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1. Managing Gout in Women: Current Perspectives

Author

Patel AV and Gaffo AL

Subjects
gout, women, treatment, flare, prophylaxis, pregnancy, Pathology, RB1-214, Therapeutics. Pharmacology, RM1-950
Abstract

Aakash V Patel,1 Angelo L Gaffo2,3 1Tinsley Harrison Internal Medicine Residency Program, University of Alabama at Birmingham, Birmingham, AL, USA; 2Division of Rheumatology and Clinical Immunology, University of Alabama at Birmingham, Birmingham, AL, USA; 3Birmingham VA Medical Center, Birmingham, AL, USACorrespondence: Angelo L Gaffo, Division of Rheumatology and Clinical Immunology, University of Alabama at Birmingham, 1825 Shelby Biomedical Building, Birmingham, AL, 35294, USA, Tel +1 205-933-8101, Fax +1 205-996-6788, Email agaffo@uabmc.eduAbstract: Gout is a common inflammatory arthritis that tends to affect significantly more men than women. However, female gout patients are more likely to have comorbidities such as hypertension, diabetes mellitus, and renal dysfunction. Furthermore, they experience a greater disease burden due to gout than males. While nonbiological causes may possibly contribute to this sex discrepancy in burden, this raises questions regarding whether current gout pharmacotherapies are as efficacious in females as they are in males. In this review, we examine how the clinical profile of female gout patients differs from male patients; we then survey the literature for data on outcomes for female gout patients treated with urate-lowering therapies for chronic management of gout as well as commonly used agents for acute flares. We also discuss considerations for managing gout in women during pregnancy and lactation.Keywords: gout, women, treatment, flare, prophylaxis, pregnancy

Published
2022

2. Analgesic Use and Ovarian Cancer Risk: An Analysis in the Ovarian Cancer Cohort Consortium

Author

Trabert, B, Poole, EM, White, E, Visvanathan, K, Adami, HO, Anderson, GL, Brasky, TM, Brinton, LA, Fortner, RT, Gaudet, M, Hartge, P, Hoffman-Bolton, J, Jones, M, Lacey, JV, Larsson, SC, Mackenzie, GG, Schouten, LJ, Sandler, DP, O'Brien, K, Patel, AV, Peters, U, Prizment, A, Robien, K, Setiawan, WV, Swerdlow, A, Van Den Brandt, PA, Weiderpass, E, Wilkens, LR, Wolk, A, Wentzensen, N, and Tworoger, SS

Subjects
Cancer, Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine
Published
2018

4. Daily steps and all-cause mortality: a meta-analysis of 15 international cohorts

Author

Paluch, AE, Bajpai, S, Bassett, DR, Carnethon, MR, Ekelund, U, Evenson, KR, Galuska, DA, Jefferis, BJ, Kraus, WE, Lee, I-M, Matthews, CE, Omura, JD, Patel, AV, Pieper, CF, Rees-Punia, E, Dallmeier, D, Klenk, J, Whincup, PH, Dooley, EE, Pettee Gabriel, K, Palta, P, Pompeii, LA, Chernofsky, A, Larson, MG, Vasan, RS, Spartano, N, Ballin, M, Nordström, P, Nordström, A, Anderssen, SA, Hansen, BH, Cochrane, JA, Dwyer, T, Wang, J, Ferrucci, L, Liu, F, Schrack, J, Urbanek, J, Saint-Maurice, PF, Yamamoto, N, Yoshitake, Y, Newton, RL, Yang, S, Shiroma, EJ, Fulton, JE, and Steps for Health Collaborative

Abstract

BACKGROUND: Although 10 000 steps per day is widely promoted to have health benefits, there is little evidence to support this recommendation. We aimed to determine the association between number of steps per day and stepping rate with all-cause mortality. METHODS: In this meta-analysis, we identified studies investigating the effect of daily step count on all-cause mortality in adults (aged ≥18 years), via a previously published systematic review and expert knowledge of the field. We asked participating study investigators to process their participant-level data following a standardised protocol. The primary outcome was all-cause mortality collected from death certificates and country registries. We analysed the dose-response association of steps per day and stepping rate with all-cause mortality. We did Cox proportional hazards regression analyses using study-specific quartiles of steps per day and calculated hazard ratios (HRs) with inverse-variance weighted random effects models. FINDINGS: We identified 15 studies, of which seven were published and eight were unpublished, with study start dates between 1999 and 2018. The total sample included 47 471 adults, among whom there were 3013 deaths (10·1 per 1000 participant-years) over a median follow-up of 7·1 years ([IQR 4·3-9·9]; total sum of follow-up across studies was 297 837 person-years). Quartile median steps per day were 3553 for quartile 1, 5801 for quartile 2, 7842 for quartile 3, and 10 901 for quartile 4. Compared with the lowest quartile, the adjusted HR for all-cause mortality was 0·60 (95% CI 0·51-0·71) for quartile 2, 0·55 (0·49-0·62) for quartile 3, and 0·47 (0·39-0·57) for quartile 4. Restricted cubic splines showed progressively decreasing risk of mortality among adults aged 60 years and older with increasing number of steps per day until 6000-8000 steps per day and among adults younger than 60 years until 8000-10 000 steps per day. Adjusting for number of steps per day, comparing quartile 1 with quartile 4, the association between higher stepping rates and mortality was attenuated but remained significant for a peak of 30 min (HR 0·67 [95% CI 0·56-0·83]) and a peak of 60 min (0·67 [0·50-0·90]), but not significant for time (min per day) spent walking at 40 steps per min or faster (1·12 [0·96-1·32]) and 100 steps per min or faster (0·86 [0·58-1·28]). INTERPRETATION: Taking more steps per day was associated with a progressively lower risk of all-cause mortality, up to a level that varied by age. The findings from this meta-analysis can be used to inform step guidelines for public health promotion of physical activity. FUNDING: US Centers for Disease Control and Prevention.

Published
2022

5. Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women.

Author

Wang, X, Kapoor, PM, Auer, PL, Dennis, J, Dunning, AM, Wang, Q, Lush, M, Michailidou, K, Bolla, MK, Aronson, KJ, Murphy, RA, Brooks-Wilson, A, Lee, DG, Cordina-Duverger, E, Guénel, P, Truong, T, Mulot, C, Teras, LR, Patel, AV, Dossus, L, Kaaks, R, Hoppe, R, Lo, W-Y, Brüning, T, Hamann, U, Czene, K, Gabrielson, M, Hall, P, Eriksson, M, Jung, A, Becher, H, Couch, FJ, Larson, NL, Olson, JE, Ruddy, KJ, Giles, GG, MacInnis, RJ, Southey, MC, Le Marchand, L, Wilkens, LR, Haiman, CA, Olsson, H, Augustinsson, A, Krüger, U, Wagner, P, Scott, C, Winham, SJ, Vachon, CM, Perou, CM, Olshan, AF, Troester, MA, Hunter, DJ, Eliassen, HA, Tamimi, RM, Brantley, K, Andrulis, IL, Figueroa, J, Chanock, SJ, Ahearn, TU, García-Closas, M, Evans, GD, Newman, WG, van Veen, EM, Howell, A, Wolk, A, Håkansson, N, Anton-Culver, H, Ziogas, A, Jones, ME, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Kitahara, CM, Linet, M, Prentice, RL, Easton, DF, Milne, RL, Kraft, P, Chang-Claude, J, Lindström, S, Wang, X, Kapoor, PM, Auer, PL, Dennis, J, Dunning, AM, Wang, Q, Lush, M, Michailidou, K, Bolla, MK, Aronson, KJ, Murphy, RA, Brooks-Wilson, A, Lee, DG, Cordina-Duverger, E, Guénel, P, Truong, T, Mulot, C, Teras, LR, Patel, AV, Dossus, L, Kaaks, R, Hoppe, R, Lo, W-Y, Brüning, T, Hamann, U, Czene, K, Gabrielson, M, Hall, P, Eriksson, M, Jung, A, Becher, H, Couch, FJ, Larson, NL, Olson, JE, Ruddy, KJ, Giles, GG, MacInnis, RJ, Southey, MC, Le Marchand, L, Wilkens, LR, Haiman, CA, Olsson, H, Augustinsson, A, Krüger, U, Wagner, P, Scott, C, Winham, SJ, Vachon, CM, Perou, CM, Olshan, AF, Troester, MA, Hunter, DJ, Eliassen, HA, Tamimi, RM, Brantley, K, Andrulis, IL, Figueroa, J, Chanock, SJ, Ahearn, TU, García-Closas, M, Evans, GD, Newman, WG, van Veen, EM, Howell, A, Wolk, A, Håkansson, N, Anton-Culver, H, Ziogas, A, Jones, ME, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Kitahara, CM, Linet, M, Prentice, RL, Easton, DF, Milne, RL, Kraft, P, Chang-Claude, J, and Lindström, S

Abstract

Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10-8 as genome-wide significant, and p-values < 1 × 10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10-7), which showed genome-wide significant interaction (p-value = 3.8 × 10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.

Published
2022

6. Genetic insights into biological mechanisms governing human ovarian ageing

Author

Ruth, KS, Day, FR, Hussain, J, Martinez-Marchal, A, Aiken, CE, Azad, A, Thompson, DJ, Knoblochova, L, Abe, H, Tarry-Adkins, JL, Gonzalez, JM, Fontanillas, P, Claringbould, A, Bakker, OB, Sulem, P, Walters, RG, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, NC, Sankar, A, Hertz, EPT, Timshel, PN, Shukla, V, Borup, R, Olsen, KW, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, PRHJ, Ahearn, TU, Alizadeh, BZ, Naderi, E, Andrulis, IL, Arnold, AM, Aronson, KJ, Augustinsson, A, Bandinelli, S, Barbieri, CM, Beaumont, RN, Becher, H, Beckmann, MW, Benonisdottir, S, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Boomsma, DI, Bowker, N, Brody, JA, Broer, L, Buring, JE, Campbell, A, Campbell, H, Castelao, JE, Catamo, E, Chanock, SJ, Chenevix-Trench, G, Ciullo, M, Corre, T, Couch, FJ, Cox, A, Crisponi, L, Cross, SS, Cucca, F, Czene, K, Smith, GD, de Geus, EJCN, de Mutsert, R, De Vivo, I, Demerath, EW, Dennis, J, Dunning, AM, Dwek, M, Eriksson, M, Esko, T, Fasching, PA, Faul, JD, Ferrucci, L, Franceschini, N, Frayling, TM, Gago-Dominguez, M, Mezzavilla, M, Garcia-Closas, M, Gieger, C, Giles, GG, Grallert, H, Gudbjartsson, DF, Gudnason, V, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hayward, C, He, C, He, W, Heiss, G, Hoffding, MK, Hopper, JL, Hottenga, JJ, Hu, F, Hunter, D, Ikram, MA, Jackson, RD, Joaquim, MDR, John, EM, Joshi, PK, Karasik, D, Kardia, SLR, Kartsonaki, C, Karlsson, R, Kitahara, CM, Kolcic, I, Kooperberg, C, Kraft, P, Kurian, AW, Kutalik, Z, La Bianca, M, LaChance, G, Langenberg, C, Launer, LJ, Laven, JSE, Lawlor, DA, Le Marchand, L, Li, J, Lindblom, A, Lindstrom, S, Lindstrom, T, Linet, M, Liu, Y, Liu, S, Luan, J, Magi, R, Magnusson, PKE, Mangino, M, Mannermaa, A, Marco, B, Marten, J, Martin, NG, Mbarek, H, McKnight, B, Medland, SE, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Milani, L, Milne, RL, Montgomery, GW, Mook-Kanamori, DO, Mulas, A, Mulligan, AM, Murray, A, Nalls, MA, Newman, A, Noordam, R, Nutile, T, Nyholt, DR, Olshan, AF, Olsson, H, Painter, JN, Patel, AV, Pedersen, NL, Perjakova, N, Peters, A, Peters, U, Pharoah, PDP, Polasek, O, Porcu, E, Psaty, BM, Rahman, I, Rennert, G, Rennert, HS, Ridker, PM, Ring, SM, Robino, A, Rose, LM, Rosendaal, FR, Rossouw, J, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Saloustros, E, Sandler, DP, Sanna, S, Sawyer, EJ, Sarnowski, C, Schlessinger, D, Schmidt, MK, Schoemaker, MJ, Schraut, KE, Scott, C, Shekari, S, Shrikhande, A, Smith, AV, Smith, BH, Smith, JA, Sorice, R, Southey, MC, Spector, TD, Spinelli, JJ, Stampfer, M, Stoeckl, D, van Meurs, JBJ, Strauch, K, Styrkarsdottir, U, Swerdlow, AJ, Tanaka, T, Teras, LR, Teumer, A, thorsteinsdottir, U, Timpson, NJ, Toniolo, D, Traglia, M, Troester, MA, Truong, T, Tyrrell, J, Uitterlinden, AG, Ulivi, S, Vachon, CM, Vitart, V, Voelker, U, Vollenweider, P, Voelzke, H, Wang, Q, Wareham, NJ, Weinberg, CR, Weir, DR, Wilcox, AN, van Dijk, KW, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wolk, A, Wood, AR, Zhao, W, Zygmunt, M, Chen, Z, Li, L, Franke, L, Burgess, S, Deelen, P, Pers, TH, Grondahl, ML, Andersen, CY, Pujol, A, Lopez-Contreras, AJ, Daniel, JA, Stefansson, K, Chang-Claude, J, van der Schouw, YT, Lunetta, KL, Chasman, DI, Easton, DF, Visser, JA, Ozanne, SE, Namekawa, SH, Solc, P, Murabito, JM, Ong, KK, Hoffmann, ER, Roig, I, Perry, JRB, Ruth, KS, Day, FR, Hussain, J, Martinez-Marchal, A, Aiken, CE, Azad, A, Thompson, DJ, Knoblochova, L, Abe, H, Tarry-Adkins, JL, Gonzalez, JM, Fontanillas, P, Claringbould, A, Bakker, OB, Sulem, P, Walters, RG, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, NC, Sankar, A, Hertz, EPT, Timshel, PN, Shukla, V, Borup, R, Olsen, KW, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, PRHJ, Ahearn, TU, Alizadeh, BZ, Naderi, E, Andrulis, IL, Arnold, AM, Aronson, KJ, Augustinsson, A, Bandinelli, S, Barbieri, CM, Beaumont, RN, Becher, H, Beckmann, MW, Benonisdottir, S, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Boomsma, DI, Bowker, N, Brody, JA, Broer, L, Buring, JE, Campbell, A, Campbell, H, Castelao, JE, Catamo, E, Chanock, SJ, Chenevix-Trench, G, Ciullo, M, Corre, T, Couch, FJ, Cox, A, Crisponi, L, Cross, SS, Cucca, F, Czene, K, Smith, GD, de Geus, EJCN, de Mutsert, R, De Vivo, I, Demerath, EW, Dennis, J, Dunning, AM, Dwek, M, Eriksson, M, Esko, T, Fasching, PA, Faul, JD, Ferrucci, L, Franceschini, N, Frayling, TM, Gago-Dominguez, M, Mezzavilla, M, Garcia-Closas, M, Gieger, C, Giles, GG, Grallert, H, Gudbjartsson, DF, Gudnason, V, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hayward, C, He, C, He, W, Heiss, G, Hoffding, MK, Hopper, JL, Hottenga, JJ, Hu, F, Hunter, D, Ikram, MA, Jackson, RD, Joaquim, MDR, John, EM, Joshi, PK, Karasik, D, Kardia, SLR, Kartsonaki, C, Karlsson, R, Kitahara, CM, Kolcic, I, Kooperberg, C, Kraft, P, Kurian, AW, Kutalik, Z, La Bianca, M, LaChance, G, Langenberg, C, Launer, LJ, Laven, JSE, Lawlor, DA, Le Marchand, L, Li, J, Lindblom, A, Lindstrom, S, Lindstrom, T, Linet, M, Liu, Y, Liu, S, Luan, J, Magi, R, Magnusson, PKE, Mangino, M, Mannermaa, A, Marco, B, Marten, J, Martin, NG, Mbarek, H, McKnight, B, Medland, SE, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Milani, L, Milne, RL, Montgomery, GW, Mook-Kanamori, DO, Mulas, A, Mulligan, AM, Murray, A, Nalls, MA, Newman, A, Noordam, R, Nutile, T, Nyholt, DR, Olshan, AF, Olsson, H, Painter, JN, Patel, AV, Pedersen, NL, Perjakova, N, Peters, A, Peters, U, Pharoah, PDP, Polasek, O, Porcu, E, Psaty, BM, Rahman, I, Rennert, G, Rennert, HS, Ridker, PM, Ring, SM, Robino, A, Rose, LM, Rosendaal, FR, Rossouw, J, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Saloustros, E, Sandler, DP, Sanna, S, Sawyer, EJ, Sarnowski, C, Schlessinger, D, Schmidt, MK, Schoemaker, MJ, Schraut, KE, Scott, C, Shekari, S, Shrikhande, A, Smith, AV, Smith, BH, Smith, JA, Sorice, R, Southey, MC, Spector, TD, Spinelli, JJ, Stampfer, M, Stoeckl, D, van Meurs, JBJ, Strauch, K, Styrkarsdottir, U, Swerdlow, AJ, Tanaka, T, Teras, LR, Teumer, A, thorsteinsdottir, U, Timpson, NJ, Toniolo, D, Traglia, M, Troester, MA, Truong, T, Tyrrell, J, Uitterlinden, AG, Ulivi, S, Vachon, CM, Vitart, V, Voelker, U, Vollenweider, P, Voelzke, H, Wang, Q, Wareham, NJ, Weinberg, CR, Weir, DR, Wilcox, AN, van Dijk, KW, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wolk, A, Wood, AR, Zhao, W, Zygmunt, M, Chen, Z, Li, L, Franke, L, Burgess, S, Deelen, P, Pers, TH, Grondahl, ML, Andersen, CY, Pujol, A, Lopez-Contreras, AJ, Daniel, JA, Stefansson, K, Chang-Claude, J, van der Schouw, YT, Lunetta, KL, Chasman, DI, Easton, DF, Visser, JA, Ozanne, SE, Namekawa, SH, Solc, P, Murabito, JM, Ong, KK, Hoffmann, ER, Roig, I, and Perry, JRB

Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Published
2021

7. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author

Escala-Garcia, M, Canisius, S, Keeman, R, Beesley, J, Anton-Culver, H, Arndt, V, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bojesen, SE, Bolla, MK, Brenner, H, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Couch, FJ, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dork, T, Dunning, AM, Easton, DF, Ekici, AB, Eliassen, AH, Fasching, PA, Flyger, H, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Geisler, J, Giles, GG, Grip, M, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hartikainen, JM, Heemskerk-Gerritsen, BAM, Hollestelle, A, Hoppe, R, Hopper, JL, Hunter, DJ, Jacot, W, Jakubowska, A, John, EM, Jung, AY, Kaaks, R, Khusnutdinova, E, Koppert, LB, Kraft, P, Kristensen, VN, Kurian, AW, Lambrechts, D, Le Marchand, L, Lindblom, A, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Muranen, TA, Nevanlinna, H, Olshan, AF, Olsson, H, Park-Simon, T-W, Patel, AV, Peterlongo, P, Pharoah, PDP, Punie, K, Radice, P, Rennert, G, Rennert, HS, Romero, A, Roylance, R, Ruediger, T, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Scott, C, Southey, MC, Surowy, H, Swerdlow, AJ, Tamimi, RM, Teras, LR, Thomas, E, Tomlinson, I, Troester, MA, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Ziogas, A, Michailidou, K, Chenevix-Trench, G, Bachelot, T, Schmidt, MK, Escala-Garcia, M, Canisius, S, Keeman, R, Beesley, J, Anton-Culver, H, Arndt, V, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bojesen, SE, Bolla, MK, Brenner, H, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Couch, FJ, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dork, T, Dunning, AM, Easton, DF, Ekici, AB, Eliassen, AH, Fasching, PA, Flyger, H, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Geisler, J, Giles, GG, Grip, M, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hartikainen, JM, Heemskerk-Gerritsen, BAM, Hollestelle, A, Hoppe, R, Hopper, JL, Hunter, DJ, Jacot, W, Jakubowska, A, John, EM, Jung, AY, Kaaks, R, Khusnutdinova, E, Koppert, LB, Kraft, P, Kristensen, VN, Kurian, AW, Lambrechts, D, Le Marchand, L, Lindblom, A, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Muranen, TA, Nevanlinna, H, Olshan, AF, Olsson, H, Park-Simon, T-W, Patel, AV, Peterlongo, P, Pharoah, PDP, Punie, K, Radice, P, Rennert, G, Rennert, HS, Romero, A, Roylance, R, Ruediger, T, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Scott, C, Southey, MC, Surowy, H, Swerdlow, AJ, Tamimi, RM, Teras, LR, Thomas, E, Tomlinson, I, Troester, MA, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Ziogas, A, Michailidou, K, Chenevix-Trench, G, Bachelot, T, and Schmidt, MK

Abstract

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

Published
2021

8. Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

Author

Park, J, Choi, J-Y, Choi, J, Chung, S, Song, N, Park, SK, Han, W, Noh, D-Y, Ahn, S-H, Lee, JW, Kim, MK, Jee, SH, Wen, W, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Shah, M, Conroy, DM, Harrington, PA, Mayes, R, Czene, K, Hall, P, Teras, LR, Patel, AV, Couch, FJ, Olson, JE, Sawyer, EJ, Roylance, R, Bojesen, SE, Flyger, H, Lambrechts, D, Baten, A, Matsuo, K, Ito, H, Guenel, P, Truong, T, Keeman, R, Schmidt, MK, Wu, AH, Tseng, C-C, Cox, A, Cross, SS, Andrulis, IL, Hopper, JL, Southey, MC, Wu, P-E, Shen, C-Y, Fasching, PA, Ekici, AB, Muir, K, Lophatananon, A, Brenner, H, Arndt, V, Jones, ME, Swerdlow, AJ, Hoppe, R, Ko, Y-D, Hartman, M, Li, J, Mannermaa, A, Hartikainen, JM, Benitez, J, Gonzalez-Neira, A, Haiman, CA, Doerk, T, Bogdanova, NV, Teo, SH, Mohd Taib, NA, Fletcher, O, Johnson, N, Grip, M, Winqvist, R, Blomqvist, C, Nevanlinna, H, Lindblom, A, Wendt, C, Kristensen, VN, Tollenaar, RAEM, Heemskerk-Gerritsen, BAM, Radice, P, Bonanni, B, Hamann, U, Manoochehri, M, Lacey, JV, Martinez, ME, Dunning, AM, Pharoah, PDP, Easton, DF, Yoo, K-Y, Kang, D, Park, J, Choi, J-Y, Choi, J, Chung, S, Song, N, Park, SK, Han, W, Noh, D-Y, Ahn, S-H, Lee, JW, Kim, MK, Jee, SH, Wen, W, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Shah, M, Conroy, DM, Harrington, PA, Mayes, R, Czene, K, Hall, P, Teras, LR, Patel, AV, Couch, FJ, Olson, JE, Sawyer, EJ, Roylance, R, Bojesen, SE, Flyger, H, Lambrechts, D, Baten, A, Matsuo, K, Ito, H, Guenel, P, Truong, T, Keeman, R, Schmidt, MK, Wu, AH, Tseng, C-C, Cox, A, Cross, SS, Andrulis, IL, Hopper, JL, Southey, MC, Wu, P-E, Shen, C-Y, Fasching, PA, Ekici, AB, Muir, K, Lophatananon, A, Brenner, H, Arndt, V, Jones, ME, Swerdlow, AJ, Hoppe, R, Ko, Y-D, Hartman, M, Li, J, Mannermaa, A, Hartikainen, JM, Benitez, J, Gonzalez-Neira, A, Haiman, CA, Doerk, T, Bogdanova, NV, Teo, SH, Mohd Taib, NA, Fletcher, O, Johnson, N, Grip, M, Winqvist, R, Blomqvist, C, Nevanlinna, H, Lindblom, A, Wendt, C, Kristensen, VN, Tollenaar, RAEM, Heemskerk-Gerritsen, BAM, Radice, P, Bonanni, B, Hamann, U, Manoochehri, M, Lacey, JV, Martinez, ME, Dunning, AM, Pharoah, PDP, Easton, DF, Yoo, K-Y, and Kang, D

Abstract

In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10-3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10-4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

Published
2021

9. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author

Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Brüning, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Sahlberg, KK, Ottestad, L, Kåresen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebråten, O, Naume, B, Fosså, A, Kiserud, CE, Reinertsen, KV, Helland, Å, Riis, M, Geisler, J, Collée, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dörk, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, González-Neira, A, Alnæs, GIG, Grip, M, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Clarke, C, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, C, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Fox, S, Campbell, I, Bowtell, D, Spurdle, A, Webb, P, de Fazio, A, Tassell, M, Kirk, J, Lindeman, G, Price, M, Southey, M, Milne, R, Deb, S, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Krüger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, AV, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkäs, K, Radice, P, Rennert, G, Romero, A, Rüdiger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schöttker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, García-Closas, M, Chatterjee, N, Ahearn, Thomas U [0000-0003-0771-7752], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Apollo - University of Cambridge Repository, Medicum, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, Clinical Genetics, Medical Oncology, and Pathology

Subjects
False discovery rate, Oncology, Common breast cancer susceptibility variants, Receptor, ErbB-2, Estrogen receptor, PROGRESSION, Etiologic heterogeneity, Logistic regression, Basic medicine, Breast cancer, 0302 clinical medicine, PRIMARY THERAPY, HETEROGENEITY, RC254-282, HISTOLOGICAL GRADE, 0303 health sciences, Breast Neoplasms/epidemiology, Receptors, Estrogen/genetics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, INTERNATIONAL EXPERT CONSENSUS, humanities, Receptor, ErbB-2/genetics, 3. Good health, Receptors, Estrogen, Receptors, Progesterone/genetics, 030220 oncology & carcinogenesis, Female, Biomarkers, Tumor/genetics, Receptors, Progesterone, Medical Genetics, Research Article, Risk, medicine.medical_specialty, SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, Biomarkers, Tumor, medicine, Genetic predisposition, Humans, ddc:610, GENOME-WIDE ASSOCIATION, Genetic association, Medicinsk genetik, 030304 developmental biology, Cancer och onkologi, medicine.disease, Cancer and Oncology, Clinical medicine, Genome-Wide Association Study
Abstract

Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate p Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

Published
2020

10. Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies

Author

van den Brandt, PA, Ziegler, RG, Wang, M, Hou, T, Li, R, Adami, H-O, Agnoli, C, Bernstein, L, Buring, JE, Chen, Y, Connor, AE, Eliassen, AH, Genkinger, JM, Gierach, G, Giles, GG, Goodman, GG, Hakansson, N, Krogh, V, Le Marchand, L, Lee, I-M, Liao, LM, Martinez, ME, Miller, AB, Milne, RL, Neuhouser, ML, Patel, AV, Prizment, A, Robien, K, Rohan, TE, Sawada, N, Schouten, LJ, Sinha, R, Stolzenberg-Solomon, RZ, Teras, LR, Tsugane, S, Visvanathan, K, Weiderpass, E, White, KK, Willett, WC, Wolk, A, Zeleniuch-Jacquotte, A, Smith-Warner, SA, van den Brandt, PA, Ziegler, RG, Wang, M, Hou, T, Li, R, Adami, H-O, Agnoli, C, Bernstein, L, Buring, JE, Chen, Y, Connor, AE, Eliassen, AH, Genkinger, JM, Gierach, G, Giles, GG, Goodman, GG, Hakansson, N, Krogh, V, Le Marchand, L, Lee, I-M, Liao, LM, Martinez, ME, Miller, AB, Milne, RL, Neuhouser, ML, Patel, AV, Prizment, A, Robien, K, Rohan, TE, Sawada, N, Schouten, LJ, Sinha, R, Stolzenberg-Solomon, RZ, Teras, LR, Tsugane, S, Visvanathan, K, Weiderpass, E, White, KK, Willett, WC, Wolk, A, Zeleniuch-Jacquotte, A, and Smith-Warner, SA

Abstract

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associ

Published
2020

11. Genetically Determined Height and Risk of Non-hodgkin Lymphoma

Author

Moore, A, Kane, E, Wang, Z, Panagiotou, OA, Teras, LR, Monnereau, A, Wong Doo, N, Machiela, MJ, Skibola, CF, Slager, SL, Salles, G, Camp, NJ, Bracci, PM, Nieters, A, Vermeulen, RCH, Vijai, J, Smedby, KE, Zhang, Y, Vajdic, CM, Cozen, W, Spinelli, JJ, Hjalgrim, H, Giles, GG, Link, BK, Clavel, J, Arslan, AA, Purdue, MP, Tinker, LF, Albanes, D, Ferri, GM, Habermann, TM, Adami, H-O, Becker, N, Benavente, Y, Bisanzi, S, Boffetta, P, Brennan, P, Brooks-Wilson, AR, Canzian, F, Conde, L, Cox, DG, Curtin, K, Foretova, L, Gapstur, SM, Ghesquieres, H, Glenn, M, Glimelius, B, Jackson, RD, Lan, Q, Liebow, M, Maynadie, M, McKay, J, Melbye, M, Miligi, L, Milne, RL, Molina, TJ, Morton, LM, North, KE, Offit, K, Padoan, M, Patel, AV, Piro, S, Ravichandran, V, Riboli, E, de Sanjose, S, Severson, RK, Southey, MC, Staines, A, Stewart, C, Travis, RC, Weiderpass, E, Weinstein, S, Zheng, T, Chanock, SJ, Chatterjee, N, Rothman, N, Birmann, BM, Cerhan, JR, Berndt, SI, Moore, A, Kane, E, Wang, Z, Panagiotou, OA, Teras, LR, Monnereau, A, Wong Doo, N, Machiela, MJ, Skibola, CF, Slager, SL, Salles, G, Camp, NJ, Bracci, PM, Nieters, A, Vermeulen, RCH, Vijai, J, Smedby, KE, Zhang, Y, Vajdic, CM, Cozen, W, Spinelli, JJ, Hjalgrim, H, Giles, GG, Link, BK, Clavel, J, Arslan, AA, Purdue, MP, Tinker, LF, Albanes, D, Ferri, GM, Habermann, TM, Adami, H-O, Becker, N, Benavente, Y, Bisanzi, S, Boffetta, P, Brennan, P, Brooks-Wilson, AR, Canzian, F, Conde, L, Cox, DG, Curtin, K, Foretova, L, Gapstur, SM, Ghesquieres, H, Glenn, M, Glimelius, B, Jackson, RD, Lan, Q, Liebow, M, Maynadie, M, McKay, J, Melbye, M, Miligi, L, Milne, RL, Molina, TJ, Morton, LM, North, KE, Offit, K, Padoan, M, Patel, AV, Piro, S, Ravichandran, V, Riboli, E, de Sanjose, S, Severson, RK, Southey, MC, Staines, A, Stewart, C, Travis, RC, Weiderpass, E, Weinstein, S, Zheng, T, Chanock, SJ, Chatterjee, N, Rothman, N, Birmann, BM, Cerhan, JR, and Berndt, SI

Abstract

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.

Published
2020

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

Author

Klein, AP, Wolpin, BM, Risch, HA, Stolzenberg-Solomon, RZ, Mocci, E, Zhang, M, Canzian, F, Childs, EJ, Hoskins, JW, Jermusyk, A, Zhong, J, Chen, F, Albanes, D, Andreotti, G, Arslan, AA, Babic, A, Bamlet, WR, Beane-Freeman, L, Berndt, SI, Blackford, A, Borges, M, Borgida, A, Bracci, PM, Brais, L, Brennan, P, Brenner, H, Bueno-de-Mesquita, B, Buring, J, Campa, D, Capurso, G, Cavestro, GM, Chaffee, KG, Chung, CC, Cleary, S, Cotterchio, M, Dijk, F, Duell, EJ, Foretova, L, Fuchs, C, Funel, N, Gallinger, S, Gaziano, JMM, Gazouli, M, Giles, GG, Giovannucci, E, Goggins, M, Goodman, GE, Goodman, PJ, Hackert, T, Haiman, C, Hartge, P, Hasan, M, Hegyi, P, Helzlsouer, KJ, Herman, J, Holcatova, I, Holly, EA, Hoover, R, Hung, RJ, Jacobs, EJ, Jamroziak, K, Janout, V, Kaaks, R, Khaw, K-T, Klein, EA, Kogevinas, M, Kooperberg, C, Kulke, MH, Kupcinskas, J, Kurtz, RJ, Laheru, D, Landi, S, Lawlor, RT, Lee, I-M, LeMarchand, L, Lu, L, Malats, N, Mambrini, A, Mannisto, S, Milne, RL, Mohelnikova-Duchonova, B, Neale, RE, Neoptolemos, JP, Oberg, AL, Olson, SH, Orlow, I, Pasquali, C, Patel, AV, Peters, U, Pezzilli, R, Porta, M, Real, FX, Rothman, N, Scelo, G, Sesso, HD, Severi, G, Shu, X-O, Silverman, D, Smith, JP, Soucek, P, Sund, M, Talar-Wojnarowska, R, Tavano, F, Thornquist, MD, Tobias, GS, Van Den Eeden, SK, Vashist, Y, Visvanathan, K, Vodicka, P, Wactawski-Wende, J, Wang, Z, Wentzensen, N, White, E, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Zheng, W, Kraft, P, Li, D, Chanock, S, Obazee, O, Petersen, GM, Amundadottir, LT, Klein, AP, Wolpin, BM, Risch, HA, Stolzenberg-Solomon, RZ, Mocci, E, Zhang, M, Canzian, F, Childs, EJ, Hoskins, JW, Jermusyk, A, Zhong, J, Chen, F, Albanes, D, Andreotti, G, Arslan, AA, Babic, A, Bamlet, WR, Beane-Freeman, L, Berndt, SI, Blackford, A, Borges, M, Borgida, A, Bracci, PM, Brais, L, Brennan, P, Brenner, H, Bueno-de-Mesquita, B, Buring, J, Campa, D, Capurso, G, Cavestro, GM, Chaffee, KG, Chung, CC, Cleary, S, Cotterchio, M, Dijk, F, Duell, EJ, Foretova, L, Fuchs, C, Funel, N, Gallinger, S, Gaziano, JMM, Gazouli, M, Giles, GG, Giovannucci, E, Goggins, M, Goodman, GE, Goodman, PJ, Hackert, T, Haiman, C, Hartge, P, Hasan, M, Hegyi, P, Helzlsouer, KJ, Herman, J, Holcatova, I, Holly, EA, Hoover, R, Hung, RJ, Jacobs, EJ, Jamroziak, K, Janout, V, Kaaks, R, Khaw, K-T, Klein, EA, Kogevinas, M, Kooperberg, C, Kulke, MH, Kupcinskas, J, Kurtz, RJ, Laheru, D, Landi, S, Lawlor, RT, Lee, I-M, LeMarchand, L, Lu, L, Malats, N, Mambrini, A, Mannisto, S, Milne, RL, Mohelnikova-Duchonova, B, Neale, RE, Neoptolemos, JP, Oberg, AL, Olson, SH, Orlow, I, Pasquali, C, Patel, AV, Peters, U, Pezzilli, R, Porta, M, Real, FX, Rothman, N, Scelo, G, Sesso, HD, Severi, G, Shu, X-O, Silverman, D, Smith, JP, Soucek, P, Sund, M, Talar-Wojnarowska, R, Tavano, F, Thornquist, MD, Tobias, GS, Van Den Eeden, SK, Vashist, Y, Visvanathan, K, Vodicka, P, Wactawski-Wende, J, Wang, Z, Wentzensen, N, White, E, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Zheng, W, Kraft, P, Li, D, Chanock, S, Obazee, O, Petersen, GM, and Amundadottir, LT

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.

Published
2018

16. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Author

Fang, J, Jia, J, Makowski, M, Xu, M, Wang, Z, Zhang, T, Hoskins, Jw, Choi, J, Han, Y, Zhang, M, Thomas, J, Kovacs, M, Collins, I, Dzyadyk, M, Thompson, A, O'Neill, M, Das, S, Lan, Q, Koster, R, Solomon, Rs, Kraft, P, Wolpin, Bm, Jansen, Pwtc, Olson, S, Mcglynn, Ka, Kanetsky, Pa, Chatterjee, N, Barrett, Jh, Dunning, Am, Taylor, Jc, Newton Bishop, Ja, Bishop, Dt, Andresson, T, Petersen, Gm, Amos, Ci, Iles, Mm, Nathanson, Kl, Landi, Mt, Vermeulen, M, Brown, Km, Amundadottir, Lt, Canzian, F, Kooperberg, C, Arslan, Aa, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Jacobs, Ej, Kamineni, A, Van Den Eeden, S, Klein, Ap, Kolonel, Ln, Li, D, Olson, Sh, Risch, Ha, Sesso, Hd, Visvanathan, K, Zheng, W, Albanes, D, Austin, Ma, Boutron Ruault, Mc, Bueno de Mesquita, Hb, Cotterchio, M, Gaziano, Jm, Giovannucci, El, Goggins, M, Gross, M, Hassan, M, Helzlsouer, Kj, Holly, Ea, Hunter, Dj, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Krogh, V, Kurtz, Rc, Lacroix, A, Le Marchand, L, Mannisto, S, Patel, Av, Peeters, Phm, Riboli, E, Shu, Xo, Sund, M, Thornquist, M, Tjønneland, A, Tobias, Gs, Trichopoulos, D, Wactawski Wende, J, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, Sj, Stevens, V, Caporaso, Ne, Brennan, P, Mckay, J, Wu, X, Hung, Rj, Mclaughlin, Jr, Bickeboller, H, Risch, A, Wichmann, E, Houlston, R, Mann, G, Hopper, J, Aitken, J, Armstrong, B, Giles, G, Holland, E, Kefford, R, Cust, A, Jenkins, M, Schmid, H, Puig, S, Aguilera, P, Badenas, C, Barreiro, A, Carrera, C, Gabriel, D, Xavier, Pg, Iglesias Garcia, P, Malvehy, J, Mila, M, Pigem, R, Potrony, M, Batille, Ja, Marti, Gt, Hayward, N, Martin, N, Montgomery, G, Duffy, D, Whiteman, D, Gregor, Sm, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, Pa, Ghiorzo, Paola, Bianchi, Giovanna, Pastorino, Lorenza, Bruno, William, Andreotti, Virginia, Queirolo, P, Spagnolo, Francesco, Mackie, R, Lang, J, Gruis, N, van Nieuwpoort, Fa, Out, C, Bergman, W, Kukutsch, N, Bavinck, Jnb, Bakker, B, van der Stoep, N, Ter Huurne, J, van der Rhee, H, Bekkenk, M, Snels, D, van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Janssen, B, Ingvar, C, Olsson, H, Jonsson, G, Borg, A, Harbst, K, Nielsen, K, Zander, As, Molvern, A, Helsing, P, Andresen, Pa, Rootwelt, H, Akslen, La, Bressac de Paillerets, B, Demenais, F, Avril, Mf, Chaudru, V, Jeannin, P, Lesueur, F, Maubec, E, Mohamdi, H, Bossard, M, Vaysse, A, Boitier, F, Caron, O, Caux, F, Dalle, S, Dereure, O, Leroux, D, Martin, L, Mateus, C, Robert, C, Stoppa Lyonnet, D, Thomas, L, Wierzbicka, E, Elder, D, Ming, M, Mitra, N, Debniak, T, Lubinski, J, Hocevar, M, Novakovic, S, Peric, B, Skerl, P, Hansson, J, Hoiom, V, Freidman, E, Azizi, E, Baron Epel, O, Scope, A, Pavlotsky, F, Cohen Manheim, I, Laitman, Y, Harland, M, Randerson Moor, J, Laye, J, Davies, J, Nsengimana, J, O'Shea, S, Chan, M, Gascoyne, J, Tucker, Ma, Goldstein, Am, and Yang, X. r.

Subjects
0301 basic medicine, Male, Lung Neoplasms, Skin Neoplasms, General Physics and Astronomy, Genome-wide association study, VARIANTS, Histones, Skin cancer, RNA, Small Interfering, Melanoma, Telomerase, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Pancreas cancer, Regulation of gene expression, Genetics, Zinc finger, Gene knockdown, Multidisciplinary, Proteomics and Chromatin Biology, TRICL Consortium, Chromosome Mapping, GenoMEL Consortium, PANCREATIC-CANCER, Multidisciplinary Sciences, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Science & Technology - Other Topics, Chromosomes, Human, Pair 5, Female, Lung cancer, Signal Transduction, SUSCEPTIBILITY LOCI, Science, Locus (genetics), Single-nucleotide polymorphism, PROMOTES GROWTH, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, LUNG-CANCER, Testicular Neoplasms, Cell Line, Tumor, MD Multidisciplinary, Humans, Genetic Predisposition to Disease, QUANTITATIVE PROTEOMICS, GENOME-WIDE ASSOCIATION, Gene, PanScan Consortium, Càncer de pell, Càncer de pàncrees, Alleles, Science & Technology, Kirurgi, HUMAN-CELLS, Telomere Homeostasis, Correction, General Chemistry, Molecular biology, TERT-CLPTM1L LOCUS, Telomere, Pancreatic Neoplasms, 030104 developmental biology, Genetic Loci, TELOMERE LENGTH, Càncer de pulmó, Surgery, Genètica, Genome-Wide Association Study, Transcription Factors
Abstract

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele., Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.

Published
2017

17. Ovarian cancer and smoking: individual participant meta-analysis including 28,114 women with ovarian cancer from 51 epidemiological studies

Author

Gaitskell, K, Hermon, C, Moser, K, Reeves, G, Peto, R, Brinton, L, Marchbanks, P, Negri, E, Ness, R, Peeters, PHM, Vessey, M, Calle, EE, Gapstur, SM, Patel, AV, Dal Maso, L, Talamini, R, Chetrit, A, Hirsh-Yechezkel, G, Lubin, F, Sadetzki, S, Banks, E, Beral, V, Bull, D, Callaghan, K, Crossley, B, Goodill, A, Green, J, Key, T, Sitas, F, Collins, R, Doll, R, Gonzalez, A, Lee, N, Ory, HW, Peterson, HB, Wingo, PA, Martin, N, Pardthaisong, T, Silpisornkosol, S, Theetranont, C, Boosiri, B, Chutivongse, S, Jimakorn, P, Virutamasen, P, Wongsrichanalai, C, Tjonneland, A, Titus-Ernstoff, L, Byers, T, Rohan, T, Mosgaard, BJ, Yeates, D, Freudenheim, JL, Chang-Claude, J, Kaaks, R, Anderson, KE, Folsom, A, Robien, K, Hampton, J, Newcomb, PA, Rossing, MA, Thomas, DB, Weiss, NS, Riboli, E, Clavel-Chapelon, F, Cramer, D, Hankinson, SE, Tworoger, SS, Franceschi, S, La Vecchia, C, Adami, HO, Magnusson, C, Riman, T, Weiderpass, Elisabete, Wolk, A, Schouten, LJ, van den Brandt, PA, Chantarakul, N, Koetsawang, S, Rachawat, D, Palli, D, Black, A, Brinton, LA, Freedman, DM, Hartge, P, Hsing, AW, Lacey, JV, Hoover, RN, Schairer, C, Urban, M, Graff-Iversen, Sidsel, Selmer, Randi, Bain, CJ, Green, AC, Purdie, DM, Siskind, V, Webb, PM, Moysich, K, McCann, SE, Hannaford, P, Kay, C, Binns, CW, Lee, AH, Zhang, M, Ness, RB, Nasca, P, Coogan, PF, Palmer, JR, Rosenberg, L, Kelsey, J, Paffenbarger, R, Whittemore, A, Katsouyanni, K, Trichopoulou, A, Trichopoulos, D, Tzonou, A, Dabancens, A, Martinez, L, Molina, R, Salas, O, Goodman, MT, Lurie, G, Carney, ME, Wilkens, LR, Hartman, L, Manjer, J, Olsson, H, Grisso, JA, Morgan, M, Wheeler, JE, Bunker, CH, Edwards, RP, Modugno, F, Casagrande, J, Pike, MC, Ross, RK, Wu, AH, Miller, AB, Kumle, Merethe, Gram, Inger Torhild, Lund, Eiliv, McGowan, L, Shu, XO, Zheng, W, Farley, TMM, Holck, S, Meirik, O, Risch, HA, E. E. Calle, S. M. Gapstur, A. V. Patel, L. Dal Maso, R. Talamini, A. Chetrit, G. Hirsh Yechezkel, F. Lubin, S. Sadetzki, E. Bank, V. Beral, D. Bull, K. Callaghan, B. Crossley, K. Gaitskell, A. Goodill, J. Green, C. Hermon, T. Key, K. Moser, G. Reeve, F. Sita, R. Collin, R. Doll, R. Peto, C. A. Gonzalez, N. Lee, P. Marchbank, H. W. Ory, H. B. Peterson, P. A. Wingo, N. Martin, T. Pardthaisong, S. Silpisornkosol, C. Theetranont, B. Boosiri, S. Chutivongse, P. Jimakorn, P. Virutamasen, C. Wongsrichanalai, A. Tjonneland, L. Titus Ernstoff, T. Byer, T. Rohan, B. J. Mosgaard, M. Vessey, D. Yeate, J. L. Freudenheim, J. Chang Claude, R. Kaak, K. E. Anderson, A. Folsom, K. Robien, J. Hampton, P. A. Newcomb, M. A. Rossing, D. B. Thoma, N. S. Wei, E. Riboli, F. Clavel Chapelon, D. Cramer, S. E. Hankinson, S. S. Tworoger, S. Franceschi, C. La Vecchia, E. Negri, H. O. Adami, C. Magnusson, T. Riman, E. Weiderpa, A. Wolk, L. J. Schouten, P. A. van den Brandt, N. Chantarakul, S. Koetsawang, D. Rachawat, D. Palli, A. Black, L. A. Brinton, D. M. Freedman, P. Hartge, A. W. Hsing, J. Lacey, R. N. Hoover, C. Schairer, M. Urban, S. Graff Iversen, R. Selmer, C. J. Bain, A. C. Green, D. M. Purdie, V. Siskind, P. M. Webb, K. Moysich, S. E. Mccann, P. Hannaford, C. Kay, C. W. Binn, A. H. Lee, M. Zhang, R. B. Ne, P. Nasca, P. F. Coogan, J. R. Palmer, L. Rosenberg, J. Kelsey, R. Paffenbarger, A. Whittemore, K. Katsouyanni, A. Trichopoulou, D. Trichopoulo, A. Tzonou, A. Dabancen, L. Martinez, R. Molina, O. Sala, M. T. Goodman, G. Lurie, M. E. Carney, L. R. Wilken, L. Hartman, J. Manjer, H. Olsson, J. A. Grisso, M. Morgan, J. E. Wheeler, C. H. Bunker, R. P. Edward, F. Modugno, P. H. M. Peeter, J. Casagrande, M. C. Pike, R. K. Ro, A. H. Wu, A. B. Miller, M. Kumle, I. T. Gram, E. Lund, L. Mcgowan, X. O. Shu, W. Zheng, T. M. M. Farley, S. Holck, O. Meirik, H. A. Risch, Epidemiologie, RS: CAPHRI School for Public Health and Primary Care, and RS: GROW - School for Oncology and Reproduction

Subjects
hormonal factor, Oncology, body-mass index, Comorbidity, anthropometric measurement, Body Mass Index, 0302 clinical medicine, Epidemiology, Cancer Type - Ovarian Cancer, 030212 general & internal medicine, epithelial ovarian, Prospective cohort study, oral contraceptives, Ovarian Neoplasms, Incidence (epidemiology), Incidence, Smoking, Articles, Middle Aged, Adenocarcinoma, Mucinous, 3. Good health, Causality, Europe, risk-factor, Serous fluid, 030220 oncology & carcinogenesis, Meta-analysis, Adenocarcinoma, Female, Risk, Adult, medicine.medical_specialty, prospective cohort, Etiology - Exogenous Factors in the Origin and Cause of Cancer, Risk Assessment, methods, 03 medical and health sciences, Internal medicine, oral-contraceptive use, medicine, cancer, Humans, Women, tobacco smoking, therapy, cigarette-smoking, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, business.industry, Research, medicine.disease, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, Relative risk, North America, Other, United-State, business, Ovarian cancer, Meta-Analysis
Abstract

BACKGROUND: Smoking has been linked to mucinous ovarian cancer, but its effects on other ovarian cancer subtypes and on overall ovarian cancer risk are unclear, and the findings from most studies with relevant data are unpublished. To assess these associations, we review the published and unpublished evidence. METHODS: Eligible epidemiological studies were identified by electronic searches, review articles, and discussions with colleagues. Individual participant data for 28,114 women with and 94,942 without ovarian cancer from 51 epidemiological studies were analysed centrally, yielding adjusted relative risks (RRs) of ovarian cancer in smokers compared with never smokers. FINDINGS: After exclusion of studies with hospital controls, in which smoking could have affected recruitment, overall ovarian cancer incidence was only slightly increased in current smokers compared with women who had never smoked (RR 1·06, 95% CI 1·01-1·11, p=0·01). Of 17,641 epithelial cancers with specified histology, 2314 (13%) were mucinous, 2360 (13%) endometrioid, 969 (5%) clear-cell, and 9086 (52%) serous. Smoking-related risks varied substantially across these subtypes (p(heterogeneity)

Published
2016

20. Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women

Author

Ekelund, U, Steene-Johannessen, J, Brown, WJ, Fagerland, MW, Owen, N, Powell, KE, Bauman, A, Lee, IM, Ding, D, Heath, G, Hallal, PC, Kohl, HW, Pratt, M, Reis, R, Sallis, J, Aadahl, M, Blot, WJ, Chey, T, Deka, A, Dunstan, David, Ford, ES, Færch, K, Inoue, M, Katzmarzyk, PT, Keadle, SK, Matthews, CE, Martinez, D, Patel, AV, Pavey, T, Petersen, CB, Van Der Ploeg, H, Rangul, V, Sethi, P, Sund, ER, Westgate, K, Wijndaele, K, Yi-Park, S, Ekelund, U, Steene-Johannessen, J, Brown, WJ, Fagerland, MW, Owen, N, Powell, KE, Bauman, A, Lee, IM, Ding, D, Heath, G, Hallal, PC, Kohl, HW, Pratt, M, Reis, R, Sallis, J, Aadahl, M, Blot, WJ, Chey, T, Deka, A, Dunstan, David, Ford, ES, Færch, K, Inoue, M, Katzmarzyk, PT, Keadle, SK, Matthews, CE, Martinez, D, Patel, AV, Pavey, T, Petersen, CB, Van Der Ploeg, H, Rangul, V, Sethi, P, Sund, ER, Westgate, K, Wijndaele, K, and Yi-Park, S

Abstract

Background High amounts of sedentary behaviour have been associated with increased risks of several chronic conditions and mortality. However, it is unclear whether physical activity attenuates or even eliminates the detrimental effects of prolonged sitting. We examined the associations of sedentary behaviour and physical activity with all-cause mortality. Methods We did a systematic review, searching six databases (PubMed, PsycINFO, Embase, Web of Science, Sport Discus, and Scopus) from database inception until October, 2015, for prospective cohort studies that had individual level exposure and outcome data, provided data on both daily sitting or TV-viewing time and physical activity, and reported effect estimates for all-cause mortality, cardiovascular disease mortality, or breast, colon, and colorectal cancer mortality. We included data from 16 studies, of which 14 were identified through a systematic review and two were additional unpublished studies where pertinent data were available. All study data were analysed according to a harmonised protocol, which categorised reported daily sitting time and TV-viewing time into four standardised groups each, and physical activity into quartiles (in metabolic equivalent of task [MET]-hours per week). We then combined data across all studies to analyse the association of daily sitting time and physical activity with all-cause mortality, and estimated summary hazard ratios using Cox regression. We repeated these analyses using TV-viewing time instead of daily sitting time. Findings Of the 16 studies included in the meta-analysis, 13 studies provided data on sitting time and all-cause mortality. These studies included 1 005 791 individuals who were followed up for 2–18·1 years, during which 84 609 (8·4%) died. Compared with the referent group (ie, those sitting <4 h/day and in the most active quartile [>35·5 MET-h per week]), mortality rates during follow-up were 12–59% higher in the two lowest quartiles of physical activit

Published
2016

21. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, EJ, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, CC, Hautman, C, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Kamineni, A, Kolonel, LN, Kulke, MH, Malats, N, Olson, SH, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Brais, L, Bueno-de-Mesquita, HB, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Bijlsma, MF, Brenner, H, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Cavestro, GM, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, JM, Gazouli, M, Giovannucci, EL, Goggins, M, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Hu, N, Hunter, DJ, Iskierka-Jazdzewska, E, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Neale, RE, Oberg, AL, Panico, S, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Ramon Quiros, J, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, X-O, Silverman, DT, Soucek, P, Strobel, O, Sund, M, Malecka-Panas, E, Taylor, PR, Tavano, F, Travis, RC, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Kooperberg, C, Risch, HA, Jacobs, EJ, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, SJ, Petersen, GM, Stolzenberg-Solomon, RS, Wolpin, BM, Kraft, P, Klein, AP, Canzian, F, Amundadottir, LT, Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, EJ, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, CC, Hautman, C, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Kamineni, A, Kolonel, LN, Kulke, MH, Malats, N, Olson, SH, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Brais, L, Bueno-de-Mesquita, HB, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Bijlsma, MF, Brenner, H, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Cavestro, GM, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, JM, Gazouli, M, Giovannucci, EL, Goggins, M, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Hu, N, Hunter, DJ, Iskierka-Jazdzewska, E, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Neale, RE, Oberg, AL, Panico, S, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Ramon Quiros, J, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, X-O, Silverman, DT, Soucek, P, Strobel, O, Sund, M, Malecka-Panas, E, Taylor, PR, Tavano, F, Travis, RC, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Kooperberg, C, Risch, HA, Jacobs, EJ, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, SJ, Petersen, GM, Stolzenberg-Solomon, RS, Wolpin, BM, Kraft, P, Klein, AP, Canzian, F, and Amundadottir, LT

Abstract

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

Published
2016

22. Association between Class III Obesity (BMI of 40-59 kg/m2) and Mortality: A Pooled Analysis of 20 Prospective Studies

Author

Kitahara, CM, Flint, AJ, Berrington de Gonzalez, A, Bernstein, L, Brotzman, M, MacInnis, RJ, Moore, SC, Robien, K, Rosenberg, PS, Singh, PN, Weiderpass, E, Adami, HO, Anton-Culver, H, Ballard-Barbash, R, Buring, JE, Freedman, DM, Fraser, GE, Beane Freeman, LE, Gapstur, SM, Gaziano, JM, Giles, GG, Håkansson, N, Hoppin, JA, Hu, FB, Koenig, K, Linet, MS, Park, Y, Patel, AV, Purdue, MP, Schairer, C, Sesso, HD, Visvanathan, K, White, E, Wolk, A, Zeleniuch-Jacquotte, A, and Hartge, P

Abstract

Background:The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity.Methods and Findings:In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m2) compared with those classified as normal weight (BMI 18.5-24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976-2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report.Conclusions:Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight.Please see later in the article for the Editors' Summary.

Published
2014

24. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies

Author

Beral, V, Bull, D, Pirie, K, Reeves, G, Peto, R, Skegg, D, LaVecchia, C, Magnusson, C, Pike, MC, Thomas, D, Hamajima, N, Hirose, K, Tajima, K, Rohan, T, Friedenreich, CM, Calle, EE, Gapstur, SM, Patel, AV, Coates, RJ, Liff, JM, Talamini, R, Chantarakul, N, Koetsawang, S, Rachawat, D, Marcou, Y, Kakouri, E, Duffy, SW, Morabia, A, Schuman, L, Stewart, W, Szklo, M, Coogan, PF, Palmer, JR, Rosenberg, L, Band, P, Coldman, AJ, Gallagher, RP, Hislop, TG, Yang, P, Cummings, SR, Canfell, K, Sitas, F, Chao, P, Lissowska, J, Horn-Ross, PL, John, EM, Kolonel, LM, Nomura, AMY, Ghiasvand, R, Hu, J, Johnson, KC, Mao, Y, Callaghan, K, Crossley, B, Goodill, A, Green, J, Hermon, C, Key, T, Lindgard, I, Liu, B, Collins, R, Doll, R, Bishop, T, Fentiman, IS, De Sanjose, S, Gonzaler, CA, Lee, N, Marchbanks, P, Ory, HW, Peterson, HB, Wingo, P, Ebeling, K, Kunde, D, Nishan, P, Hopper, JL, Eliassen, H, Gajalakshmi, V, Martin, N, Pardthaisong, T, Silpisornkosol, S, Theetranont, C, Boosiri, B, Chutivongse, S, Jimakorn, P, Virutamasen, P, Wongsrichanalai, C, Neugut, A, Santella, R, Baines, CJ, Kreiger, N, Miller, AB, Wall, C, Tjonneland, A, Jorgensen, T, Stahlberg, C, Pedersen, AT, Flesch-Janys, D, Hakansson, N, Cauley, J, Heuch, I, Adami, HO, Persson, I, Weiderpass, E, Chang-Claude, J, Kaaks, R, McCredie, M, Paul, C, Skegg, DCG, Spears, GFS, Iwasaki, M, Tsugane, S, Anderson, G, Daling, JR, Hampton, J, Hutchinson, WB, Li, CI, Malone, K, Mandelson, M, Newcomb, P, Noonan, EA, Ray, RM, Stanford, JL, Tang, MTC, Thomas, DB, Weiss, NS, White, E, Izquierdo, A, Viladiu, P, Fourkala, EO, Jacobs, I, Menon, U, Ryan, A, Cuevas, HR, Ontiveros, P, Palet, A, Salazar, SB, Aristizabal, N, Cuadros, A, Tryggvadottir, L, Tulinius, H, Riboli, E, Andrieu, N, Bachelot, A, Le, MG, Bremond, A, Gairard, B, Lansac, J, Piana, L, Renaud, R, Clavel-Chapelon, F, Fournier, A, Touillaud, M, Mesrine, S, Chabbert-Buffet, N, Boutron-Ruault, MC, Wolk, A, Torres-Mejia, G, Franceschi, S, Romieu, I, Boyle, P, Lubin, F, Modan, B, Ron, E, Wax, Y, Friedman, GD, Hiatt, RA, Levi, F, Kosmelj, K, Primic-Zakelj, M, Ravnihar, B, Stare, J, Ekbom, A, Erlandsson, G, Beeson, WL, Fraser, G, Peto, J, Hanson, RL, Leske, MC, Mahoney, MC, Nasca, PC, Varma, AO, Weinstein, AL, Hartman, ML, Olsson, H, Goldbohm, RA, van den Brandt, PA, Palli, D, Teitelbaum, S, Apelo, RA, Baens, J, de la Cruz, JR, Javier, B, Lacaya, LB, Ngelangel, CA, La Vecchia, C, Negri, E, Marubini, E, Ferraroni, M, Gerber, M, Richardson, S, Segala, C, Gatei, D, Kenya, P, Kungu, A, Mati, JG, Brinton, LA, Freedman, M, Hoover, R, Schairer, C, Ziegler, R, Banks, E, Spirtas, R, Lee, HP, Rookus, MA, van Leeuwen, FE, Schoenberg, JA, Graff-Iversen, S, Selmer, R, Jones, L, McPherson, K, Neil, A, Vessey, M, Yeates, D, Mabuchi, K, Preston, D, Hannaford, P, Kay, C, McCann, SE, Rosero-Bixby, L, Gao, YT, Jin, F, Yuan, J-M, Wei, HY, Yun, T, Zhiheng, C, Berry, G, Booth, JC, Jelihovsky, T, MacLennan, R, Shearman, R, Hadjisavvas, A, Kyriacou, K, Loisidou, M, Zhou, X, Wang, Q-S, Kawai, M, Minami, Y, Tsuji, I, Lund, E, Kumle, M, Stalsberg, H, Shu, XO, Zheng, W, Monninkhof, EM, Onland-Moret, NC, Peeters, PHM, Katsouyanni, K, Trichopoulou, A, Trichopoulos, D, Tzonou, A, Baltzell, KA, Dabancens, A, Martinez, L, Molina, R, Salas, O, Alexander, FE, Anderson, K, Folsom, AR, Gammon, MD, Hulka, BS, Millikan, R, Chilvers, CED, Lumachi, F, Bain, C, Schofield, F, Siskind, V, Rebbeck, TR, Bernstein, LR, Enger, S, Haile, RW, Paganini-Hill, A, Ross, RK, Ursin, G, Wu, AH, Yu, MC, Ewertz, DM, Clarke, EA, Bergkvist, L, Anderson, GL, Gass, M, O'Sullivan, MJ, Kalache, A, Farley, TMM, Holck, S, Meirik, O, Fukao, A, Factors, CGH, Grp, SHNHSIIIR, Epidemiologie, RS: CAPHRI School for Public Health and Primary Care, RS: GROW - School for Oncology and Reproduction, RS: GROW - R1 - Prevention, RS: CAPHRI - R5 - Optimising Patient Care, and Collaborative Group on Hormonal Factors in Breast Cancer

Subjects
Aging, Breast cancer, Risk factors, Menopause, Menarche, cancer, malignancy, Ethnic origin, Disease, 0302 clinical medicine, Breast cancer, Risk Factors, Neoplasms, Receptors, Epidemiology, 80 and over, 030212 general & internal medicine, skin and connective tissue diseases, Aged, 80 and over, Patient, Obstetrics, Reproduction, Smoking, Age Factors, Middle Aged, Reproducibility, 3. Good health, Menopause, Receptors, Estrogen, Oncology, 030220 oncology & carcinogenesis, Menarche, Hormonal therapy, Female, epidemiology, Cancer Type - Breast Cancer, history, Adult, Risk, trends, medicine.medical_specialty, Design, Neoplasms, Hormone-Dependent, Requiring prolonged observation, Hormone Replacement Therapy, Oncology and Carcinogenesis, Breast Neoplasms, and over, Validity, methods, 03 medical and health sciences, Age, Clinical Research, Breast Cancer, medicine, Humans, cancer, Neoplasm Invasiveness, Women, Oncology & Carcinogenesis, Hormone-Dependent, breast, Aged, Gynecology, Collaborative Group on Hormonal Factors in Breast Cancer, therapy, business.industry, Contraception/Reproduction, Research, Estrogens, Etiology - Resources and Infrastructure, medicine.disease, Estrogen, Good Health and Well Being, cessation, Premenopause, Risk factors, Relative risk, Recall, business, malignancy, Meta-Analysis
Abstract

Background Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.Methods Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.Findings Breast cancer risk increased by a factor of 1.050 (95% CI 1.044-1.057; p < 0.0001) for every year younger at menarche, and independently by a smaller amount (1.029, 1.025-1.032; p < 0.0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1.43, 1.33-1.52, p < 0.001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p < 0.006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p < 0.01 for both comparisons).Interpretation The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.Funding Cancer Research UK.

Published
2012

25. Menarche, menopause, and breast cancer risk: Individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies

Author

Hamajima, N, Hirose, K, Tajima, K, Rohan, T, Friedenreich, CM, Calle, EE, Gapstur, SM, Patel, AV, Coates, RJ, Liff, JM, Talamini, R, Chantarakul, N, Koetsawang, S, Rachawat, D, Marcou, Y, Kakouri, E, Duffy, SW, Morabia, A, Schuman, L, Stewart, W, Szklo, M, Coogan, PF, Palmer, JR, Rosenberg, L, Band, P, Coldman, AJ, Gallagher, RP, Hislop, TG, Yang, P, Cummings, SR, Canfell, K, Sitas, F, Chao, P, Lissowska, J, Horn-Ross, PL, John, EM, Kolonel, LM, Nomura, AMY, Ghiasvand, R, Hu, J, Johnson, KC, Mao, Y, Beral, V, Bull, D, Callaghan, K, Crossley, B, Goodill, A, Green, J, Hermon, C, Key, T, Lindgard, I, Liu, B, Pirie, K, Reeves, G, Collins, R, Doll, R, Peto, R, Bishop, T, Fentiman, IS, De Sanjosé, S, Gonzalez, CA, Lee, N, Marchbanks, P, Ory, HW, Peterson, HB, Wingo, P, Ebeling, K, Kunde, D, Nishan, P, Hopper, JL, Eliassen, H, Hankinson, S, Gajalakshmi, V, Martin, N, Pardthaisong, T, Silpisornkosol, S, Theetranont, C, Boosiri, B, Chutivongse, S, Jimakorn, P, Virutamasen, P, Wongsrichanalai, C, Neugut, A, Santella, R, Baines, CJ, Kreiger, N, Miller, AB, Wall, C, Tjonneland, A, Jorgensen, T, Stahlberg, C, Pedersen, AT, Flesch-Janys, D, Hakansson, N, Cauley, J, Heuch, I, Adami, HO, Persson, I, Weiderpass, E, and Magnusson, C

Subjects
skin and connective tissue diseases
Abstract

Background Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women. Methods Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression. Findings Breast cancer risk increased by a factor of 1.050 (95% CI 1.044-1.057; p

Published
2012

26. A Pooled Analysis of Waist Circumference and Mortality in 650,000 Adults

Author

Cerhan, JR, Moore, SC, Jacobs, EJ, Kitahara, CM, Rosenberg, PS, Adami, H-O, Ebbert, JO, English, DR, Gapstur, SM, Giles, GG, Horn-Ross, PL, Park, Y, Patel, AV, Robien, K, Weiderpass, E, Willett, WC, Wolk, A, Zeleniuch-Jacquotte, A, Hartge, P, Bernstein, L, de Gonzalez, AB, Cerhan, JR, Moore, SC, Jacobs, EJ, Kitahara, CM, Rosenberg, PS, Adami, H-O, Ebbert, JO, English, DR, Gapstur, SM, Giles, GG, Horn-Ross, PL, Park, Y, Patel, AV, Robien, K, Weiderpass, E, Willett, WC, Wolk, A, Zeleniuch-Jacquotte, A, Hartge, P, Bernstein, L, and de Gonzalez, AB

Abstract

OBJECTIVES: To assess the independent effect of waist circumference on mortality across the entire body mass index (BMI) range and to estimate the loss in life expectancy related to a higher waist circumference. PATIENTS AND METHODS: We pooled data from 11 prospective cohort studies with 650,386 white adults aged 20 to 83 years and enrolled from January 1, 1986, through December 31, 2000. We used proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs for the association of waist circumference with mortality. RESULTS: During a median follow-up of 9 years (maximum, 21 years), 78,268 participants died. After accounting for age, study, BMI, smoking status, alcohol consumption, and physical activity, a strong positive linear association of waist circumference with all-cause mortality was observed for men (HR, 1.52 for waist circumferences of ≥110 vs <90 cm; 95% CI, 1.45-1.59; HR, 1.07 per 5-cm increment in waist circumference; 95% CI, 1.06-1.08) and women (HR, 1.80 for waist circumferences of ≥95 vs <70 cm; 95% CI, 1.70-1.89; HR, 1.09 per 5-cm increment in waist circumference; 95% CI, 1.08-1.09). The estimated decrease in life expectancy for highest vs lowest waist circumference was approximately 3 years for men and approximately 5 years for women. The HR per 5-cm increment in waist circumference was similar for both sexes at all BMI levels from 20 to 50 kg/m(2), but it was higher at younger ages, higher for longer follow-up, and lower among male current smokers. The associations were stronger for heart and respiratory disease mortality than for cancer. CONCLUSIONS: In white adults, higher waist circumference was positively associated with higher mortality at all levels of BMI from 20 to 50 kg/m(2). Waist circumference should be assessed in combination with BMI, even for those in the normal BMI range, as part of risk assessment for obesity-related premature mortality.

Published
2014

27. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

Author

Wolpin, BM, Rizzato, C, Kraft, P, Kooperberg, C, Petersen, GM, Wang, Z, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Canzian, F, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Jacobs, EJ, Kamineni, A, Klein, AP, Kolonel, LN, Kulke, MH, Li, D, Malats, N, Olson, SH, Risch, HA, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Austin, MA, Barfield, R, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Brotzman, M, Buechler, MW, Bueno-de-Mesquita, HB, Bugert, P, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Chung, C, Cotterchio, M, Costello, E, Elena, J, Funel, N, Gaziano, JM, Giese, NA, Goggins, M, Gorman, MJ, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Henderson, BE, Holly, EA, Hu, N, Hunter, DJ, Innocenti, F, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, LaCroix, A, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Nakamura, Y, Oberg, AL, Owzar, K, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Piepoli, A, Porta, M, Real, FX, Riboli, E, Rothman, N, Scarpa, A, Shu, X-O, Silverman, DT, Soucek, P, Sund, M, Talar-Wojnarowska, R, Taylor, PR, Theodoropoulos, GE, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Wu, C, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, SJ, Stolzenberg-Solomon, RS, Amundadottir, LT, Wolpin, BM, Rizzato, C, Kraft, P, Kooperberg, C, Petersen, GM, Wang, Z, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Canzian, F, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Jacobs, EJ, Kamineni, A, Klein, AP, Kolonel, LN, Kulke, MH, Li, D, Malats, N, Olson, SH, Risch, HA, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Austin, MA, Barfield, R, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Brotzman, M, Buechler, MW, Bueno-de-Mesquita, HB, Bugert, P, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Chung, C, Cotterchio, M, Costello, E, Elena, J, Funel, N, Gaziano, JM, Giese, NA, Goggins, M, Gorman, MJ, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Henderson, BE, Holly, EA, Hu, N, Hunter, DJ, Innocenti, F, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, LaCroix, A, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Nakamura, Y, Oberg, AL, Owzar, K, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Piepoli, A, Porta, M, Real, FX, Riboli, E, Rothman, N, Scarpa, A, Shu, X-O, Silverman, DT, Soucek, P, Sund, M, Talar-Wojnarowska, R, Taylor, PR, Theodoropoulos, GE, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Wu, C, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, SJ, Stolzenberg-Solomon, RS, and Amundadottir, LT

Abstract

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

Published
2014

28. Association between Class III Obesity (BMI of 40-59 kg/m(2)) and Mortality: A Pooled Analysis of 20 Prospective Studies

Author

Khaw, K-T, Kitahara, CM, Flint, AJ, de Gonzalez, AB, Bernstein, L, Brotzman, M, MacInnis, RJ, Moore, SC, Robien, K, Rosenberg, PS, Singh, PN, Weiderpass, E, Adami, HO, Anton-Culver, H, Ballard-Barbash, R, Buring, JE, Freedman, DM, Fraser, GE, Freeman, LEB, Gapstur, SM, Gaziano, JM, Giles, GG, Hakansson, N, Hoppin, JA, Hu, FB, Koenig, K, Linet, MS, Park, Y, Patel, AV, Purdue, MP, Schairer, C, Sesso, HD, Visvanathan, K, White, E, Wolk, A, Zeleniuch-Jacquotte, A, Hartge, P, Khaw, K-T, Kitahara, CM, Flint, AJ, de Gonzalez, AB, Bernstein, L, Brotzman, M, MacInnis, RJ, Moore, SC, Robien, K, Rosenberg, PS, Singh, PN, Weiderpass, E, Adami, HO, Anton-Culver, H, Ballard-Barbash, R, Buring, JE, Freedman, DM, Fraser, GE, Freeman, LEB, Gapstur, SM, Gaziano, JM, Giles, GG, Hakansson, N, Hoppin, JA, Hu, FB, Koenig, K, Linet, MS, Park, Y, Patel, AV, Purdue, MP, Schairer, C, Sesso, HD, Visvanathan, K, White, E, Wolk, A, Zeleniuch-Jacquotte, A, and Hartge, P

Abstract

BACKGROUND: The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. METHODS AND FINDINGS: In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m2) compared with those classified as normal weight (BMI 18.5-24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976-2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7-7

Published
2014

36. Circulating 25-hydroxyvitamin D and risk of epithelial ovarian cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.

Author

Zheng W, Danforth KN, Tworoger SS, Goodman MT, Arslan AA, Patel AV, McCullough ML, Weinstein SJ, Kolonel LN, Purdue MP, Shu X, Snyder K, Steplowski E, Visvanathan K, Yu K, Zeleniuch-Jacquotte A, Gao Y, Hankinson SE, Harvey C, and Hayes RB

Abstract

A role for vitamin D in ovarian cancer etiology is supported by ecologic studies of sunlight exposure, experimental mechanism studies, and some studies of dietary vitamin D intake and genetic polymorphisms in the vitamin D receptor. However, few studies have examined the association of circulating 25-hydroxyvitamin D (25(OH)D), an integrated measure of vitamin D status, with ovarian cancer risk. A nested case-control study was conducted among 7 prospective studies to evaluate the circulating 25(OH)D concentration in relation to epithelial ovarian cancer risk. Logistic regression models were used to estimate odds ratios and 95% confidence intervals among 516 cases and 770 matched controls. Compared with 25(OH)D concentrations of 50-<75 nmol/L, no statistically significant associations were observed for <37.5 (odds ratio (OR) = 1.21, 95% confidence interval (CI): 0.87, 1.70), 37.5-<50 (OR = 1.03, 95% CI: 0.75, 1.41), or > or =75 (OR = 1.11, 95% CI: 0.79, 1.55) nmol/L. Analyses stratified by tumor subtype, age, body mass index, and other variables were generally null but suggested an inverse association between 25(OH)D and ovarian cancer risk among women with a body mass index of > or =25 kg/m(2) (P(interaction) < 0.01). In conclusion, this large pooled analysis did not support an overall association between circulating 25(OH)D and ovarian cancer risk, except possibly among overweight women. [ABSTRACT FROM AUTHOR]

Published
2010
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37. Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.

Author

Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, Qi D, Patel AV, Helzlsouer KJ, Weinstein SJ, McCullough ML, Purdue MP, Shu X, Snyder K, Virtamo J, Wilkins LR, Yu K, Zeleniuch-Jacquotte A, Zheng W, Albanes D, Cai Q, Harvey C, and Hayes R

Abstract

Results from epidemiologic studies examining pancreatic cancer risk and vitamin D intake or 25-hydroxyvitamin D (25(OH)D) concentrations (the best indicator of vitamin D derived from diet and sun) have been inconsistent. Therefore, the authors conducted a pooled nested case-control study of participants from 8 cohorts within the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) (1974-2006) to evaluate whether prediagnostic circulating 25(OH)D concentrations were associated with the development of pancreatic cancer. In total, 952 incident pancreatic adenocarcinoma cases occurred among participants (median follow-up, 6.5 years). Controls (n = 1,333) were matched to each case by cohort, age, sex, race/ethnicity, date of blood draw, and follow-up time. Conditional logistic regression analysis was used to calculate smoking-, body mass index-, and diabetes-adjusted odds ratios and 95% confidence intervals for pancreatic cancer. Clinically relevant 25(OH)D cutpoints were compared with a referent category of 50-<75 nmol/L. No significant associations were observed for participants with lower 25(OH)D status. However, a high 25(OH)D concentration (> or =100 nmol/L) was associated with a statistically significant 2-fold increase in pancreatic cancer risk overall (odds ratio = 2.12, 95% confidence interval: 1.23, 3.64). Given this result, recommendations to increase vitamin D concentrations in healthy persons for the prevention of cancer should be carefully considered. [ABSTRACT FROM AUTHOR]

Published
2010
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38. Circulating 25-hydroxyvitamin D and risk of endometrial cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.

Author

Zeleniuch-Jacquotte A, Gallicchio L, Hartmuller V, Helzlsouer KJ, McCullough ML, Setiawan VW, Shu X, Weinstein SJ, Weiss JM, Arslan AA, De Vivo I, Gao Y, Hayes RB, Henderson BE, Horst RL, Koenig KL, Patel AV, Purdue MP, Snyder K, and Steplowski E

Abstract

A nested case-control study, including 830 cases and 992 controls from 7 cohorts, was conducted to evaluate the association of circulating 25-hydroxyvitamin D (25(OH)D), the best indicator of vitamin D status, with risk of endometrial cancer. Matching factors included age at blood donation, date of blood donation, and race. Conditional logistic regression was used in the main analysis. The median concentration of 25(OH)D was slightly lower in cases (49.4 nmol/L) than in controls (50.8 nmol/L) (P = 0.08). However, there was no association between 25(OH)D concentration and disease risk, after adjustment for body mass index. Compared with the 50-<75 nmol/L 25(OH)D category, the body mass index-adjusted odds ratios and 95% confidence intervals were 1.08 (95% confidence interval: 0.73, 1.57) for the <25 nmol/L category and 0.90 (95% confidence interval: 0.51, 1.58) for the > or =100 nmol/L category (P(trend) = 0.99). Similarly null results were observed after further adjustment for other known risk factors and in stratified analyses. Although an effect of circulating 25(OH)D at high concentrations cannot be ruled out (the highest category of 25(OH)D was > or =100 nmol/L, and for stratified analyses, > or =75 nmol/L), these results do not support a protective role of vitamin D against endometrial cancer. [ABSTRACT FROM AUTHOR]

Published
2010
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40. A prospective study of fruits, vegetables, and risk of endometrial cancer.

Author

McCullough ML, Bandera EV, Patel R, Patel AV, Gansler T, Kushi LH, Thun MJ, and Calle EE

Abstract

Case-control studies support a lower risk of endometrial cancer associated with greater vegetable consumption but not fruit consumption. One prospective study suggested an inverse association with fruits and vegetables combined. The authors examined associations for vegetables and fruits separately among women in the American Cancer Society's Cancer Prevention Study II Nutrition Cohort. After exclusions, 41,400 postmenopausal women completed a questionnaire on diet, lifestyle, and medical history at baseline in 1992-1993. Information on diet was updated in 1999; historical dietary information from 1982 was also available. The authors identified 435 eligible cases of endometrial cancer through 2003. In multivariate models, neither fruit consumption (top quintile vs. bottom: rate ratio (RR) = 1.24, 95% confidence interval (CI): 0.90, 1.70; p-trend = 0.30) nor vegetable consumption (RR = 1.21, 95% CI: 0.89, 1.65; p-trend = 0.24) at baseline was associated with risk. Results were similar when diet was cumulatively updated. Only among women who had never used hormone replacement therapy was the risk of endometrial cancer lower in the highest (vs. lowest) tertile of fruit (RR = 0.75, 95% CI: 0.52, 1.07; p-interaction = 0.03, p-trend = 0.11) or vegetable (RR = 0.80, 95% CI: 0.57, 1.13; p-interaction = 0.01, p-trend = 0.29) consumption. This prospective study does not support an association between vegetable or fruit consumption and endometrial cancer. [ABSTRACT FROM AUTHOR]

Published
2007
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41. Neuropsychological performance, postural stability, and symptoms after dehydration.

Author

Patel AV, Mihalik JP, Notebaert AJ, Guskiewicz KM, and Prentice WE

Abstract

Context: Dehydration and concussion are common in athletic performance. Some experts have speculated that dehydration may negatively influence performance on tests commonly used for concussion assessment. Objective: To determine how the signs and symptoms, neuropsychological performance, and postural stability are affected by dehydration. Design: Repeated-measures design assessing subjects in the euhydrated and dehydrated conditions. Setting: Sports Medicine Research Laboratory. Patients or Other Participants: Twenty-four healthy, male recreational athletes participated in the study. Intervention(s): Subjects participated in 2 counterbalanced sessions (euhydrated and dehydrated) separated by at least 7 days. Subjects were dehydrated using fluid restriction and an exercise task. No direct intervention was provided for the euhydrated condition. Main Outcome Measure(s): We used the Standardized Assessment of Concussion to test mental status, the Automated Neuropsychological Assessment Metrics (ANAM) to evaluate neuropsychological performance, the NeuroCom Sensory Organization Test and Balance Error Scoring System to test postural stability, the Graded Symptom Checklist to assess symptom presence and severity in our participants, and urine specific gravity and body mass to determine hydration status. Results: No differences were noted for the Standardized Assessment of Concussion, total Balance Error Scoring System errors, composite Sensory Organization Test, and composite ANAM scores between conditions. Subjects in the dehydrated condition had significant deterioration in visual memory (t[23] = 2. 130, P < . 001) and fatigue measures (t[23] =-7. 880, P < . 001) as assessed by ANAM. The dehydrated condition resulted in subjects reporting a significantly higher number (t[23] =-8. 585, P < . 001) and severity (t[23] =-7. 673, P < . 001) of symptoms than the euhydrated subjects on the Graded Symptom Checklist. Conclusions: Our results suggest that moderate dehydration (-2. 5 ± 0. 63%) significantly influenced the self-report of symptoms commonly associated with concussion. Dehydration resulted in a deterioration of visual memory and increases in the self-report of fatigue. Despite these findings, dehydration did not affect other neuropsychological and postural stability objective testing measures for concussion. [ABSTRACT FROM AUTHOR]

Published
2007

43. Familial systemic amyloidosis associated with bilateral sensorineural hearing loss and bilateral facial palsies.

Author

Hornigold R, Patel AV, Ward VM, and O'Connor AF

Abstract

The Finnish type of familial amyloid polyneuropathy due to variant gelsolin is a rare form of familial amyloidosis. The subtype was first described in 1969 and is characterized by progressive cranial neuropathies, corneal lattice dystrophy and distal sensorimotor dysfunction. It is extremely uncommon, with only two families known to be affected in the UK. We discuss the case of a 70-year-old woman who presented with bilateral facial nerve palsies, bilateral sensorineural hearing loss and Finnish type familial hereditary amyloidosis. A literature search of the Medline database (1966-2005) was performed, using the keywords 'amyloid', 'hearing loss' and 'facial palsy'; however, this association appears to be a novel finding. We review the current literature and discuss otorhinolaryngological presentations of amyloidosis. [ABSTRACT FROM AUTHOR]

Published
2006
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45. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Author

Hidemi Ito, Stephen K. Van Den Eeden, Abdisamad M. Ibrahim, Ching C. Lau, Preetha Rajaraman, Gloria M. Petersen, Judith Hoffman-Bolton, Colin P.N. Dinney, Chang Hyun Kang, Melinda C. Aldrich, Mark P. Purdue, Xiao-Ou Shu, William J. Blot, Sanjay Shete, Alpa V. Patel, Charles Kooperberg, Paolo Vineis, David Van Den Berg, Chao A. Hsiung, Anthony J. Swerdlow, Qing Lan, Wu Chou Su, Afshan Siddiq, Ulrike Peters, Katia Scotlandi, Sara H. Olson, Kendra Schwartz, Kelly L. Bolton, Chancellor Hohensee, Josep Lloreta, Kevin B. Jacobs, Debra T. Silverman, Rudolf Kaaks, Wei Zheng, Steven Gallinger, Junwen Wang, Angela Carta, Massimo Serra, Petra H.M. Peeters, Victoria L. Stevens, Yasushi Yatabe, Geraldine Cancel-Tassin, Joshua N. Sampson, Young Tae Kim, Graham A. Colditz, Pan-Chyr Yang, Baosen Zhou, Fredrick R. Schumacher, Nicolas Wentzensen, Evelyn Tay, Claudia Maria Hattinger, Chen Wu, Pilar Amiano, Mattias Johansson, Maxwell P. Lee, Christian P. Kratz, Michael B. Cook, Mingfeng Zhang, Kay-Tee Khaw, Jian-Min Yuan, Anne Zeleniuch-Jacquotte, Jinping Jia, Roberto Tirabosco, Jing Ma, Neil E. Caporaso, Christopher A. Haiman, Bu Tian Ji, Adrienne M. Flanagan, Neyssa Marina, Eric J. Jacobs, Sophia S. Wang, Chong-Jen Yu, Edward Giovannucci, Margaret Wrensch, Robert L. Grubb, Bin Zhu, Daniel O. Stram, Manolis Kogevinas, Margaret R. Karagas, Mazda Jenab, Alison M. Mondul, Jun Xu, Preethi S. Raj, Anders Ahlbom, Christine D. Berg, Shelley Niwa, Kala Visvanathan, Loic Le Marchand, Jorge R. Toro, Robert N. Hoover, Heather Spencer Feigelson, Michelle Brotzman, Laurence N. Kolonel, Krista A. Zanetti, Chengfeng Wang, Mary Ann Butler, Ann Truelove, Irene L. Andrulis, Hongbing Shen, H. Dean Hosgood, Ming Shyan Huang, Gee-Chen Chang, Jianjun Liu, John K. Wiencke, Stephanie J. Weinstein, Beatrice Melin, Kouya Shiraishi, Zhihua Yin, Lee E. Moore, Börje Ljungberg, Jolanta Lissowska, Elizabeth M. Gillanders, M. T. Landi, Cari M. Kitahara, Maria Feychting, Kuan-Yu Chen, Matthias Simon, Brian M. Wolpin, Hemang Parikh, Hannah P. Yang, Graham G. Giles, Alison Johnson, Demetrius Albanes, Carlos González, Brian E. Henderson, Xifeng Wu, Harvey A. Risch, Amy Hutchinson, Christopher Hautman, Constance Chen, Zhibin Hu, Donghui Li, Elio Riboli, Julie E. Buring, Curtis C. Harris, Xu Che, Núria Malats, Roger Henriksson, Rosario Tumino, Joanne S. Colt, Alfredo Carrato, Paolo Boffetta, Maria Pik Wong, Hideo Tanaka, Federico Canzian, Alan D. L. Sihoe, Chien-Jen Chen, Kenneth Muir, Chen Ying, Qincheng He, Melissa C. Southey, Marc Sanson, Victoria K. Cortessis, Sharon A. Savage, Wei Hu, Yao Tettey, Daniela S. Gerhard, Sofia Pavanello, Guangwen Cao, H. Barton Grossman, Michael Goggins, Hideo Kunitoh, Peter D. Inskip, Seth P. Lerner, Peter Kraft, David Thomas, Peng Guan, Chung Hsing Chen, I. Shou Chang, Christoffer Johansen, Roberta McKean-Cowdin, Lee J. Helman, Yuh Min Chen, Ana Patiño-García, Pär Stattin, Xiaoping Miao, Tangchun Wu, Jay S. Wunder, Ann W. Hsing, Yu-Tang Gao, Brooke L. Fridley, Tania Carreón, Charles C. Chung, Nan Hu, Yoo Jin Jung, Richard B. Biritwum, Eric J. Duell, Philip R. Taylor, Satu Männistö, Kai Yu, Meredith Yeager, Xia Pu, Vittorio Krogh, Anand P. Chokkalingam, Susan M. Gapstur, W. Ryan Diver, Yuanqing Ye, Keitaro Matsuo, Cecilia Arici, You-Lin Qiao, Alan R. Schned, Dominique S. Michaud, Joanne W. Elena, Christopher Kim, Dongxin Lin, Yun-Chul Hong, Daru Lu, Reina García-Closas, Jonine D. Figueroa, Linda M. Liao, Yi-Long Wu, Heiner Boeing, Mark Lathrop, Göran Hallmans, Elizabeth A. Holly, Carol Giffen, Andrew A. Adjei, Consol Serra, Anne Tjønneland, Joseph F. Fraumeni, Alisa M. Goldstein, Ruth C. Travis, Rebecca Troisi, Dalsu Baris, Nalan Gokgoz, Olivier Cussenot, Xiang Deng, Yeul Hong Kim, Malin Sund, Sonja I. Berndt, E. David Crawford, Edward D. Yeboah, Sook Whan Sung, Françoise Clavel-Chapelon, Woon-Puay Koh, Nilgun Kurucu, Richard B. Hayes, Ashish M. Kamat, Beata Peplonska, Laurie Burdette, Ze Zhang Tang, Alan A. Arslan, Malcolm C. Pike, Sabina Sierri, J. Michael Gaziano, Lorna H. McNeil, Katherine A. McGlynn, Ulla Vogel, Logan G. Spector, H. Bas Bueno-de-Mesquita, Stephen J. Chanock, Jae Yong Park, Jennifer Prescott, Fernando Lecanda, Margaret A. Tucker, Ti Ding, Christian C. Abnet, Jenny Chang-Claude, Dimitrios Trichopoulos, Wei-Yen Lim, Wen Tan, Nick Orr, Jin Hee Kim, Stefano Porru, Chand Khanna, Robert R. McWilliams, Zhaoming Wang, Jeong Seon Ryu, David V. Conti, Alison P. Klein, Adonina Tardón, Robert J. Klein, Rebecca J. Rodabough, Mark H. Greene, Aruna Kamineni, Jie Lin, Rachael Z. Stolzenberg-Solomon, Patricia Hartge, Susan E. Hankinson, Young-Chul Kim, In Sam Kim, Luis Sierrasesúmaga, Roel Vermeulen, Paige M. Bracci, Mariana C. Stern, Louise A. Brinton, Myron D. Gross, Yong-Bing Xiang, Chih Yi Chen, G. A. Gerald Andriole, Paul S. Meltzer, Ying-Huang Tsai, Faith G. Davis, Ulrika Andersson, Paul Brennan, Sara Lindström, Chaoyu Wang, Giuseppe Mastrangelo, Laufey T. Amundadottir, Immaculata De Vivo, Bryan A. Bassig, Elisabete Weiderpass, Takashi Kohno, Nilanjan Chatterjee, Margaret R. Spitz, Pier Alberto Bertazzi, William Wheeler, David J. Hunter, Wei Tang, Qiuyin Cai, Naomi E. Allen, Molly Schwenn, Emily White, Min Shen, Adeline Seow, Laura E. Beane Freeman, James E. Mensah, Howard D. Sesso, Anna Luisa Di Stefano, Amanda Black, Manuela Gago-Dominguez, Christine B. Ambrosone, Avima M. Ruder, Martha S. Linet, Meir J. Stampfer, Robert C. Kurtz, Donald A. Barkauskas, Lisa W. Chu, Montserrat Garcia-Closas, Jason W. Hoskins, Melissa A. Austin, Kyoung Mu Lee, Jianxin Shi, Charles S. Fuchs, Nathaniel Rothman, Richard Gorlick, Piero Picci, Gianluca Severi, Ann G. Schwartz, Jian Gu, Christopher I. Amos, Marie-Christine Boutron-Ruault, Salvatore Panico, Alicja Wolk, Sara S. Strom, Lisa Mirabello, Jin-Hu Fan, Chin-Fu Hsiao, Neal D. Freedman, Geoffrey S. Tobias, Julie M. Gastier-Foster, Wang, Z, Zhu, B, Zhang, M, Parikh, H, Jia, J, Chung, Cc, Sampson, Jn, Hoskins, Jw, Hutchinson, A, Burdette, L, Ibrahim, A, Hautman, C, Raj, P, Abnet, Cc, Adjei, Aa, Ahlbom, A, Albanes, D, Allen, Ne, Ambrosone, Cb, Aldrich, M, Amiano, P, Amos, C, Andersson, U, Andriole G., Jr, Andrulis, Il, Arici, C, Arslan, Aa, Austin, Ma, Baris, D, Barkauskas, Da, Bassig, Ba, Beane Freeman, Le, Berg, Cd, Berndt, Si, Bertazzi, Pa, Biritwum, Rb, Black, A, Blot, W, Boeing, H, Boffetta, P, Bolton, K, Boutron Ruault, Mc, Bracci, Pm, Brennan, P, Brinton, La, Brotzman, M, Bueno de Mesquita, Hb, Buring, Je, Butler, Ma, Cai, Q, Cancel Tassin, G, Canzian, F, Cao, G, Caporaso, Ne, Carrato, A, Carreon, T, Carta, A, Chang, Gc, Chang, I, Chang Claude, J, Che, X, Chen, Cj, Chen, Cy, Chen, Ch, Chen, C, Chen, Ky, Chen, Ym, Chokkalingam, Ap, Chu, Lw, Clavel Chapelon, F, Colditz, Ga, Colt, J, Conti, D, Cook, Mb, Cortessis, Vk, Crawford, Ed, Cussenot, O, Davis, Fg, De Vivo, I, Deng, X, Ding, T, Dinney, Cp, Di Stefano, Al, Diver, Wr, Duell, Ej, Elena, Jw, Fan, Jh, Feigelson, H, Feychting, M, Figueroa, Jd, Flanagan, Am, Fraumeni JF, Jr, Freedman, Nd, Fridley, Bl, Fuchs, C, Gago Dominguez, M, Gallinger, S, Gao, Yt, Gapstur, Sm, Garcia Closas, M, Garcia Closas, R, Gastier Foster, Jm, Gaziano, Jm, Gerhard, D, Giffen, Ca, Giles, Gg, Gillanders, Em, Giovannucci, El, Goggins, M, Gokgoz, N, Goldstein, Am, Gonzalez, C, Gorlick, R, Greene, Mh, Gross, M, Grossman, Hb, Grubb R., 3rd, Gu, J, Guan, P, Haiman, Ca, Hallmans, G, Hankinson, Se, Harris, Cc, Hartge, P, Hattinger, C, Hayes, Rb, He, Q, Helman, L, Henderson, Be, Henriksson, R, Hoffman Bolton, J, Hohensee, C, Holly, Ea, Hong, Yc, Hoover, Rn, Hosgood HD, 3rd, Hsiao, Cf, Hsing, Aw, Hsiung, Ca, Hu, N, Hu, W, Hu, Z, Huang, M, Hunter, Dj, Inskip, Pd, Ito, H, Jacobs, Ej, Jacobs, Kb, Jenab, M, Ji, Bt, Johansen, C, Johansson, M, Johnson, A, Kaaks, R, Kamat, Am, Kamineni, A, Karagas, M, Khanna, C, Khaw, Kt, Kim, C, Kim, I, Kim, Yh, Kim, Yc, Kim, Yt, Kang, Ch, Jung, Yj, Kitahara, Cm, Klein, Ap, Klein, R, Kogevinas, M, Koh, Wp, Kohno, T, Kolonel, Ln, Kooperberg, C, Kratz, Cp, Krogh, V, Kunitoh, H, Kurtz, Rc, Kurucu, N, Lan, Q, Lathrop, M, Lau, Cc, Lecanda, F, Lee, Km, Lee, Mp, Le Marchand, L, Lerner, Sp, Li, D, Liao, Lm, Lim, Wy, Lin, D, Lin, J, Lindstrom, S, Linet, M, Lissowska, J, Liu, J, Ljungberg, B, Lloreta, J, Lu, D, Ma, J, Malats, N, Mannisto, S, Marina, N, Mastrangelo, G, Matsuo, K, Mcglynn, Ka, McKean Cowdin, R, Mcneill, Lh, Mcwilliams, Rr, Melin, B, Meltzer, P, Mensah, Je, Miao, X, Michaud, D, Mondul, Am, Moore, Le, Muir, K, Niwa, S, Olson, Sh, Orr, N, Panico, Salvatore, Park, Jy, Patel, Av, Patino Garcia, A, Pavanello, S, Peeters, Ph, Peplonska, B, Peters, U, Petersen, Gm, Picci, P, Pike, Mc, Porru, S, Prescott, J, Pu, X, Purdue, Mp, Qiao, Yl, Rajaraman, P, Riboli, E, Risch, Ha, Rodabough, Rj, Rothman, N, Ruder, Am, Ryu, J, Sanson, M, Schned, A, Schumacher, Fr, Schwartz, Ag, Schwartz, Kl, Schwenn, M, Scotlandi, K, Seow, A, Serra, C, Serra, M, Sesso, Hd, Severi, G, Shen, H, Shen, M, Shete, S, Shiraishi, K, Shu, Xo, Siddiq, A, Sierrasesumaga, L, Sierri, S, Loon Sihoe, Ad, Silverman, Dt, Simon, M, Southey, Mc, Spector, L, Spitz, M, Stampfer, M, Stattin, P, Stern, Mc, Stevens, Vl, Stolzenberg Solomon, Rz, Stram, Do, Strom, S, Su, Wc, Sund, M, Sung, Sw, Swerdlow, A, Tan, W, Tanaka, H, Tang, W, Tang, Zz, Tardon, A, Tay, E, Taylor, Pr, Tettey, Y, Thomas, Dm, Tirabosco, R, Tjonneland, A, Tobias, G, Toro, Jr, Travis, Rc, Trichopoulos, D, Troisi, R, Truelove, A, Tsai, Yh, Tucker, Ma, Tumino, R, Van Den Berg, D, Van Den Eeden, Sk, Vermeulen, R, Vineis, P, Visvanathan, K, Vogel, U, Wang, C, Wang, J, Wang, S, Weiderpass, E, Weinstein, Sj, Wentzensen, N, Wheeler, W, White, E, Wiencke, Jk, Wolk, A, Wolpin, Bm, Wong, Mp, Wrensch, M, Wu, C, Wu, T, Wu, X, Wu, Yl, Wunder, J, Xiang, Yb, Xu, J, Yang, Hp, Yang, Pc, Yatabe, Y, Ye, Y, Yeboah, Ed, Yin, Z, Ying, C, Yu, Cj, Yu, K, Yuan, Jm, Zanetti, Ka, Zeleniuch Jacquotte, A, Zheng, W, Zhou, B, Mirabello, L, Savage, Sa, Kraft, P, Chanock, Sj, Yeager, M, Landi, Mt, Shi, J, Chatterjee, N, Amundadottir, Lt, Wang, Z., Zhu, B., Zhang, M., Parikh, H., Jia, J., Chung, C.C., Sampson, J.N., Hoskins, J.W., Hutchinson, A., Burdette, L., Ibrahim, A., Hautman, C., Raj, P.S., Abnet, C.C., Adjei, A.A., Ahlbom, A., Albanes, D., Allen, N.E., Ambrosone, C.B., Aldrich, M., Amiano, P., Amos, C., Andersson, U., Gerald Andriole, G.A., Jr., Andrulis, I.L., Arici, C., Arslan, A.A., Austin, M.A., Baris, D., Barkauskas, D.A., Bassig, B.A., Freeman, L.E.B., Berg, C.D., Berndt, S.I., Bertazzi, P.A., Biritwum, R.B., Black, A., Blot, W., Boeing, H., Boffetta, P., Bolton, K., Boutron-Ruault, M.-C., Bracci, P.M., Brennan, P., Brinton, L.A., Brotzman, M., Bueno-de-Mesquita, H.B., Buring, J.E., Butler, M.A., Cai, Q., Cancel-Tassin, G., Canzian, F., Cao, G., Caporaso, N.E., Carrato, A., Carreon, T., Carta, A., Chang, G.-C., Chang, I.-S., Chang-Claude, J., Che, X., Chen, C.-J., Chen, C.-Y., Chen, C.-H., Chen, C., Chen, K.-Y., Chen, Y.-M., Chokkalingam, A.P., Chu, L.W., Clavel-Chapelon, F., Colditz, G.A., Colt, J.S., Conti, D., Cook, M.B., Cortessis, V.K., Crawford, E.D., Cussenot, O., Davis, F.G., De Vivo, I., Deng, X., Ding, T., Dinney, C.P., Di Stefano, A.L., Diver, W.R., Duell, E.J., Elena, J.W., Fan, J.-H., Feigelson, H.S., Feychting, M., Figueroa, J.D., Flanagan, A.M., Fraumeni, J.F., Jr., Freedman, N.D., Fridley, B.L., Fuchs, C.S., Gago-Dominguez, M., Gallinger, S., Gao, Y.-T., Gapstur, S.M., Garcia-Closas, M., Garcia-Closas, R., Gastier-Foster, J.M., Gaziano, J.M., Gerhard, D.S., Giffen, C.A., Giles, G.G., Gillanders, E.M., Giovannucci, E.L., Goggins, M., Gokgoz, N., Goldstein, A.M., Gonzalez, C., Gorlick, R., Greene, M.H., Gross, M., Grossman, H.B., Grubb, R., III and Gu, J., Guan, P., Haiman, C.A., Hallmans, G., Hankinson, S.E., Harris, C.C., Hartge, P., Hattinger, C., Hayes, R.B., He, Q., Helman, L., Henderson, B.E., Henriksson, R., Hoffman-Bolton, J., Hohensee, C., Holly, E.A., Hong, Y.-C., Hoover, R.N., Dean Hosgood, H., Hsiao, C.-F., Hsing, A.W., Hsiung, C.A., Hu, N., Hu, W., Hu, Z., Huang, M.-S., Hunter, D.J., Inskip, P.D., Ito, H., Jacobs, E.J., Jacobs, K.B., Jenab, M., Ji, B.-T., Johansen, C., Johansson, M., Johnson, A., Kaaks, R., Kamat, A.M., Kamineni, A., Karagas, M., Khanna, C., Khaw, K.-T., Kim, C., Kim, I.-S., Kim, J.H., Kim, Y.H., Kim, Y.-C., Kim, Y.T., Kang, C.H., Jung, Y.J., Kitahara, C.M., Klein, A.P., Klein, R., Kogevinas, M., Koh, W.-P., Kohno, T., Kolonel, L.N., Kooperberg, C., Kratz, C.P., Krogh, V., Kunitoh, H., Kurtz, R.C., Kurucu, N., Lan, Q., Lathrop, M., Lau, C.C., Lecanda, F., Lee, K.-M., Lee, M.P., Marchand, L.L., Lerner, S.P., Li, D., Liao, L.M., Lim, W.-Y., Lin, D., Lin, J., Lindstrom, S., Linet, M.S., Lissowska, J., Liu, J., Ljungberg, B., Lloreta, J., Lu, D., Ma, J., Malats, N., Mannisto, S., Marina, N., Mastrangelo, G., Matsuo, K., McGlynn, K.A., McKean-Cowdin, R., McNeil, L.H., McWilliams, R.R., Melin, B.S., Meltzer, P.S., Mensah, J.E., Miao, X., Michaud, D.S., Mondul, A.M., Moore, L.E., Muir, K., Niwa, S., Olson, S.H., Orr, N., Panico, S., Park, J.Y., Patel, A.V., Patino-Garcia, A., Pavanello, S., Peeters, P.H.M., Peplonska, B., Peters, U., Petersen, G.M., Picci, P., Pike, M.C., Porru, S., Prescott, J., Pu, X., Purdue, M.P., Qiao, Y.-L., Rajaraman, P., Riboli, E., Risch, H.A., Rodabough, R.J., Rothman, N., Ruder, A.M., Ryu, J.-S., Sanson, M., Schned, A., Schumacher, F.R., Schwartz, A.G., Schwartz, K.L., Schwenn, M., Scotlandi, K., Seow, A., Serra, C., Serra, M., Sesso, H.D., Severi, G., Shen, H., Shen, M., Shete, S., Shiraishi, K., Shu, X.-O., Siddiq, A., Sierrasesumaga, L., Sierri, S., Sihoe, A.D.L., Silverman, D.T., Simon, M., Southey, M.C., Spector, L., Spitz, M., Stampfer, M., Stattin, P., Stern, M.C., Stevens, V.L., Stolzenberg-Solomon, R.Z., Stram, D.O., Strom, S.S., Su, W.-C., Sund, M., Sung, S.W., Swerdlow, A., Tan, W., Tanaka, H., Tang, W., Tang, Z.-Z., Tardon, A., Tay, E., Taylor, P.R., Tettey, Y., Thomas, D.M., Tirabosco, R., Tjonneland, A., Tobias, G.S., Toro, J.R., Travis, R.C., Trichopoulos, D., Troisi, R., Truelove, A., Tsai, Y.-H., Tucker, M.A., Tumino, R., Van Den Berg, D., Van Den Eeden, S.K., Vermeulen, R., Vineis, P., Visvanathan, K., Vogel, U., Wang, C., Wang, J., Wang, S.S., Weiderpass, E., Weinstein, S.J., Wentzensen, N., Wheeler, W., White, E., Wiencke, J.K., Wolk, A., Wolpin, B.M., Wong, M.P., Wrensch, M., Wu, C., Wu, T., Wu, X., Wu, Y.-L., Wunder, J.S., Xiang, Y.-B., Xu, J., Yang, H.P., Yang, P.-C., Yatabe, Y., Ye, Y., Yeboah, E.D., Yin, Z., Ying, C., Yu, C.-J., Yu, K., Yuan, J.-M., Zanetti, K.A., Zeleniuch-Jacquotte, A., Zheng, W., Zhou, B., Mirabello, L., Savage, S.A., Kraft, P., Chanock, S.J., Yeager, M., Landi, M.T., Shi, J., Chatterjee, N., and Amundadottir, L.T.

Subjects
Male, SINGLE-NUCLEOTIDE POLYMORPHISM, Genome-wide association study, Epigenesis, Genetic, Gene Frequency, Molecular Biology, Genetics, Genetics (clinical), Neoplasms, Odds Ratio, Genome-wide association studies (GWAS), Telomerase, DNA METHYLATION Author Information, Association Studies Articles, General Medicine, PANCREATIC-CANCER, PROSTATE-CANCER, Neoplasm Proteins, POSTMENOPAUSAL BREAST-CANCER, TERT PROMOTER MUTATIONS, Gene Expression Regulation, Neoplastic, 2 SUSCEPTIBILITY LOCI, DNA methylation, Chromosomes, Human, Pair 5, Female, Risk, Locus (genetics), Single-nucleotide polymorphism, TERT and CLPTM1L gene, Biology, Polymorphism, Single Nucleotide, LUNG-CANCER, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, Gene, Allele frequency, Alleles, Genetic association, chromosome 5p15.33, Computational Biology, Membrane Proteins, DNA Methylation, Genetic Loci, TELOMERE LENGTH, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Published
2014

46. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Anne Tjønneland, Jason W. Hoskins, Kala Visvanathan, Yogesh K. Vashist, Dimitrios Trichopoulos, Matthew H. Kulke, Ruth C. Travis, Charles S. Fuchs, Herbert Yu, Kai Yu, Phyllis J. Goodman, Michael Goggins, Jean Wactawski-Wende, Laurie Burdette, Joanne W. Elena, Andrea Mambrini, Petra H.M. Peeters, H. Bas Bueno-de-Mesquita, Maria Teresa Landi, Ulrike Peters, Mingfeng Zhang, Laurence N. Kolonel, Hermann Brenner, Elżbieta Iskierka-Jażdżewska, Robert C. Kurtz, Stephen J. Chanock, Marie-Christine Boutron-Ruault, Ann L. Oberg, Elio Riboli, Maarten F. Bijlsma, Eric J. Jacobs, Manolis Kogevinas, Evelina Mocci, Steven Gallinger, Jinping Jia, Mark P. Purdue, Raffaele Pezzilli, Harvey A. Risch, Demetrius Albanes, Irene Collins, Maria Gazouli, Michelle Cotterchio, Oliver Strobel, Erica J. Childs, Charles C. Chung, Geoffrey S. Tobias, J. Ramón Quirós, Núria Malats, Robert N. Hoover, Pavel Vodicka, Brian M. Wolpin, Ugo Boggi, Patricia Hartge, Gloria M. Petersen, Peter Kraft, Christopher Hautman, Gary E. Goodman, Manal Hassan, Donghui Li, Howard D. Sesso, Malin Sund, Julie E. Buring, Loic Le Marchand, Wei Zheng, Xiao-Ou Shu, Ewa Małecka-Panas, Pavel Soucek, Salvatore Panico, Nicolas Wentzensen, Graham G. Giles, Alpa V. Patel, Daniele Campa, Myron D. Gross, Ghislaine Scelo, J. Michael Gaziano, Juozas Kupcinskas, Debra T. Silverman, Laufey T. Amundadottir, Rachael S. Stolzenberg-Solomon, Neil E. Caporaso, Mazda Jenab, Sara H. Olson, Stefano Landi, Giulia Martina Cavestro, Aruna Kamineni, Laura Beane-Freeman, Roger L. Milne, Rachel E. Neale, Aldo Scarpa, Kathy J. Helzlsouer, Miquel Porta, Emily White, Eric J. Duell, Paige M. Bracci, Nan Hu, Federico Canzian, Eric A. Klein, Gabriele Capurso, Anne Zeleniuch-Jacquotte, Eithne Costello, David J. Hunter, Rudolf Kaaks, Sonja I. Berndt, Kay-Tee Khaw, Nathaniel Rothman, Christian C. Abnet, Francesca Tavano, Christopher A. Haiman, Zhaoming Wang, Ofure Obazee, Alan A. Arslan, Edward Giovannucci, Alison P. Klein, Daniela Basso, Charles Kooperberg, Philip R. Taylor, Satu Männistö, Timothy J. Key, Mark D. Thornquist, Gabriella Andreotti, Lauren K. Brais, Gisella Figlioli, Vittorio Krogh, University Medical Center Utrecht, Imperial College Trust, Cancer Research UK, Medical Research Council UK (MRC), National Institute for Health Research (NIHR), Cancer Research UK (Reino Unido), Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Zhang, Mingfeng, Wang, Zhaoming, Obazee, Ofure, Jia, Jinping, Childs, Erica J, Hoskins, Jason, Figlioli, Gisella, Mocci, Evelina, Collins, Irene, Chung, Charles C, Hautman, Christopher, Arslan, Alan A, Beane Freeman, Laura, Bracci, Paige M, Buring, Julie, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Kamineni, Aruna, Kolonel, Laurence N, Kulke, Matthew H, Malats, Núria, Olson, Sara H, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetriu, Andreotti, Gabriella, Brais, Lauren, Bueno de Mesquita, H. Ba, Basso, Daniela, Berndt, Sonja I, Boutron Ruault, Marie Christine, Bijlsma, Maarten F, Brenner, Hermann, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Cavestro, Giulia Martina, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Boggi, Ugo, Gaziano, J. Michael, Gazouli, Maria, Giovannucci, Edward L, Goggins, Michael, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Hu, Nan, Hunter, David J, Iskierka Jazdzewska, Elzbieta, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay Tee, Klein, Eric A, Kogevinas, Manoli, Krogh, Vittorio, Kupcinskas, Juoza, Kurtz, Robert C, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Neale, Rachel E, Oberg, Ann L, Panico, Salvatore, Patel, Alpa V, Peeters, Petra H. M, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Purdue, Mark, Quiros, J. Ramón, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Scelo, Ghislaine, Shu, Xiao Ou, Silverman, Debra T, Soucek, Pavel, Strobel, Oliver, Sund, Malin, Małecka Panas, Ewa, Taylor, Philip R, Tavano, Francesca, Travis, Ruth C, Thornquist, Mark, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrio, Vashist, Yogesh, Vodicka, Pavel, Wactawski Wende, Jean, Wentzensen, Nicola, Yu, Herbert, Yu, Kai, Zeleniuch Jacquotte, Anne, Kooperberg, Charle, Risch, Harvey A, Jacobs, Eric J, Li, Donghui, Fuchs, Charle, Hoover, Robert, Hartge, Patricia, Chanock, Stephen J, Petersen, Gloria M, Stolzenberg Solomon, Rachael S, Wolpin, Brian M, Kraft, Peter, Klein, Alison P, Canzian, Federico, Amundadottir, Laufey T., Khaw, Kay-Tee [0000-0002-8802-2903], Apollo - University of Cambridge Repository, CCA -Cancer Center Amsterdam, Center of Experimental and Molecular Medicine, Radiotherapy, Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, Ej, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, Cc, Hautman, C, Arslan, Aa, Beane Freeman, L, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Giles, Gg, Goodman, Ge, Goodman, Pj, Kamineni, A, Kolonel, Ln, Kulke, Mh, Malats, N, Olson, Sh, Sesso, Hd, Visvanathan, K, White, E, Zheng, W, Abnet, Cc, Albanes, D, Andreotti, G, Brais, L, Bueno de Mesquita, Hb, Basso, D, Berndt, Si, Boutron Ruault, Mc, Bijlsma, Mf, Brenner, H, Burdette, L, Campa, D, Caporaso, Ne, Capurso, G, Cavestro, GIULIA MARTINA, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, Jm, Gazouli, M, Giovannucci, El, Goggins, M, Gross, M, Haiman, Ca, Hassan, M, Helzlsouer, Kj, Hu, N, Hunter, Dj, Iskierka Jazdzewska, E, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Klein, Ea, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, Rc, Landi, Mt, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, Rl, Neale, Re, Oberg, Al, Panico, S, Patel, Av, Peeters, Ph, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Quiros, Jr, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, Xo, Silverman, Dt, Soucek, P, Strobel, O, Sund, M, Małecka Panas, E, Taylor, Pr, Tavano, F, Travis, Rc, Thornquist, M, Tjønneland, A, Tobias, G, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Kooperberg, C, Risch, Ha, Jacobs, Ej, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, Sj, Petersen, Gm, Stolzenberg Solomon, R, Wolpin, Bm, Kraft, P, Klein, Ap, Canzian, F, and Amundadottir, L. T.

Subjects
0301 basic medicine, Candidate gene, Pancreatic disease, GENETIC SUSCEPTIBILITY, pancreatic cancer, Datasets as Topic, Genome-wide association study, imputation, TRET, 0302 clinical medicine, Fine-mapping, GWAS, Imputation, NR5A2, Pancreatic cancer, Oncology, Genotype, Genetics, 3. Good health, fine-mapping, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 8, 616.37-006.6 [udc], BLADDER-CANCER, Single-nucleotide polymorphism, GENOTYPE IMPUTATION, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Journal Article, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Pàncrees -- Càncer, Cancer och onkologi, LONG-RANGE INTERACTION, business.industry, medicine.disease, Pancreatic neoplasms, genetics, Polymorphism, single nucleotide, RISK LOCI, Fold change, COMMON VARIANT, Cromosomes, Pancreatic Neoplasms, 030104 developmental biology, Cancer and Oncology, business, Imputation (genetics), LRH-1, Priority Research Paper, Genome-Wide Association Study
Abstract

Altres ajuts: The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials. Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88×10 −15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10 −9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10 −8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L - TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7×10 −8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5×10 −4 -2.0×10 −3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

Published
2016

47. Genome-wide Association Study Of Survival In Patients With Pancreatic Adenocarcinoma

Author

Kala Visvanathan, Jean Wactawski-Wende, Salvatore Panico, Andrea Z. LaCroix, Patricia Hartge, Charles S. Fuchs, Chen Wu, Mazda Jenab, Chengfeng Wang, Brian M. Wolpin, Poorva Mudgal, Anne Zeleniuch-Jacquotte, Kay-Tee Khaw, Laufey T. Amundadottir, Elio Riboli, Marie-Christine Boutron-Ruault, Edward Giovannucci, Wei Zheng, Federico Canzian, Guoliang Jiang, Emily Steplowski, Julie E. Buring, H. Bas Bueno-de-Mesquita, Myron D. Gross, Michelle Brotzman, Eric J. Jacobs, Joanne W. Elena, Demetrius Albanes, Eric J. Duell, Stephen J. Chanock, Dongxin Lin, Göran Hallmans, David J. Hunter, Charles Kooperberg, Geoffrey S. Tobias, Alan A. Arslan, Zhi Rong Qian, Guangwen Cao, Anne Tjønneland, Kathy J. Helzlsouer, Alpa V. Patel, Howard D. Sesso, Jarmo Virtamo, Rachael Z. Stolzenberg-Solomon, Robert N. Hoover, J. Michael Gaziano, Mousheng Xu, Hongbing Shen, Gloria M. Petersen, Kai Yu, Peter Kraft, Xiao-Ou Shu, Dimitrios Trichopoulos, Zhao-Shen Li, Julie B. Mendelsohn, Amy Hutchinson, Wu, C, Kraft, P, Stolzenberg Solomon, R, Steplowski, E, Brotzman, M, Xu, M, Mudgal, P, Amundadottir, L, Arslan, Aa, Bueno de Mesquita, Hb, Gross, M, Helzlsouer, K, Jacobs, Ej, Kooperberg, C, Petersen, Gm, Zheng, W, Albanes, D, Boutron Ruault, Mc, Buring, Je, Canzian, F, Cao, G, Duell, Ej, Elena, Jw, Gaziano, Jm, Giovannucci, El, Hallmans, G, Hutchinson, A, Hunter, Dj, Jenab, M, Jiang, G, Khaw, Kt, Lacroix, A, Li, Z, Mendelsohn, Jb, Panico, Salvatore, Patel, Av, Qian, Zr, Riboli, E, Sesso, H, Shen, H, Shu, Xo, Tjonneland, A, Tobias, G, Trichopoulos, D, Virtamo, J, Visvanathan, K, Wactawski Wende, J, Wang, C, Yu, K, Zeleniuch Jacquotte, A, Chanock, S, Hoover, R, Hartge, P, Fuchs, C, Lin, D, and Wolpin, Bm

Subjects
Oncology, Male, Genome-wide association study, Kaplan-Meier Estimate, Gastroenterology, 0302 clinical medicine, Models, 80 and over, 2.1 Biological and endogenous factors, Non-Receptor, Pancreas cancer, Cancer, Aged, 80 and over, 0303 health sciences, Principal Component Analysis, Molecular Epidemiology, Tumor, Single Nucleotide, Middle Aged, Protein Tyrosine Phosphatases, Non-Receptor, 3. Good health, Survival Rate, Europe, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Adult, Asian Continental Ancestry Group, medicine.medical_specialty, China, European Continental Ancestry Group, Clinical Sciences, and over, Biology, Genetic polymorphisms, Polymorphism, Single Nucleotide, White People, Article, Paediatrics and Reproductive Medicine, 03 medical and health sciences, Pancreatic Cancer, Rare Diseases, Asian People, Genetic, Internal medicine, Pancreatic cancer, Biomarkers, Tumor, medicine, Cancer Genetics, Genetics, Humans, In patient, Polymorphism, Càncer de pàncrees, 030304 developmental biology, Proportional Hazards Models, Aged, Models, Genetic, Molecular epidemiology, Gastroenterology & Hepatology, Prevention, Polimorfisme genètic, Human Genome, medicine.disease, Pancreatic Neoplasms, Cancer genetics, Protein Tyrosine Phosphatases, Digestive Diseases, Biomarkers, Follow-Up Studies, Genome-Wide Association Study
Abstract

Background and objective: Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma. Methods: We analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p10(-5)) were advanced to a joint analysis with 363 additional patients from China (ChinaPC). Results: In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63x10(-7)), rs981621 (p=1.65x10(-7)) and rs16861827 (p=3.75x10(-7)), respectively. 131 SNPs with p10(-5) were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72x10(-7)) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis. Conclusions: Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

48. Most cited articles involving lacrosse since 1990 primarily focus on concussion and traumatic brain injury.

Author

Gross BD, Yendluri A, Iyer AI, Patel AV, and Cagle PJ

Subjects
Humans, Periodicals as Topic statistics & numerical data, Bibliometrics, Brain Concussion epidemiology, Racquet Sports injuries, Brain Injuries, Traumatic epidemiology
Abstract

Objectives: The purpose of this study was to identify the 50 most-cited publications relating to lacrosse since 1990 and conduct a bibliometric analysis of the identified studies., Methods: Clarivate Analytics Web of Science database was queried to identify all publication titles, abstracts, and keywords for the term 'lacrosse' on 9 June 2023. The resulting articles were sorted by total number of citations. Titles and abstracts were included based on their relevance to lacrosse. Once the 50 most cited articles were identified, each article was further analyzed to obtain author name, publication year, country of origin, journal name, article type, research topic, competition level, total number of citations, and the level of evidence. Citation density (total number of citations/years since publication) was calculated and recorded for each of the most-cited studies., Results: The 50 most-cited articles were cited 4237 of times with an average of 84 citations per article. The most cited article was cited 637 (15.0%) times. The articles came from 2 different countries, with the United States and Australia comprising 49 and 1 articles, respectively. All articles were published in English. The American Journal of Sports Medicine published the most articles ( n  = 21, 42.0%). The most studied topic was concussion/traumatic brain injury ( n  = 18) followed by studies assessing all injuries ( n  = 7). Collegiate-level lacrosse was the most studied level of competition ( n  = 22), while high school-level followed ( n  = 12)., Conclusions: The majority of the 50 most-cited articles related to lacrosse since 1990 focus on the prevalence, diagnosis and identification of concussion/traumatic brain injury in high school and collegiate-level athletes. These articles are predominantly epidemiological or cohort studies with Level III or IV evidence that almost unanimously originate from the United States.

Published
2024
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49. Adaptation of the socioecological model to address disparities in engagement of Black men in prostate cancer genetic testing.

Author

Leader AE, Rebbeck TR, Oh WK, Patel AV, Winer EP, Bailey LO, Gomella LG, Lumpkins CY, Garraway IP, Aiello LB, Baskin ML, Cheng HH, Cooney KA, Ganzak A, George DJ, Halabi S, Hathaway F, Healy C, Kim JW, Leapman MS, Loeb S, Maxwell KN, McNair C, Morgan TM, Prindeville B, Soule HR, Steward WL, Suttiratana SC, Taplin ME, Yamoah K, Fortune T, Bennett K, Blanding-Godbolt J, Gross L, and Giri VN

Subjects
Humans, Male, Africa ethnology, Black or African American, Delphi Technique, United States, Genetic Testing, Healthcare Disparities, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics, Black People
Abstract

Background: Black men consistently have higher rates of prostate cancer (PCA)- related mortality. Advances in PCA treatment, screening, and hereditary cancer assessment center around germline testing (GT). Of concern is the significant under-engagement of Black males in PCA GT, limiting the benefit of precision therapy and tailored cancer screening despite longstanding awareness of these disparities. To address these critical disparities, the Socioecological Model (SEM) was employed to develop comprehensive recommendations to overcome barriers and implement equitable strategies to engage Black males in PCA GT., Methods: Clinical/research experts, national organization leaders, and community stakeholders spanning multiple regions in US and Africa participated in developing a framework for equity in PCA GT grounded in the SEM. A novel mixed-methods approach was employed to generate key areas to be addressed and informed statements for consensus consideration utilizing the modified Delphi model. Statements achieving strong consensus (> =75% agreement) were included in final equity frameworks addressing clinical/community engagement and research engagement., Results: All societal levels of the SEM (interpersonal, institutional, community, and policy/advocacy) must deliver information about PCA GT to Black males that address benefits/limitations, clinical impact, hereditary cancer implications, with acknowledgment of mistrust (mean scores [MS] 4.57-5.00). Interpersonal strategies for information delivery included engagement of family/friends/peers/Black role models to improve education/awareness and overcome mistrust (MS 4.65-5.00). Institutional strategies included diversifying clinical, research, and educational programs and integrating community liaisons into healthcare institutions (MS 4.57-5.00). Community strategies included partnerships with healthcare institutions and visibility of healthcare providers/researchers at community events (MS 4.65-4.91). Policy/advocacy included improving partnerships between advocacy and healthcare/community organizations while protecting patient benefits (MS 4.57-5.00). Media strategies were endorsed for the first time at every level (MS 4.56-5.00)., Conclusion: The SEM-based equity frameworks proposed provide the first multidisciplinary strategies dedicated to increase engagement of Black males in PCA GT, which are critical to reduce disparities in PCA-mortality through informing tailored screening, targeted therapy, and cascade testing in families., (© 2024. The Author(s).)

Published
2024
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50. Sleep and cancer mortality in the Cancer Prevention Study-II.

Author

Donzella SM, Deubler E, Patel AV, Phipps AI, and Zhong C

Abstract

Purpose: Sleep is a multi-dimensional human function that is associated with cancer outcomes. Previous work on sleep and cancer mortality have not investigated how this relationship varies by sex and cancer site. We investigated the association of sleep duration and perceived insomnia with site-specific and overall cancer mortality among participants in the Cancer Prevention Study-II., Methods: Sleep was collected at baseline in 1982 among 1.2 million cancer-free US adults. Cancer-specific mortality was determined through 2018. We used multivariable Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals for overall and site-specific cancer mortality, stratified by sex., Results: Among 983,105 participants (56% female) followed for a median of 27.9 person-years, there were 146,911 primary cancer deaths. Results from the adjusted model showed short (6 h/night) and long (8 h/night and 9-14 h/night) sleep duration, compared to 7 h/night, were associated with a modest 2%, 2%, and 5% higher risk of overall cancer mortality, respectively, and there was a significant non-linear trend (p-trend < 0.01). This non-linear trend was statistically significant among male (p-trend < 0.001) but not female (p-trend 0.71) participants. For male participants, short and long sleep were associated with higher risk of lung cancer mortality and long sleep was associated with higher risk of colorectal cancer mortality. Perceived insomnia was associated with a 3-7% lower risk of overall cancer mortality., Conclusion: Sleep is important to consider in relation to sex- and site-specific cancer mortality. Future research should investigate other components of sleep in relation to cancer mortality., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Published
2024
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