD = 3.3) years were included. Stearic acid (18:0) was inversely associated with total prostate cancer (odds ratio [OR] Q5 vs Q1 = 0.88, 95% confidence interval [CI] = 0.78 to 1.00, P trend = .043). Prostate cancer risk was, respectively, 14% and 16% greater in the highest fifth of eicosapentaenoic acid (20:5n-3) (OR = 1.14, 95% CI = 1.01 to 1.29, P trend = .001) and docosapentaenoic acid (22:5n-3) (OR = 1.16, 95% CI = 1.02 to 1.33, P trend = .003), but in each case there was heterogeneity between studies (P = .022 and P < .001, respectively). There was heterogeneity in the association between docosapentaenoic acid and prostate cancer by grade of disease (P = .006); the association was statistically significant for low-grade disease but not high-grade disease. The remaining 11 fatty acids were not statistically associated with total prostate cancer risk. Conclusion: There was no strong evidence that circulating fatty acids are important predictors of prostate cancer risk. It is not clear whether the modest associations of stearic, eicosapentaenoic, and docosapentaenoic acid are causal., Version of Record
Published: 2014
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23. Neural Control and Modulation of Swimming Speed in the Larval Zebrafish

Author: Severi, Kristen E., Portugues, Ruben, Marques, João C., O’Malley, Donald M., Orger, Michael B., and Engert, Florian
Abstract: Vertebrate locomotion at different speeds is driven by descending excitatory connections to central pattern generators in the spinal cord. To investigate how these inputs determine locomotor kinematics, we used whole-field visual motion to drive zebrafish to swim at different speeds. Larvae match the stimulus speed by utilizing more locomotor events, or modifying kinematic parameters such as the duration and speed of swimming bouts, the tail-beat frequency, and the choice of gait. We used laser ablations, electrical stimulation, and activity recordings in descending neurons of the nucleus of the medial longitudinal fasciculus (nMLF) to dissect their contribution to controlling forward movement. We found that the activity of single identified neurons within the nMLF is correlated with locomotor kinematics, and modulates both the duration and oscillation frequency of tail movements. By identifying the contribution of individual supraspinal circuit elements to locomotion kinematics, we build a better understanding of how the brain controls movement., Molecular and Cellular Biology, Accepted Manuscript
Published: 2014
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24. Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study

Author: Johnson, Nichola, Dudbridge, Frank, Orr, Nick, Gibson, Lorna, Jones, Michael E, Schoemaker, Minouk J, Folkerd, Elizabeth J, Haynes, Ben P, Hopper, John L, Southey, Melissa C, Dite, Gillian S, Apicella, Carmel, Schmidt, Marjanka K, Broeks, Annegien, Van’t Veer, Laura J, Atsma, Femke, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Renner, Stefan P, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Guénel, Pascal, Truong, Therese, Cordina, Emilie, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Flyger, Henrik, Milne, Roger, Zamora, M Pilar, Arias Perez, Jose Ignacio, Benitez, Javier, Bernstein, Leslie, Anton-Culver, Hoda, Ziogas, Argyrios, Clarke Dur, Christina, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Dieffenbach, Aida Karina, Meindl, Alfons, Heil, Joerg, Bartram, Claus R, Schmutzler, Rita K, Brauch, Hiltrud, Justenhoven, Christina, Ko, Yon-Dschun, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Dörk, Thilo, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Chenevix-Trench, Georgia, Beesley, Jonathan, Wu, Anna H, Van den Berg, David, Tseng, Chiu-Chen, Lambrechts, Diether, Smeets, Dominiek, Neven, Patrick, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Nickels, Stefan, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Pensotti, Valeria, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Pankratz, Vernon S, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, Haiman, Chris, Simard, Jacques, Goldberg, Mark S, Labrèche, France, Dumont, Martine, Soucy, Penny, Teo, Soo, Yip, Cheng Har, Phuah, Sze Yee, Cornes, Belinda K, Kristensen, Vessela N, Grenaker Alnæs, Grethe, Børresen-Dale, Anne-Lise, Zheng, Wei, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Andrulis, Irene L, Knight, Julia A, Glendon, Gord, Mulligan, Anna Marie, Devillee, Peter, Figueroa, Jonine, Chanock, Stephen J, Lissowska, Jolanta, Sherman, Mark E, Hall, Per, Schoof, Nils, Hooning, Maartje, Hollestelle, Antoinette, Oldenburg, Rogier A, Tilanus-Linthorst, Madeleine, Liu, Jianjun, Cox, Angie, Brock, Ian W, Reed, Malcolm WR, Cross, Simon S, Blot, William, Pharoah, Paul DP, Dunning, Alison M, Shah, Mitul, Kang, Daehee, Noh, Dong-Young, Park, Sue K, Choi, Ji-Yeob, Hartman, Mikael, Miao, Hui, Lim, Wei Yen, Tang, Anthony, Hamann, Ute, Försti, Asta, Rüdiger, Thomas, Ulmer, Hans Ulrich, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Sangrajrang, Suleeporn, Gaborieau, Valerie, Brennan, Paul, McKay, James, Slager, Susan, Toland, Amanda E, Vachon, Celine, Yannoukakos, Drakoulis, Shen, Chen-Yang, Yu, Jyh-Cherng, Huang, Chiun-Sheng, Hou, Ming-Feng, González-Neira, Anna, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Luccarini, Craig, Dennis, Joe, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Jean, Easton, Douglas F, García-Closas, Montserrat, Dowsett, Mitch, Ashworth, Alan, Swerdlow, Anthony J, Peto, Julian, dos Santos Silva, Isabel, Fletcher, Olivia, and Signorello, Lisa B
Abstract: Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29). Conclusions: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels., Version of Record
Published: 2014
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25. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Author: Al Olama, Ali Amin, Kote-Jarai, Zsofia, Berndt, Sonja I., Conti, David V., Schumacher, Fredrick, Han, Ying, Benlloch, Sara, Hazelett, Dennis J., Wang, Zhaoming, Saunders, Ed, Leongamornlert, Daniel, Lindstrom, Sara, Jugurnauth-Little, Sara, Dadaev, Tokhir, Tymrakiewicz, Malgorzata, Stram, Daniel O., Rand, Kristin, Wan, Peggy, Stram, Alex, Sheng, Xin, Pooler, Loreall C., Park, Karen, Xia, Lucy, Tyrer, Jonathan, Kolonel, Laurence N., Le Marchand, Loic, Hoover, Robert N., Machiela, Mitchell J., Yeager, Merideth, Burdette, Laurie, Chung, Charles C., Hutchinson, Amy, Yu, Kai, Goh, Chee, Ahmed, Mahbubl, Govindasami, Koveela, Guy, Michelle, Tammela, Teuvo L.J., Auvinen, Anssi, Wahlfors, Tiina, Schleutker, Johanna, Visakorpi, Tapio, Leinonen, Katri A., Xu, Jianfeng, Aly, Markus, Donovan, Jenny, Travis, Ruth C., Key, Tim J., Siddiq, Afshan, Canzian, Federico, Khaw, Kay-Tee, Takahashi, Atsushi, Kubo, Michiaki, Pharoah, Paul, Pashayan, Nora, Weischer, Maren, Nordestgaard, Borge G., Nielsen, Sune F., Klarskov, Peter, Røder, Martin Andreas, Iversen, Peter, Thibodeau, Stephen N., McDonnell, Shannon K, Schaid, Daniel J, Stanford, Janet L., Kolb, Suzanne, Holt, Sarah, Knudsen, Beatrice, Coll, Antonio Hurtado, Gapstur, Susan M., Diver, W. Ryan, Stevens, Victoria L., Maier, Christiane, Luedeke, Manuel, Herkommer, Kathleen, Rinckleb, Antje E., Strom, Sara S., Pettaway, Curtis, Yeboah, Edward D., Tettey, Yao, Biritwum, Richard B., Adjei, Andrew A., Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P., Cannon-Albright, Lisa, Cybulski, Cezary, Wokołorczyk, Dominika, Kluźniak, Wojciech, Park, Jong, Sellers, Thomas, Lin, Hui-Yi, Isaacs, William B., Partin, Alan W., Brenner, Hermann, Dieffenbach, Aida Karina, Stegmaier, Christa, John, Esther M., Ingles, Sue A., Kittles, Rick A., Murphy, Adam B., Pandha, Hardev, Michael, Agnieszka, Kierzek, Andrzej M., Blot, William, Zheng, Wei, Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Nemesure, Barbara, Carpten, John, Leske, Cristina, Wu, Suh-Yuh, Hennis, Anselm, Kibel, Adam S., Rybicki, Benjamin A., Neslund-Dudas, Christine, Hsing, Ann W., Chu, Lisa, Goodman, Phyllis J., Klein, Eric A, Zheng, S. Lilly, Batra, Jyotsna, Clements, Judith, Spurdle, Amanda, Teixeira, Manuel R., Paulo, Paula, Maia, Sofia, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Witte, John S., Casey, Graham, Gillanders, Elizabeth M., Seminara, Daniella, Riboli, Elio, Hamdy, Freddie C., Coetzee, Gerhard A., Li, Qiyuan, Freedman, Matthew L., Muir, Kenneth, Gronberg, Henrik, Neal, David E., Southey, Melissa, Giles, Graham G., Severi, Gianluca, Cook, Michael B., Nakagawa, Hidewaki, Wiklund, Fredrik, Chanock, Stephen J., Henderson, Brian E., Easton, Douglas F., Eeles, Rosalind A., Haiman, Christopher A., Turman, Constance, Giovannucci, Edward, Ma, Jing, Stampfer, Meir, Penney, Kathryn, Mucci, Lorelei, Signorello, Lisa B, Hunter, David, and Kraft, Phillip
Abstract: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three novel susceptibility loci were revealed at P<5×10-8; 15 variants were identified among men of European ancestry, 7 from multiethnic analyses and one was associated with early-onset prostate cancer. These 23 variants, in combination with the known prostate cancer risk variants, explain 33% of the familial risk of the disease in European ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the utility of combining ancestrally diverse populations to discover risk loci for disease., Version of Record
Published: 2014
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26. A Genome-Wide 'Pleiotropy Scan' Does Not Identify New Susceptibility Loci for Estrogen Receptor Negative Breast Cancer

Author: Campa, Daniele, Barrdahl, Myrto, Tsilidis, Konstantinos K., Severi, Gianluca, Diver, W. Ryan, Siddiq, Afshan, Chanock, Stephen, Hoover, Robert N., Ziegler, Regina G., Berg, Christine D., Buys, Saundra S., Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick R., Le Marchand, Loïc, Flesch-Janys, Dieter, Lindström, Sara, Cox, David G., Khaw, Kay-Tee, Tjønneland, Anne, Dossus, Laure, Panico, Salvatore, van Gils, Carla H., Weiderpass, Elisabete, Barricarte, Aurelio, Sund, Malin, Gaudet, Mia M., Giles, Graham, Southey, Melissa, Baglietto, Laura, Chang-Claude, Jenny, Kaaks, Rudolf, Canzian, Federico, Hunter, David, Hankinson, Susan, Willett, Walter, Kraft, Phillip, and Trichopoulos, Dimitrios
Subjects: Biology, Genetics, Human Genetics, Genetic Association Studies, Genome-Wide Association Studies, Population Genetics, Genetic Polymorphism, Cancer Genetics, Population Biology, Epidemiology, Genetic Epidemiology, Medicine, Cancer Epidemiology, Obstetrics and Gynecology, Breast Cancer, Oncology, Cancers and Neoplasms, Breast Tumors
Abstract: Approximately 15–30% of all breast cancer tumors are estrogen receptor negative (ER−). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5×10−8) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER− cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER− breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3×10−4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a “pleiotropic approach”., Version of Record
Published: 2014
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27. Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer

Author: Saunders, Edward J., Dadaev, Tokhir, Leongamornlert, Daniel A., Jugurnauth-Little, Sarah, Tymrakiewicz, Malgorzata, Wiklund, Fredrik, Al Olama, Ali Amin, Benlloch, Sara, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Giles, Graham G., Severi, Gianluca, Gronberg, Henrik, Aly, Markus, Haiman, Christopher A., Schumacher, Fredrick, Henderson, Brian E., Lindstrom, Sara, Gapstur, Susan, Chanock, Stephen, Berndt, Sonja I., Albanes, Demetrius, Andriole, Gerald, Schleutker, Johanna, Weischer, Maren, Nordestgaard, Børge G., Canzian, Federico, Campa, Daniele, Riboli, Elio, Key, Tim J., Travis, Ruth C., Ingles, Sue A., John, Esther M., Hayes, Richard B., Pharoah, Paul, Khaw, Kay-Tee, Stanford, Janet L., Ostrander, Elaine A., Signorello, Lisa B., Thibodeau, Stephen N., Schaid, Daniel, Maier, Christiane, Kibel, Adam S., Cybulski, Cezary, Cannon-Albright, Lisa, Brenner, Hermann, Park, Jong Y., Kaneva, Radka, Batra, Jyotsna, Clements, Judith A., Teixeira, Manuel R., Xu, Jianfeng, Mikropoulos, Christos, Goh, Chee, Govindasami, Koveela, Guy, Michelle, Wilkinson, Rosemary A., Sawyer, Emma J., Morgan, Angela, Easton, Douglas F., Muir, Ken, Eeles, Rosalind A., Kote-Jarai, Zsofia, Kraft, Phillip, and Hunter, David
Subjects: Biology, Genetics, Cancer genetics
Abstract: The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10−14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility., Version of Record
Published: 2014
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28. A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

Author: Olama, Ali Amin Al, Kote-Jarai, Zsofia, Schumacher, Fredrick, Wiklund, Fredrik, Berndt, Sonja, Benlloch, Sara, Giles, Graham, Severi, Gianluca, Neal, David, Hamdy, Freddie, Donovan, Jenny, Hunter, David, Henderson, Brian, Thun, Michael, Gaziano, Michael, Giovannucci, Edward, Siddiq, Afshan, Travis, Ruth, Cox, David, Canzian, Federico, Riboli, Elio, Key, Timothy, Andriole, Gerald, Albanes, Demetrius, Hayes, Richard, Schleutker, Johanna, Auvinen, Anssi, Tammela, Teuvo L. J., Weischer, Maren, Stanford, Janet, Ostrander, Elaine, Cybulski, Cezary, Lubinski, Jan, Thibodeau, Stephen, Schaid, Daniel, Sorensen, Karina, Batra, Jyotsna, Clements, Judith, Chambers, Suzanne, Aitken, Joanne, Gardiner, Robert, Maier, Christiane, Vogel, Walther, Dörk, Thilo, Brenner, Hermann, Habuchi, Tomonori, Ingles, Sue, John, Esther, Dickinson, Joanne, Cannon-Albright, Lisa, Teixeira, Manuel, Kaneva, Radka, Zhang, Hong-Wei, Lu, Yong-Jie, Park, Jong, Cooney, Kathleen, Muir, Kenneth, Leongamornlert, Daniel, Saunders, Edward, Tymrakiewicz, Malgorzata, Mahmud, Nadiya, Guy, Michelle, Govindasami, Koveela, O'Brien, Lynne T., Wilkinson, Rosemary, Hall, Amanda, Sawyer, Emma, Dadaev, Tokhir, Morrison, Jonathan, Dearnaley, David, Horwich, Alan, Huddart, Robert, Khoo, Vincent, Parker, Christopher, Van As, Nicholas, Woodhouse, Christopher, Thompson, Alan, Dudderidge, Tim, Ogden, Chris, Cooper, Colin, Lophatonanon, Artitaya, Southey, Melissa, Hopper, John, English, Dallas, Virtamo, Jarmo, Le Marchand, Loic, Campa, Daniele, Kaaks, Rudolf, Lindstrom, Sara, Diver, W. Ryan, Gapstur, Susan, Yeager, Meredith, Cox, Angela, Stern, Mariana, Corral, Roman, Aly, Markus, Isaacs, William, Adolfsson, Jan, Xu, Jianfeng, and Zheng, S. Lilly
Abstract: Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio 1.12 (95 confidence interval 1.031.21), P 1.4 10(8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis., Version of Record
Published: 2013

29. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Author: Bojesen, Stig E, Pooley, Karen A, Johnatty, Sharon E, Beesley, Jonathan, Michailidou, Kyriaki, Tyrer, Jonathan P, Edwards, Stacey L, Pickett, Hilda A, Shen, Howard C, Smart, Chanel E, Hillman, Kristine M, Mai, Phuong L, Lawrenson, Kate, Stutz, Michael D, Lu, Yi, Karevan, Rod, Woods, Nicholas, Johnston, Rebecca L, French, Juliet D, Chen, Xiaoqing, Weischer, Maren, Nielsen, Sune F, Maranian, Melanie J, Ghoussaini, Maya, Ahmed, Shahana, Baynes, Caroline, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, Healey, Sue, Lush, Michael, Tessier, Daniel C, Vincent, Daniel, Bacot, Françis, Vergote, Ignace, Lambrechts, Sandrina, Despierre, Evelyn, Risch, Harvey A, González-Neira, Anna, Rossing, Mary Anne, Pita, Guillermo, Doherty, Jennifer A, Álvarez, Nuria, Larson, Melissa C, Fridley, Brooke L, Schoof, Nils, Chang-Claude, Jenny, Cicek, Mine S, Peto, Julian, Kalli, Kimberly R, Broeks, Annegien, Armasu, Sebastian M, Schmidt, Marjanka K, Braaf, Linde M, Winterhoff, Boris, Nevanlinna, Heli, Konecny, Gottfried E, Lambrechts, Diether, Rogmann, Lisa, Guénel, Pascal, Teoman, Attila, Milne, Roger L, Garcia, Joaquin J, Cox, Angela, Shridhar, Vijayalakshmi, Burwinkel, Barbara, Marme, Frederik, Hein, Rebecca, Sawyer, Elinor J, Haiman, Christopher A, Wang-Gohrke, Shan, Andrulis, Irene L, Moysich, Kirsten B, Hopper, John L, Odunsi, Kunle, Lindblom, Annika, Giles, Graham G, Brenner, Hermann, Simard, Jacques, Lurie, Galina, Fasching, Peter A, Carney, Michael E, Radice, Paolo, Wilkens, Lynne R, Swerdlow, Anthony, Goodman, Marc T, Brauch, Hiltrud, Garcia-Closas, Montserrat, Hillemanns, Peter, Winqvist, Robert, Dürst, Matthias, Devilee, Peter, Runnebaum, Ingo, Jakubowska, Anna, Lubinski, Jan, Mannermaa, Arto, Butzow, Ralf, Bogdanova, Natalia V, Dörk, Thilo, Pelttari, Liisa M, Zheng, Wei, Leminen, Arto, Anton-Culver, Hoda, Bunker, Clareann H, Kristensen, Vessela, Ness, Roberta B, Muir, Kenneth, Edwards, Robert, Meindl, Alfons, Heitz, Florian, Matsuo, Keitaro, du Bois, Andreas, Wu, Anna H, Harter, Philipp, Teo, Soo-Hwang, Schwaab, Ira, Shu, Xiao-Ou, Blot, William, Hosono, Satoyo, Kang, Daehee, Nakanishi, Toru, Hartman, Mikael, Yatabe, Yasushi, Hamann, Ute, Karlan, Beth Y, Sangrajrang, Suleeporn, Kjaer, Susanne Krüger, Gaborieau, Valerie, Jensen, Allan, Eccles, Diana, Høgdall, Estrid, Shen, Chen-Yang, Brown, Judith, Woo, Yin Ling, Shah, Mitul, Azmi, Mat Adenan Noor, Luben, Robert, Omar, Siti Zawiah, Czene, Kamila, Vierkant, Robert A, Nordestgaard, Børge G, Flyger, Henrik, Vachon, Celine, Olson, Janet E, Wang, Xianshu, Levine, Douglas A, Rudolph, Anja, Weber, Rachel Palmieri, Flesch-Janys, Dieter, Iversen, Edwin, Nickels, Stefan, Schildkraut, Joellen M, Silva, Isabel Dos Santos, Cramer, Daniel, Gibson, Lorna, Terry, Kathryn, Fletcher, Olivia, Vitonis, Allison F, van der Schoot, C Ellen, Poole, Elizabeth M., Hogervorst, Frans B L, Tworoger, Shelley, Liu, Jianjun, Bandera, Elisa V, Li, Jingmei, Olson, Sara H, Humphreys, Keith, Orlow, Irene, Blomqvist, Carl, Rodriguez-Rodriguez, Lorna, Aittomäki, Kristiina, Salvesen, Helga B, Muranen, Taru A, Wik, Elisabeth, Brouwers, Barbara, Krakstad, Camilla, Wauters, Els, Halle, Mari K, Wildiers, Hans, Kiemeney, Lambertus A, Mulot, Claire, Aben, Katja K, Laurent-Puig, Pierre, Altena, Anne Mvan, Truong, Thérèse, Massuger, Leon F A G, Benitez, Javier, Pejovic, Tanja, Perez, Jose Ignacio Arias, Hoatlin, Maureen, Zamora, M Pilar, Cook, Linda S, Balasubramanian, Sabapathy P, Kelemen, Linda E, Schneeweiss, Andreas, Le, Nhu D, Sohn, Christof, Brooks-Wilson, Angela, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Cybulski, Cezary, Henderson, Brian E, Menkiszak, Janusz, Schumacher, Fredrick, Wentzensen, Nicolas, Le Marchand, Loic, Yang, Hannah P, Mulligan, Anna Marie, Glendon, Gord, Engelholm, Svend Aage, Knight, Julia A, Høgdall, Claus K, Apicella, Carmel, Gore, Martin, Tsimiklis, Helen, Song, Honglin, Southey, Melissa C, Jager, Agnes, den Ouweland, Ans M Wvan, Brown, Robert, Martens, John W M, Flanagan, James M, Kriege, Mieke, Paul, James, Margolin, Sara, Siddiqui, Nadeem, Severi, Gianluca, Whittemore, Alice S, Baglietto, Laura, McGuire, Valerie, Stegmaier, Christa, Sieh, Weiva, Müller, Heiko, Arndt, Volker, Labrèche, France, Gao, Yu-Tang, Goldberg, Mark S, Yang, Gong, Dumont, Martine, McLaughlin, John R, Hartmann, Arndt, Ekici, Arif B, Beckmann, Matthias W, Phelan, Catherine M, Lux, Michael P, Permuth-Wey, Jenny, Peissel, Bernard, Sellers, Thomas A, Ficarazzi, Filomena, Barile, Monica, Ziogas, Argyrios, Ashworth, Alan, Gentry-Maharaj, Aleksandra, Jones, Michael, Ramus, Susan J, Orr, Nick, Menon, Usha, Pearce, Celeste L, Brüning, Thomas, Pike, Malcolm C, Ko, Yon-Dschun, Lissowska, Jolanta, Figueroa, Jonine, Kupryjanczyk, Jolanta, Chanock, Stephen J, Dansonka-Mieszkowska, Agnieszka, Jukkola-Vuorinen, Arja, Rzepecka, Iwona K, Pylkäs, Katri, Bidzinski, Mariusz, Kauppila, Saila, Hollestelle, Antoinette, Seynaeve, Caroline, Tollenaar, Rob A E M, Durda, Katarzyna, Jaworska, Katarzyna, Hartikainen, Jaana M, Kosma, Veli-Matti, Kataja, Vesa, Antonenkova, Natalia N, Long, Jirong, Shrubsole, Martha, Deming-Halverson, Sandra, Lophatananon, Artitaya, Siriwanarangsan, Pornthep, Stewart-Brown, Sarah, Ditsch, Nina, Lichtner, Peter, Schmutzler, Rita K, Ito, Hidemi, Iwata, Hiroji, Tajima, Kazuo, Tseng, Chiu-Chen, Stram, Daniel O, van den Berg, David, Yip, Cheng Har, Ikram, M Kamran, Teh, Yew-Ching, Cai, Hui, Lu, Wei, Signorello, Lisa B, Cai, Qiuyin, Noh, Dong-Young, Yoo, Keun-Young, Miao, Hui, Iau, Philip Tsau-Choong, Teo, Yik Ying, McKay, James, Shapiro, Charles, Ademuyiwa, Foluso, Fountzilas, George, Hsiung, Chia-Ni, Yu, Jyh-Cherng, Hou, Ming-Feng, Healey, Catherine S, Luccarini, Craig, Peock, Susan, Stoppa-Lyonnet, Dominique, Peterlongo, Paolo, Rebbeck, Timothy, Piedmonte, Marion, Singer, Christian F, Friedman, Eitan, Thomassen, Mads, Offit, Kenneth, Hansen, Thomas V O, Neuhausen, Susan L, Szabo, Csilla I, Blanco, Ignacio, Garber, Judy, Narod, Steven A, Weitzel, Jeffrey N, Montagna, Marco, Olah, Edith, Godwin, Andrew K, Yannoukakos, Drakoulis, Goldgar, David E, Caldes, Trinidad, Imyanitov, Evgeny N, Tihomirova, Laima, Arun, Banu K, Campbell, Ian, Mensenkamp, Arjen R, van Asperen, Christi J, van Roozendaal, Kees E P, Meijers-Heijboer, Hanne, Collée, J Margriet, Oosterwijk, Jan C, Hooning, Maartje J, Rookus, Matti A, van der Luijt, Rob B, Os, Theo A Mvan, Evans, D Gareth, Frost, Debra, Fineberg, Elena, Barwell, Julian, Walker, Lisa, Kennedy, M John, Platte, Radka, Davidson, Rosemarie, Ellis, Steve D, Cole, Trevor, Bressac-de Paillerets, Brigitte, Buecher, Bruno, Damiola, Francesca, Faivre, Laurence, Frenay, Marc, Sinilnikova, Olga M, Caron, Olivier, Giraud, Sophie, Mazoyer, Sylvie, Bonadona, Valérie, Caux-Moncoutier, Virginie, Toloczko-Grabarek, Aleksandra, Gronwald, Jacek, Byrski, Tomasz, Spurdle, Amanda B, Bonanni, Bernardo, Zaffaroni, Daniela, Giannini, Giuseppe, Bernard, Loris, Dolcetti, Riccardo, Manoukian, Siranoush, Arnold, Norbert, Engel, Christoph, Deissler, Helmut, Rhiem, Kerstin, Niederacher, Dieter, Plendl, Hansjoerg, Sutter, Christian, Wappenschmidt, Barbara, Borg, Åke, Melin, Beatrice, Rantala, Johanna, Soller, Maria, Nathanson, Katherine L, Domchek, Susan M, Rodriguez, Gustavo C, Salani, Ritu, Kaulich, Daphne Gschwantler, Tea, Muy-Kheng, Paluch, Shani Shimon, Laitman, Yael, Skytte, Anne-Bine, Kruse, Torben A, Jensen, Uffe Birk, Robson, Mark, Gerdes, Anne-Marie, Ejlertsen, Bent, Foretova, Lenka, Savage, Sharon A, Lester, Jenny, Soucy, Penny, Kuchenbaecker, Karoline B, Olswold, Curtis, Cunningham, Julie M, Slager, Susan, Pankratz, Vernon S, Dicks, Ed, Lakhani, Sunil R, Couch, Fergus J, Hall, Per, Monteiro, Alvaro N A, Gayther, Simon A, Pharoah, Paul D P, Reddel, Roger R, Goode, Ellen L, Greene, Mark H, Easton, Douglas F, Berchuck, Andrew, Antoniou, Antonis C, Chenevix-Trench, Georgia, and Dunning, Alison M
Abstract: TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant., Accepted Manuscript
Published: 2013
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30. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Author: Earp, Madalene A., Kelemen, Linda E., Magliocco, Anthony M., Swenerton, Kenneth D., Chenevix-Trench, Georgia, Lu, Yi, Hein, Alexander, Ekici, Arif B., Beckmann, Matthias W., Fasching, Peter A., Lambrechts, Diether, Despierre, Evelyn, Vergote, Ignace, Lambrechts, Sandrina, Doherty, Jennifer A., Rossing, Mary Anne, Chang-Claude, Jenny, Rudolph, Anja, Friel, Grace, Moysich, Kirsten B., Odunsi, Kunle, Sucheston-Campbell, Lara, Lurie, Galina, Goodman, Marc T., Carney, Michael E., Thompson, Pamela J., Runnebaum, Ingo B., Dürst, Matthias, Hillemanns, Peter, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M., Butzow, Ralf, Bunker, Clareann H., Modugno, Francesmary, Edwards, Robert P., Ness, Roberta B., du Bois, Andreas, Heitz, Florian, Schwaab, Ira, Harter, Philipp, Karlan, Beth Y., Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjær, Susanne K., Høgdall, Claus K., Høgdall, Estrid, Lundvall, Lene, Sellers, Thomas A., Fridley, Brooke L., Goode, Ellen L., Cunningham, Julie M., Vierkant, Robert A., Giles, Graham G., Baglietto, Laura, Severi, Gianluca, Southey, Melissa C., Liang, Dong, Wu, Xifeng, Lu, Karen, Hildebrandt, Michelle A. T., Levine, Douglas A., Bisogna, Maria, Schildkraut, Joellen M., Iversen, Edwin S., Weber, Rachel Palmieri, Berchuck, Andrew, Cramer, Daniel, Terry, Kathryn, Poole, Elizabeth M., Tworoger, Shelley, Bandera, Elisa V., Chandran, Urmila, Orlow, Irene, Olson, Sara H., Wik, Elisabeth, Salvesen, Helga B., Bjorge, Line, Halle, Mari K., van Altena, Anne M., Aben, Katja K. H., Kiemeney, Lambertus A., Massuger, Leon F. A. G., Pejovic, Tanja, Bean, Yukie T., Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Wentzensen, Nicolas, Brinton, Louise A., Lissowska, Jolanta, Garcia-Closas, Montserrat, Dicks, Ed, Dennis, Joe, Easton, Douglas F., Song, Honglin, Tyrer, Jonathan P., Pharoah, Paul D. P., Eccles, Diana, Campbell, Ian G., Whittemore, Alice S., McGuire, Valerie, Sieh, Weiva, Rothstein, Joseph H., Flanagan, James M., Paul, James, Brown, Robert, Phelan, Catherine M., Risch, Harvey A., McLaughlin, John R., Narod, Steven A., Ziogas, Argyrios, Anton-Culver, Hoda, Gentry-Maharaj, Aleksandra, Menon, Usha, Gayther, Simon A., Ramus, Susan J., Wu, Anna H., Pearce, Celeste L., Pike, Malcolm C., Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K., Szafron, Lukasz M., Kupryjanczyk, Jolanta, Cook, Linda S., Le, Nhu D., and Brooks-Wilson, Angela
Subjects: histological subtype, serous, endometrioid, clear cell, mucinous, BPIL2
Abstract: Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS (56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low malignant potential (LMP) serous, and 24 for invasive serous EOC), selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95% confidence intervals are reported. Nine variants tagging 6 loci were associated with subtype-specific EOC risk at P<0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR=1.17, P=0.029, n=1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P=0.014, n=2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR=0.86, P=0.0043, n=892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR=0.84, P=0.0007) and LMP serous EOC risk remained statistically significant at P<0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes., Accepted Manuscript
Published: 2013
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31. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Author: Shen, Hui, Fridley, Brooke L., Song, Honglin, Lawrenson, Kate, Cunningham, Julie M., Ramus, Susan J., Cicek, Mine S., Tyrer, Jonathan, Stram, Douglas, Larson, Melissa C., Köbel, Martin, Ziogas, Argyrios, Zheng, Wei, Yang, Hannah P., Wu, Anna H., Wozniak, Eva L., Ling Woo, Yin, Winterhoff, Boris, Wik, Elisabeth, Whittemore, Alice S., Wentzensen, Nicolas, Palmieri Weber, Rachel, Vitonis, Allison F., Vincent, Daniel, Vierkant, Robert A., Vergote, Ignace, Van Den Berg, David, Van Altena, Anne M., Tworoger, Shelley, Thompson, Pamela J., Tessier, Daniel C., Terry, Kathryn, Teo, Soo-Hwang, Templeman, Claire, Stram, Daniel O., Southey, Melissa C., Sieh, Weiva, Siddiqui, Nadeem, Shvetsov, Yurii B., Shu, Xiao-Ou, Shridhar, Viji, Wang-Gohrke, Shan, Severi, Gianluca, Schwaab, Ira, Salvesen, Helga B., Rzepecka, Iwona K., Runnebaum, Ingo B., Anne Rossing, Mary, Rodriguez-Rodriguez, Lorna, Risch, Harvey A., Renner, Stefan P., Poole, Elizabeth M., Pike, Malcolm C., Phelan, Catherine M., Pelttari, Liisa M., Pejovic, Tanja, Paul, James, Orlow, Irene, Zawiah Omar, Siti, Olson, Sara H., Odunsi, Kunle, Nickels, Stefan, Nevanlinna, Heli, Ness, Roberta B., Narod, Steven A., Nakanishi, Toru, Moysich, Kirsten B., Monteiro, Alvaro N.A., Moes-Sosnowska, Joanna, Modugno, Francesmary, Menon, Usha, McLaughlin, John R., McGuire, Valerie, Matsuo, Keitaro, Mat Adenan, Noor Azmi, Massuger, Leon F.A.G, Lurie, Galina, Lundvall, Lene, Lubiński, Jan, Lissowska, Jolanta, Levine, Douglas A., Leminen, Arto, Lee, Alice W., Le, Nhu D., Lambrechts, Sandrina, Lambrechts, Diether, Kupryjanczyk, Jolanta, Krakstad, Camilla, Konecny, Gottfried E., Krüger Kjaer, Susanne, Kiemeney, Lambertus A., Kelemen, Linda E., Keeney, Gary L., Karlan, Beth Y., Karevan, Rod, Kalli, Kimberly R., Kajiyama, Hiroaki, Ji, Bu-Tian, Jensen, Allan, Jakubowska, Anna, Iversen, Edwin, Hosono, Satoyo, Høgdall, Claus K., Høgdall, Estrid, Hoatlin, Maureen, Hillemanns, Peter, Heitz, Florian, Hein, Rebecca, Harter, Philipp, Halle, Mari K., Hall, Per, Gronwald, Jacek, Gore, Martin, Goodman, Marc T., Giles, Graham G., Gentry-Maharaj, Aleksandra, Garcia-Closas, Montserrat, Flanagan, James M., Fasching, Peter A., Ekici, Arif B., Edwards, Robert, Eccles, Diana, Easton, Douglas F., Dürst, Matthias, du Bois, Andreas, Dörk, Thilo, Doherty, Jennifer A., Despierre, Evelyn, Dansonka-Mieszkowska, Agnieszka, Cybulski, Cezary, Cramer, Daniel, Cook, Linda S., Chen, Xiaoqing, Charbonneau, Bridget, Chang-Claude, Jenny, Campbell, Ian, Butzow, Ralf, Bunker, Clareann H., Brueggmann, Doerthe, Brown, Robert, Brooks-Wilson, Angela, Brinton, Louise A., Bogdanova, Natalia, Block, Matthew S., Benjamin, Elizabeth, Beesley, Jonathan, Beckmann, Matthias W., Bandera, Elisa V., Baglietto, Laura, Bacot, François, Armasu, Sebastian M., Antonenkova, Natalia, Anton-Culver, Hoda, Aben, Katja K., Liang, Dong, Wu, Xifeng, Lu, Karen, Hildebrandt, Michelle A.T., Schildkraut, Joellen M., Sellers, Thomas A., Huntsman, David, Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Pharoah, Paul D.P., Laird, Peter W., Goode, Ellen L., and Leigh Pearce, Celeste
Abstract: HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 × 10−10) and clear cell (rs11651755 OR = 0.77, P = 1.6 × 10−8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes., Version of Record
Published: 2013
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32. Risk of Ovarian Cancer and the NF- B Pathway: Genetic Association with IL1A and TNFSF10

Author: Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, Shelley, Poole, Elizabeth M., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A. S., Sieh, W., Chang-Claude, J., Bandera, E. V., Orlow, I., Terry, Kathryn, Goodman, M. T., Thompson, P. J., Cook, L. S., Rossing, M. A., Ness, R. B., Narod, S. A., Kupryjanczyk, J., Lu, K., Butzow, R., Dork, T., Pejovic, T., Campbell, I., Le, N. D., Bunker, C. H., Bogdanova, N., Runnebaum, I. B., Eccles, D., Paul, J., Wu, A. H., Gayther, S. A., Hogdall, E., Heitz, F., Kaye, S. B., Karlan, B. Y., Anton-Culver, H., Gronwald, J., Hogdall, C. K., Lambrechts, D., Fasching, P. A., Menon, U., Schildkraut, J., Pearce, C. L., Levine, D. A., Kjaer, S. K., Cramer, Daniel, Flanagan, J. M., Phelan, C. M., Brown, Robert, Massuger, L. F. A. G., Song, H., Doherty, J. A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y. T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S. H., Harter, P., Tyrer, J., Vitonis, A. F., Brooks-Wilson, A., Aben, K. K., Pike, M. C., Ramus, S. J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, Robert, McGuire, V., Lester, J., du Bois, A., Lundvall, L., Wang-Gohrke, S., Szafron, L. M., Lambrechts, S., Yang, H., Beckmann, M. W., Pelttari, L. M., Van Altena, A. M., van den Berg, D., Halle, M. K., Gentry-Maharaj, A., Schwaab, I., Chandran, U., Menkiszak, J., Ekici, A. B., Wilkens, L. R., Leminen, A., Modugno, F., Friel, G., Rothstein, J. H., Vergote, I., Garcia-Closas, M., Hildebrandt, M. A. T., Sobiczewski, P., Kelemen, L. E., Pharoah, P. D. P., Moysich, K., Knutson, K. L., Cunningham, J. M., Fridley, B. L., and Goode, E. L.
Subjects: clear cell, endometrioid, case-control, single nucleotide polymorphism, IL-1α
Abstract: A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted., Other Research Unit, Accepted Manuscript
Published: 2013
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33. Genome-wide association analysis identifies three new breast cancer susceptibility loci

Author: Ghoussaini, Maya, Fletcher, Olivia, Michailidou, Kyriaki, Turnbull, Clare, Schmidt, Marjanka K, Dicks, Ed, Dennis, Joe, Wang, Qin, Humphreys, Manjeet K, Luccarini, Craig, Baynes, Caroline, Conroy, Don, Maranian, Melanie, Ahmed, Shahana, Driver, Kristy, Johnson, Nichola, Orr, Nicholas, Silva, Isabel dos Santos, Waisfisz, Quinten, Meijers-Heijboer, Hanne, Uitterlinden, Andre G., Rivadeneira, Fernando, Hall, Per, Czene, Kamila, Irwanto, Astrid, Liu, Jianjun, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Meindl, Alfons, Schmutzler, Rita K, Müller-Myhsok, Bertram, Lichtner, Peter, Chang-Claude, Jenny, Hein, Rebecca, Nickels, Stefan, Flesch-Janys, Dieter, Tsimiklis, Helen, Makalic, Enes, Schmidt, Daniel, Bui, Minh, Hopper, John L, Apicella, Carmel, Park, Daniel J, Southey, Melissa, Hunter, David, Chanock, Stephen J, Broeks, Annegien, Verhoef, Senno, Hogervorst, Frans BL, Fasching, Peter A., Lux, Michael P., Beckmann, Matthias W., Ekici, Arif B., Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Cordina-Duverger, Emilie, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L., Alonso, M. Rosario, González-Neira, Anna, Benítez, Javier, Anton-Culver, Hoda, Ziogas, Argyrios, Bernstein, Leslie, Dur, Christina Clarke, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Justenhoven, Christina, Brauch, Hiltrud, Brüning, Thomas, Wang-Gohrke, Shan, Eilber, Ursula, Dörk, Thilo, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Bogdanova, Natalia V., Antonenkova, Natalia N., Rogov, Yuri I., Karstens, Johann H., Bermisheva, Marina, Prokofieva, Darya, Khusnutdinova, Elza, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Lambrechts, Diether, Yesilyurt, Betul T., Floris, Giuseppe, Leunen, Karin, Manoukian, Siranoush, Bonanni, Bernardo, Fortuzzi, Stefano, Peterlongo, Paolo, Couch, Fergus J, Wang, Xianshu, Stevens, Kristen, Lee, Adam, Giles, Graham G., Baglietto, Laura, Severi, Gianluca, McLean, Catriona, Alnæs, Grethe Grenaker, Kristensen, Vessela, Børrensen-Dale, Anne-Lise, John, Esther M., Miron, A, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Kauppila, Saila, Andrulis, Irene L., Glendon, Gord, Mulligan, Anna Marie, Devilee, Peter, van Asperen, Christie J., Tollenaar, Rob A.E.M., Seynaeve, Caroline, Figueroa, Jonine D, Garcia-Closas, Montserrat, Brinton, Louise, Lissowska, Jolanta, Hooning, Maartje J., Hollestelle, Antoinette, Oldenburg, Rogier A., van den Ouweland, Ans M.W., Cox, Angela, Reed, Malcolm WR, Shah, Mitul, Jakubowska, Ania, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Jones, Michael, Schoemaker, Minouk, Ashworth, Alan, Swerdlow, Anthony, Beesley, Jonathan, Chen, Xiaoqing, Muir, Kenneth R, Lophatananon, Artitaya, Rattanamongkongul, Suthee, Chaiwerawattana, Arkom, Kang, Daehee, Yoo, Keun-Young, Noh, Dong-Young, Shen, Chen-Yang, Yu, Jyh-Cherng, Wu, Pei-Ei, Hsiung, Chia-Ni, Perkins, Annie, Swann, Ruth, Velentzis, Louiza, Eccles, Diana M, Tapper, Will J, Gerty, Susan M, Graham, Nikki J, Ponder, Bruce A. J., Chenevix-Trench, Georgia, Pharoah, Paul D.P., Lathrop, Mark, Dunning, Alison M., Rahman, Nazneen, Peto, Julian, and Easton, Douglas F
Abstract: Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ~ 8% of the heritability of the disease. We followed up 72 promising associations from two independent Genome Wide Association Studies (GWAS) in ~70,000 cases and ~68,000 controls from 41 case-control studies and nine breast cancer GWAS. We identified three new breast cancer risk loci on 12p11 (rs10771399; P=2.7 × 10−35), 12q24 (rs1292011; P=4.3×10−19) and 21q21 (rs2823093; P=1.1×10−12). SNP rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) plays a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, while NRIP1 (21q21) encodes an ER co-factor and has a role in the regulation of breast cancer cell growth., Accepted Manuscript
Published: 2013
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34. Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia

Author: Berndt, Sonja I., Skibola, Christine F., Joseph, Vijai, Camp, Nicola J., Nieters, Alexandra, Wang, Zhaoming, Cozen, Wendy, Monnereau, Alain, Wang, Sophia S., Kelly, Rachel S., Lan, Qing, Teras, Lauren R., Chatterjee, Nilanjan, Chung, Charles C., Yeager, Meredith, Brooks-Wilson, Angela R., Hartge, Patricia, Purdue, Mark P., Armstrong, Bruce K., Cocco, Pierluigi, Zhang, Yawei, Severi, Gianluca, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Burdette, Laurie, Yuenger, Jeffrey, Hutchinson, Amy, Jacobs, Kevin B., Call, Timothy G., Shanafelt, Tait D., Novak, Anne J., Kay, Neil E., Liebow, Mark, Wang, Alice H., Smedby, Karin E, Melbye, Mads, Glimelius, Bengt, Chang, Ellen T., Glenn, Martha, Curtin, Karen, Cannon-Albright, Lisa A., Jones, Brandt, Diver, W. Ryan, Link, Brian K., Weiner, George J., Conde, Lucia, Bracci, Paige M., Riby, Jacques, Holly, Elizabeth A., Smith, Martyn T., Jackson, Rebecca D., Tinker, Lesley F., Benavente, Yolanda, Becker, Nikolaus, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, Rabe, Kari G., Achenbach, Sara J., Vachon, Celine M., Goldin, Lynn R, Strom, Sara S., Lanasa, Mark C., Spector, Logan G., Leis, Jose F., Cunningham, Julie M., Weinberg, J. Brice, Morrison, Vicki A., Caporaso, Neil E., Norman, Aaron D., Linet, Martha S., De Roos, Anneclaire J., Morton, Lindsay M., Severson, Richard K., Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Masala, Giovanna, Weiderpass, Elisabete, Chirlaque, María-Dolores, Vermeulen, Roel C H, Travis, Ruth C., Giles, Graham G., Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Clavel, Jacqueline, Zheng, Tongzhang, Holford, Theodore R, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J., Spinelli, John J., Kricker, Anne, Turner, Jenny, Vajdic, Claire M., Ennas, Maria Grazia, Ferri, Giovanni M., Miligi, Lucia, Sampson, Joshua, Crouch, Simon, Park, Ju-hyun, North, Kari E., Cox, Angela, Snowden, John A., Wright, Josh, Carracedo, Angel, Lopez-Otin, Carlos, Bea, Silvia, Salaverria, Itziar, Martin, David, Campo, Elias, Fraumeni, Joseph F., de Sanjose, Silvia, Hjalgrim, Henrik, Cerhan, James R., Chanock, Stephen J., Rothman, Nathaniel, Slager, Susan L., Birmann, Brenda, Adami, Hans-Olov, Trichopoulos, Dimitrios, Bertrand, Kimberly, Laden, Francine, Giovannucci, Edward, Kraft, Phillip, and Liang, Liming
Abstract: Version of Record
Published: 2013
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35. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

Author: Pharoah, Paul D. P., Tsai, Ya-Yu, Ramus, Susan J., Phelan, Catherine M., Goode, Ellen L., Lawrenson, Kate, Price, Melissa, Fridley, Brooke L., Tyrer, Jonathan P., Shen, Howard, Weber, Rachel, Karevan, Rod, Larson, Melissa C., Song, Honglin, Tessier, Daniel C., Bacot, François, Vincent, Daniel, Cunningham, Julie M., Dennis, Joe, Dicks, Ed, Aben, Katja K., Anton-Culver, Hoda, Antonenkova, Natalia, Armasu, Sebastian M., Baglietto, Laura, Bandera, Elisa V., Beckmann, Matthias W., Bloom, Greg, Bogdanova, Natalia, Brenton, James D., Brinton, Louise A., Brooks-Wilson, Angela, Brown, Robert, Butzow, Ralf, Campbell, Ian, Carney, Michael E, Carvalho, Renato S., Chang-Claude, Jenny, Chen, Y. Anne, Chen, Zhihua, Chow, Wong-Ho, Cicek, Mine S., Coetzee, Gerhard, Cook, Linda S., Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Edwards, Robert, Ekici, Arif B., Fasching, Peter A., Fenstermacher, David, Flanagan, James, Gao, Yu-Tang, Garcia-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Giles, Graham, Gjyshi, Anxhela, Gore, Martin, Gronwald, Jacek, Guo, Qi, Halle, Mari K, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hillemanns, Peter, Hoatlin, Maureen, Høgdall, Estrid, Høgdall, Claus K., Hosono, Satoyo, Jakubowska, Anna, Jensen, Allan, Kalli, Kimberly R., Karlan, Beth Y., Kelemen, Linda E., Kiemeney, Lambertus A., Kjaer, Susanne Krüger, Konecny, Gottfried E., Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D., Lee, Nathan, Lee, Janet, Leminen, Arto, Lim, Boon Kiong, Lissowska, Jolanta, Lubiński, Jan, Lundvall, Lene, Lurie, Galina, Massuger, Leon F.A.G., Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B., Nakanishi, Toru, Narod, Steven A., Ness, Roberta B., Nevanlinna, Heli, Nickels, Stefan, Noushmehr, Houtan, Odunsi, Kunle, Olson, Sara, Orlow, Irene, Paul, James, Pejovic, Tanja, Pelttari, Liisa M, Permuth-Wey, Jenny, Pike, Malcolm C, Qu, Xiaotao, Risch, Harvey A., Rodriguez-Rodriguez, Lorna, Rossing, Mary Anne, Rudolph, Anja, Runnebaum, Ingo, Rzepecka, Iwona K, Salvesen, Helga B., Schwaab, Ira, Severi, Gianluca, Shen, Hui, Shridhar, Vijayalakshmi, Shu, Xiao-Ou, Sieh, Weiva, Southey, Melissa C., Spellman, Paul, Tajima, Kazuo, Teo, Soo-Hwang, Thompson, Pamela J, Timorek, Agnieszka, van Altena, Anne M., Berg, David Van Den, Vergote, Ignace, Vierkant, Robert A., Vitonis, Allison F., Wang-Gohrke, Shan, Wentzensen, Nicolas, Whittemore, Alice S., Wik, Elisabeth, Winterhoff, Boris, Woo, Yin Ling, Wu, Anna H, Yang, Hannah P., Zheng, Wei, Ziogas, Argyrios, Zulkifli, Famida, Goodman, Marc T., Hall, Per, Easton, Douglas F, Pearce, Celeste L, Berchuck, Andrew, Chenevix-Trench, Georgia, Iversen, Edwin, Monteiro, Alvaro N.A., Gayther, Simon A., Schildkraut, Joellen M., Sellers, Thomas A., Birrer, Michael J., Cramer, Daniel, Poole, Elizabeth M., Terry, Kathryn, and Tworoger, Shelley
Abstract: Genome wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC) with another two loci being close to genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the United Kingdom. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. Follow-up genotyping was carried out in 18,174 cases and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 previously near genome-wide significance and identified three novel loci associated with risk; two loci associated with all EOC subtypes, at 8q21 (rs11782652, P=5.5×10-9) and 10p12 (rs1243180; P=1.8×10-8), and another locus specific to the serous subtype at 17q12 (rs757210; P=8.1×10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility that implicates CHMP4C in the pathogenesis of ovarian cancer., Version of Record
Published: 2013
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36. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Author: Permuth-Wey, Jennifer, Lawrenson, Kate, Shen, Howard C., Velkova, Aneliya, Tyrer, Jonathan P., Chen, Zhihua, Lin, Hui-Yi, Chen, Y. Ann, Tsai, Ya-Yu, Qu, Xiaotao, Ramus, Susan J., Karevan, Rod, Lee, Janet, Lee, Nathan, Larson, Melissa C., Aben, Katja K., Anton-Culver, Hoda, Antonenkova, Natalia, Antoniou, Antonis, Armasu, Sebastian M., Bacot, François, Baglietto, Laura, Bandera, Elisa V., Barnholtz-Sloan, Jill, Beckmann, Matthias W., Bloom, Greg, Bogdanova, Natalia, Brinton, Louise A., Brooks-Wilson, Angela, Brown, Robert, Butzow, Ralf, Cai, Qiuyin, Campbell, Ian, Chang-Claude, Jenny, Chanock, Stephen, Chenevix-Trench, Georgia, Cheng, Jin Q., Cicek, Mine S., Coetzee, Gerhard A., Cook, Linda S., Couch, Fergus J., Cunningham, Julie M., Dansonka-Mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Easton, Douglas F, Eccles, Diana, Edwards, Robert, Ekici, Arif B., Fasching, Peter A., Fenstermacher, David A., Flanagan, James M., Garcia-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Giles, Graham G., Glasspool, Rosalind M., Gonzalez-Bosquet, Jesus, Goodman, Marc T., Gore, Martin, Górski, Bohdan, Gronwald, Jacek, Hall, Per, Halle, Mari K., Harter, Philipp, Heitz, Florian, Hillemanns, Peter, Hoatlin, Maureen, Høgdall, Claus K., Høgdall, Estrid, Hosono, Satoyo, Jakubowska, Anna, Jensen, Allan, Jim, Heather, Kalli, Kimberly R., Karlan, Beth Y., Kaye, Stanley B., Kelemen, Linda E., Kiemeney, Lambertus A., Kikkawa, Fumitaka, Konecny, Gottfried E., Krakstad, Camilla, Kjaer, Susanne Krüger, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Lancaster, Johnathan M., Le, Nhu D., Leminen, Arto, Levine, Douglas A., Liang, Dong, Lim, Boon Kiong, Lin, Jie, Lissowska, Jolanta, Lu, Karen H., Lubiński, Jan, Lurie, Galina, Massuger, Leon F.A.G., Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B., Nakanishi, Toru, Narod, Steven A., Nedergaard, Lotte, Ness, Roberta B., Nevanlinna, Heli, Nickels, Stefan, Noushmehr, Houtan, Odunsi, Kunle, Olson, Sara H., Orlow, Irene, Paul, James, Pearce, Celeste L, Pejovic, Tanja, Pelttari, Liisa M., Pike, Malcolm C., Raska, Paola, Renner, Stefan P., Risch, Harvey A., Rodriguez-Rodriguez, Lorna, Rossing, Mary Anne, Rudolph, Anja, Runnebaum, Ingo B., Rzepecka, Iwona K., Salvesen, Helga B., Schwaab, Ira, Severi, Gianluca, Shridhar, Vijayalakshmi, Shu, Xiao-Ou, Shvetsov, Yurii B., Sieh, Weiva, Song, Honglin, Southey, Melissa C., Spiewankiewicz, Beata, Stram, Daniel, Sutphen, Rebecca, Teo, Soo-Hwang, Tessier, Daniel C., Thompson, Pamela J., van Altena, Anne M., Vergote, Ignace, Vierkant, Robert A., Vincent, Daniel, Vitonis, Allison F., Wang-Gohrke, Shan, Weber, Rachel Palmieri, Wentzensen, Nicolas, Whittemore, Alice S., Wik, Elisabeth, Wilkens, Lynne R., Winterhoff, Boris, Woo, Yin Ling, Wu, Anna H., Xiang, Yong-Bing, Yang, Hannah P., Zheng, Wei, Ziogas, Argyrios, Zulkifli, Famida, Phelan, Catherine M., Iversen, Edwin, Schildkraut, Joellen M., Berchuck, Andrew, Fridley, Brooke L., Goode, Ellen L., Pharoah, Paul D. P., Monteiro, Alvaro N.A., Sellers, Thomas A., Gayther, Simon A., Birrer, Michael J., Cramer, Daniel, Poole, Elizabeth M., Terry, Kathryn, and Tworoger, Shelley
Abstract: Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA) binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA binding site single nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (OR=1.12, P=10−8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10−10). Variation at 17q21.31 associates with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes., Version of Record
Published: 2013
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37. Genetically Encoded Calcium Indicators for Ulti-Color Neural Activity Imaging and Combination With Optogenetics

Author: Akerboom, Jasper, Carreras Calderón, Nicole, Tian, Lin, Wabnig, Sebastian, Prigge, Matthias, Tolö, Johan, Gordus, Andrew, Orger, Michael B., Severi, Kristen E., Macklin, John J., Patel, Ronak Bhailal, Pulver, Stefan R., Wardill, Trevor J., Fischer, Elisabeth, Schüler, Christina, Chen, Tsai-Wen, Sarkisyan, Karen S., Marvin, Jonathan S., Bargmann, Cornelia I., Kim, Douglas S., Kügler, Sebastian, Lagnado, Leon, Hegemann, Peter, Gottschalk, Alexander, Schreiter, Eric R., and Looger, Loren L.
Subjects: calcium imaging, genetically encoded calcium indicator, multi-color imaging, protein engineering, optogenetics
Abstract: Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Here we describe red, single-wavelength GECIs, “RCaMPs,” engineered from circular permutation of the thermostable red fluorescent protein mRuby. High-resolution crystal structures of mRuby, the red sensor RCaMP, and the recently published red GECI R-GECO1 give insight into the chromophore environments of the Ca\(^{2+}\)-bound state of the sensors and the engineered protein domain interfaces of the different indicators. We characterized the biophysical properties and performance of RCaMP sensors in vitro and in vivo in Caenorhabditis elegans, Drosophila larvae, and larval zebrafish. Further, we demonstrate 2-color calcium imaging both within the same cell (registering mitochondrial and somatic [Ca\(^{2+}\)]) and between two populations of cells: neurons and astrocytes. Finally, we perform integrated optogenetics experiments, wherein neural activation via channelrhodopsin-2 (ChR2) or a red-shifted variant, and activity imaging via RCaMP or GCaMP, are conducted simultaneously, with the ChR2/RCaMP pair providing independently addressable spectral channels. Using this paradigm, we measure calcium responses of naturalistic and ChR2-evoked muscle contractions in vivo in crawling C. elegans. We systematically compare the RCaMP sensors to R-GECO1, in terms of action potential-evoked fluorescence increases in neurons, photobleaching, and photoswitching. R-GECO1 displays higher Ca\(^{2+}\) affinity and larger dynamic range than RCaMP, but exhibits significant photoactivation with blue and green light, suggesting that integrated channelrhodopsin-based optogenetics using R-GECO1 may be subject to artifact. Finally, we create and test blue, cyan, and yellow variants engineered from GCaMP by rational design. This engineered set of chromatic variants facilitates new experiments in functional imaging and optogenetics., Molecular and Cellular Biology, Version of Record
Published: 2013
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38. Genome-wide Association Study of Glioma and Meta-Analysis

Author: Rajaraman, Preetha, Melin, Beatrice, Wang, Zhaoming, McKean-Cowdin, Roberta, Michaud, Dominique, Wang, Sophia, Bondy, Melissa, Houlston, Richard, Jenkins, Robert, Wrensch, Margaret, Yeager, Meredith, Ahlbom, Anders, Albanes, Demetrius, Andersson, Ulrika, Freeman, Laura E. Beane, Buring, Julie, Butler, Mary Ann, Braganza, Melissa, Carreon, Tania, Feychting, Maria, Fleming, Sarah, Gapstur, Susan, Gaziano, J. Michael, Giles, Graham, Hallmans, Goran, Henriksson, Roger, Hoffman-Bolton, Judith, Inskip, Peter, Johansen, Christoffer, Kitahara, Cari, Lathrop, Mark, Liu, Chenwei, Le Marchand, Loic, Linet, Martha, Lonn, Stefan, Peters, Ulrike, Purdue, Mark, Rothman, Nathaniel, Ruder, Avima, Sanson, Marc, Sesso, Howard, Severi, Gianluca, Shu, Xiao-Ou, Simon, Matthias, Stampfer, Meir, Stevens, Victoria, Visvanathan, Kala, White, Emily, Wolk, Alicja, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Decker, Paul, Enciso-Mora, Victor, Fridley, Brooke, Gao, Yu-Tang, Kosel, Matt, Lachance, Dan, Lau, Ching, Rice, Terri, Swerdlow, Anthony, Wiemels, Joe, Wiencke, John, Shete, Sanjay, Xiang, Yong-Bing, Xiao, Yuanyuan, Hoover, Robert, Fraumeni, Joseph Jr., Chatterjee, Nilanjan, Hartge, Patricia, and Chanock, Stephen
Abstract: Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk., Accepted Manuscript
Published: 2012

39. Interactions Between Genome-wide Significant Genetic Variants and Circulating Concentrations of Insulin-like Growth Factor 1, Sex Hormones, and Binding Proteins in Relation to Prostate Cancer Risk in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium

Author: Tsilidis, Konstantinos, Travis, Ruth, Appleby, Paul, Allen, Naomi, Lindstrom, Sara, Schumacher, Fredrick, Cox, David, Hsing, Ann, Ma, Jing, Severi, Gianluca, Albanes, Demetrius, Virtamo, Jarmo, Boeing, Heiner, Bueno-de-Mesquita, H. Bas, Johansson, Mattias, Quirós, J. Ramón, Riboli, Elio, Siddiq, Afshan, Tjønneland, Anne, Trichopoulos, Dimitrios, Tumino, Rosario, Gaziano, J. Michael, Giovannucci, Edward, Hunter, David, Kraft, Peter, Stampfer, Meir, Giles, Graham, Andriole, Gerald, Berndt, Sonja, Chanock, Stephen, Hayes, Richard, and Key, Timothy
Abstract: Version of Record
Published: 2012

40. Common genetic variants in prostate cancer risk prediction – Results from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3)

Author: Lindström, Sara, Schumacher, Fredrick, Cox, David, Travis, Ruth, Albanes, Demetrius, Allen, Naomi, Andriole, Gerald, Berndt, Sonja, Boeing, Heiner, Bueno-de-Mesquita, H. Bas, Crawford, E. David, Diver, W. Ryan, Ganziano, J. Michael, Giles, Graham, Giovannucci, Edward, Gonzalez, Carlos, Henderson, Brian, Hunter, David, Johansson, Mattias, Kolonel, Laurence, Ma, Jing, Le Marchand, Loic, Pala, Valeria, Stampfer, Meir, Stram, Daniel, Thun, Michael, Tjonneland, Anne, Trichopoulos, Dimitrios, Virtamo, Jarmo, Weinstein, Stephanie, Willett, Walter, Yeager, Meredith, Hayes, Richard, Severi, Gianluca, Haiman, Christopher, Chanock, Stephen, and Kraft, Peter
Abstract: Background: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age. Methods: We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data. Results: The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile). Conclusions: Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening.Impact: Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited. Cancer Epidemiol Biomarkers Prev; 21(3); 437-44., Accepted Manuscript
Published: 2012

41. Genome-wide association study identifies new prostate cancer susceptibility loci

Author: Schumacher, Fredrick R., Berndt, Sonja I., Siddiq, Afshan, Jacobs, Kevin B., Wang, Zhaoming, Lindstrom, Sara, Stevens, Victoria L., Chen, Constance, Mondul, Alison M., Travis, Ruth C., Stram, Daniel O., Eeles, Rosalind A., Easton, Douglas F., Giles, Graham, Hopper, John L., Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Muir, Kenneth, Olama, Ali Al, Kote-Jarai, Zsofia, Guy, Michelle, Severi, Gianluca, Grönberg, Henrik, Isaacs, William B., Karlsson, Robert, Wiklund, Fredrik, Xu, Jianfeng, Allen, Naomi E., Andriole, Gerald L., Barricarte, Aurelio, Boeing, Heiner, Bueno-de-Mesquita, H. Bas, Crawford, E. David, Diver, W. Ryan, Gonzalez, Carlos A., Gaziano, J. Michael, Giovannucci, Edward L., Johansson, Mattias, Marchand, Loic Le, Ma, Jing, Sieri, Sabina, Stattin, Pär, Stampfer, Meir, Tjonneland, Anne, Vineis, Paolo, Virtamo, Jarmo, Vogel, Ulla, Weinstein, Stephanie J., Yeager, Meredith, Thun, Michael J., Kolonel, Laurence N., Henderson, Brian E., Albanes, Demetrius, Hayes, Richard B., Feigelson, Heather Spencer, Riboli, Elio, Hunter, David J., Chanock, Stephen J., Haiman, Christopher A., and Kraft, Peter
Abstract: Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade >= 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P = 4.3 x 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P = 8.6 x 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P = 0.72 and P = 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes., Version of Record
Published: 2011

42. Characterizing Associations and SNP-Environment Interactions for GWAS-Identified Prostate Cancer Risk Markers—Results from BPC3

Author: Lindstrom, Sara, Schumacher, Fredrick, Siddiq, Afshan, Travis, Ruth C., Campa, Daniele, Berndt, Sonja I., Diver, W. Ryan, Severi, Gianluca, Allen, Naomi, Andriole, Gerald, Bueno-de-Mesquita, Bas, Chanock, Stephen J., Crawford, David, Gaziano, J. Michael, Giles, Graham G., Giovannucci, Edward, Guo, Carolyn, Haiman, Christopher A., Hayes, Richard B., Halkjaer, Jytte, Hunter, David J., Johansson, Mattias, Kaaks, Rudolf, Kolonel, Laurence N., Navarro, Carmen, Riboli, Elio, Sacerdote, Carlotta, Stampfer, Meir, Stram, Daniel O., Thun, Michael J., Trichopoulos, Dimitrios, Virtamo, Jarmo, Weinstein, Stephanie J., Yeager, Meredith, Henderson, Brian, Ma, Jing, Le Marchand, Loic, Albanes, Demetrius, Kraft, Peter, and Dubé, Marie-Pierre
Abstract: Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10(-28)). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade,8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined., Version of Record
Published: 2011

43. Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk

Author: Stevens, K N, Garcia-Closas, M, Fredericksen, Z, Kosel, M, Pankratz, V S, Hopper, J L, Dite, G S, Apicella, C, Southey, M C, Schmidt, M K, Broeks, A, Van ‘t Veer, L J, Tollenaar, R A E M, Fasching, P A, Beckmann, M W, Hein, A, Ekici, A B, Johnson, N, Peto, J, dos Santos Silva, I, Gibson, L, Sawyer, E, Tomlinson, I, Kerin, M J, Chanock, S, Lissowska, J, Hunter, David, Hoover, R N, Thomas, G D, Milne, R L, Pérez, JI Arias, González-Neira, A, Benítez, J, Burwinkel, B, Meindl, A, Schmutzler, R K, Bartrar, C R, Hamann, U, Ko, Y D, Brüning, T, Chang-Claude, J, Hein, R, Wang-Gohrke, S, Dörk, T, Schürmann, P, Bremer, M, Hillemanns, P, Bogdanova, N, Zalutsky, J V, Rogov, Y I, Antonenkova, N, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chenevix-Trench, G, Chen, X, Peterlongo, P, Bonanni, B, Bernard, L, Manoukian, S, Wang, X, Cerhan, J, Vachon, C M, Olson, J, Giles, G G, Baglietto, L, McLean, C A, Severi, G, John, E M, Miron, A, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, I, Knight, J A, Glendon, G, Mulligan, A M, Cox, A, Brock, I W, Elliott, G, Cross, S S, Pharoah, P P, Dunning, A M, Pooley, K A, Humphreys, M K, Wang, J, Kang, D, Yoo, K-Y, Noh, D-Y, Sangrajrang, S, Gabrieau, V, Brennan, P, McKay, J, Anton-Culver, H, Ziogas, A, Couch, F J, and Easton, D F
Subjects: genetic susceptibility, neoplasms, association study
Abstract: Background: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. Methods: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). Results: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95–0.99, P=4.6 × \(10^{−3}\)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96–1.01, P=0.139). Conclusion: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer., Version of Record
Published: 2011
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44. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

Author: Song, Honglin, Ramus, Susan J, Tyrer, Jonathan, Bolton, Kelly L, Gentry-Maharaj, Aleksandra, Wozniak, Eva, Anton-Culver, Hoda, Chang-Claude, Jenny, Cramer, Daniel, DiCioccio, Richard, Dörk, Thilo, Goode, Ellen L, Goodman, Marc T, Schildkraut, Joellen M, Sellers, Thomas, Baglietto, Laura, Beckmann, Matthias W, Beesley, Jonathan, Blaakaer, Jan, Carney, Michael E, Chanock, Stephen, Chen, Zhihua, Cunningham, Julie M, Dicks, Ed, Doherty, Jennifer A, Dürst, Matthias, Ekici, Arif B, Fenstermacher, David, Fridley, Brooke L, Giles, Graham, Gore, Martin E, De Vivo, Immaculata, Hillemanns, Peter, Hogdall, Claus, Hogdall, Estrid, Iversen, Edwin S, Jacobs, Ian J, Jakubowska, Anna, Li, Dong, Lissowska, Jolanta, Lubiński, , Jan, Lurie, Galina, McGuire, Valerie, McLaughlin, John, Mędrek, Krzysztof, Moorman, Patricia G, Moysich, Kirsten, Narod, Steven, Phelan, Catherine, Pye, Carole, Risch, Harvey, Runnebaum, Ingo B, Severi, Gianluca, Southey, Melissa, Stram, Daniel O, Thiel, Falk C, Terry, Kathryn, Tsai, Ya-Yu, Tworoger, Shelley, Van Den Berg, David J, Vierkant, Robert A, Wang-Gohrke, Shan, Webb, Penelope M, Wilkens, Lynne R, Wu, Anna H, Yang, Hannah, Brewster, Wendy, Ziogas, Argyrios, Houlston, Richard, Tomlinson, Ian, Whittemore, Alice S, Rossing, Mary Anne, Ponder, Bruce A J, Pearce, Celeste Leigh, Ness, Roberta B, Menon, Usha, Kjaer, Susanne Krüger, Gronwald, Jacek, Garcia-Closas, Montserrat, Fasching, Peter A, Easton, Douglas F, Chenevix-Trench, Georgia, Berchuck, Andrew, Pharoah, Paul D P, and Gayther, Simon A
Abstract: Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk1. We performed a genome wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ~2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P<10−8). The most significant SNP (rs3814113; P = 2.5 × 10−17) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls confirming its association (combined data odds ratio = 0.82 95% CI 0.79 – 0.86, P-trend = 5.1 × 10−19). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77 95% CI 0.73 – 0.81, Ptrend = 4.1 × 10−21)., Accepted Manuscript
Published: 2009
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45. Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics

Author: Garcia-Closas, Montserrat, Hall, Per, Nevanlinna, Heli, Pooley, Karen, Morrison, Jonathan, Richesson, Douglas A., Bojesen, Stig E., Nordestgaard, Børge G., Axelsson, Christen K., Arias, Jose I., Milne, Roger L., Ribas, Gloria, González-Neira, Anna, Benítez, Javier, Zamora, Pilar, Brauch, Hiltrud, Justenhoven, Christina, Hamann, Ute, Ko, Yon-Dschun, Bruening, Thomas, Haas, Susanne, Dörk, Thilo, Schürmann, Peter, Hillemanns, Peter, Bogdanova, Natalia, Bremer, Michael, Karstens, Johann Hinrich, Fagerholm, Rainer, Aaltonen, Kirsimari, Aittomäki, Kristiina, von Smitten, Karl, Blomqvist, Carl, Mannermaa, Arto, Uusitupa, Matti, Eskelinen, Matti, Tengström, Maria, Kosma, Veli-Matti, Kataja, Vesa, Chenevix-Trench, Georgia, Spurdle, Amanda B., Beesley, Jonathan, Chen, Xiaoqing, Australian Ovarian Cancer Management Group, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Devilee, Peter, van Asperen, Christi J., Jacobi, Catharina E., Tollenaar, Rob A. E. M., Huijts, Petra E. A., Klijn, Jan G. M., Chang-Claude, Jenny, Kropp, Silke, Slanger, Tracy, Flesch-Janys, Dieter, Mutschelknauss, Elke, Salazar, Ramona, Wang-Gohrke, Shan, Couch, Fergus, Goode, Ellen L., Olson, Janet E., Vachon, Celine, Fredericksen, Zachary S., Giles, Graham G., Baglietto, Laura, Severi, Gianluca, Hopper, John L., English, Dallas R., Southey, Melissa C., Haiman, Christopher A., Henderson, Brian E., Kolonel, Laurence N., Le Marchand, Loic, Stram, Daniel O., Hunter, David J., Hankinson, Susan E., Cox, David G., Tamimi, Rulla, Kraft, Peter, Sherman, Mark E., Chanock, Stephen J., Lissowska, Jolanta, Brinton, Louise A., Peplonska, Beata, Hooning, Maartje J., Meijers-Heijboer, Han, Collee, J. Margriet, van den Ouweland, Ans, Uitterlinden, Andre G., Liu, Jianjun, Lin, Low Yen, Yuqing, Li, Humphreys, Keith, Czene, Kamila, Cox, Angela, Balasubramanian, Sabapathy P., Cross, Simon S., Reed, Malcolm W. R., Blows, Fiona, and Driver, Kristy
Abstract: A three-stage genome-wide association study recently identified single nucleotide polymorphisms ( SNPs) in five loci ( fibroblast growth receptor 2 ( FGFR2), trinucleotide repeat containing 9 ( TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte- specific protein 1 ( LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER- positive ( per- allele OR ( 95%CI) = 1.31 (1.27-1.36)) than ER- negative (1.08 (1.03- 1.14)) disease ( P for heterogeneity = 10-(13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER- positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs ( rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER- negative disease, the strongest association being for rs3803662 in TNRC9 ( 1.14 ( 1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis ( per- allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER- positive and ER- negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment., Version of Record
Published: 2008

46. Control of Visually Guided Behavior by Distinct Populations of Spinal Projection Neurons

Author: Orger, Michael B, Kampff, Adam R, Severi, Kristen E, Bollmann, Johann H, and Engert, Florian
Abstract: A basic question in the field of motor control is how different actions are represented by activity in spinal projection neurons. We used a new behavioral assay to identify visual stimuli that specifically drive basic motor patterns in zebrafish. These stimuli evoked consistent patterns of neural activity in the neurons projecting to the spinal cord, which we could map throughout the entire population using in vivo two-photon calcium imaging. We found that stimuli that drive distinct behaviors activated distinct subsets of projection neurons, consisting, in some cases, of just a few cells. This stands in contrast to the distributed activation seen for more complex behaviors. Furthermore, targeted cell by cell ablations of the neurons associated with evoked turns abolished the corresponding behavioral response. This description of the functional organization of the zebrafish motor system provides a framework for identifying the complete circuit underlying a vertebrate behavior., Molecular and Cellular Biology, Accepted Manuscript
Published: 2008
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