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1. Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI.

Author: Gong, J, Nishimura, KK, Fernandez-Rhodes, L, Haessler, J, Bien, S, Graff, M, Lim, U, Lu, Y, Gross, M, Fornage, M, Yoneyama, S, Isasi, CR, Buzkova, P, Daviglus, M, Lin, D-Y, Tao, R, Goodloe, R, Bush, WS, Farber-Eger, E, Boston, J, Dilks, HH, Ehret, G, Gu, CC, Lewis, CE, Nguyen, K-DH, Cooper, R, Leppert, M, Irvin, MR, Bottinger, EP, Wilkens, LR, Haiman, CA, Park, L, Monroe, KR, Cheng, I, Stram, DO, Carlson, CS, Jackson, R, Kuller, L, Houston, D, Kooperberg, C, Buyske, S, Hindorff, LA, Crawford, DC, Loos, RJF, Le Marchand, L, Matise, TC, North, KE, and Peters, U
Subjects: Humans, Body Mass Index, Genomics, Polymorphism, Single Nucleotide, Continental Population Groups, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Medical and Health Sciences, Education, Endocrinology & Metabolism
Abstract: ObjectiveBody mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population.SubjectsUsing eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models.ResultsWe replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P
Published: 2018

2. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".

Author: Johnatty, SE, Beesley, J, Chen, X, Macgregor, S, Duffy, DL, Spurdle, AB, deFazio, A, Gava, N, Webb, PM, Rossing, MA, Doherty, JA, Goodman, MT, Lurie, G, Thompson, PJ, Wilkens, LR, Ness, RB, Moysich, KB, Chang-Claude, J, Wang-Gohrke, S, Cramer, DW, Terry, KL, Hankinson, SE, Tworoger, SS, Garcia-Closas, M, Yang, H, Lissowska, J, Chanock, SJ, Pharoah, PD, Song, H, Whitemore, AS, Pearce, CL, Stram, DO, Wu, AH, Pike, MC, Gayther, SA, Ramus, SJ, Menon, U, Gentry-Maharaj, A, Anton-Culver, H, Ziogas, A, Hogdall, E, Kjaer, SK, Hogdall, C, Berchuck, A, Schildkraut, JM, Iversen, ES, Moorman, PG, Phelan, CM, Sellers, TA, Cunningham, JM, Vierkant, RA, Rider, DN, Goode, EL, Haviv, I, Chenevix-Trench, G, Ovarian, CAC, Australian, OCSG, and Australian, CSOC
Abstract: We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.
Published: 2010

3. Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium

Author: Morra, A, Jung, AY, Behrens, S, Keeman, R, Ahearn, TU, Anton-Culver, H, Arndt, V, Augustinsson, A, Auvinen, PK, Freeman, LEB, Becher, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Brenner, H, Briceno, I, Brucker, SY, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Egan, KM, Evans, DG, Fasching, PA, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Han, SN, Hart, SN, Hartman, M, Heyworth, JS, Hoppe, R, Hopper, JL, Hunter, DJ, Ito, H, Jager, A, Jakimovska, M, Jakubowska, A, Janni, W, Kaaks, R, Kang, D, Kapoor, PM, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Mariapun, S, Matsuo, K, Mavroudis, D, Milne, RL, Muranen, TA, Newman, WG, Noh, D-Y, Nordestgaard, BG, Obi, N, Olshan, AF, Olsson, H, Park-Simon, T-W, Petridis, C, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rashid, MU, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schwentner, L, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Tamimi, RM, Tapper, W, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Wang, SS, Williams, JA, Winqvist, R, Wolk, A, Wu, AH, Yoo, K-Y, Yu, J-C, Zheng, W, Ziogas, A, Yang, XR, Eliassen, AH, Holmes, MD, Garcia-Closas, M, Teo, SH, Schmidt, MK, Chang-Claude, J, Morra, A, Jung, AY, Behrens, S, Keeman, R, Ahearn, TU, Anton-Culver, H, Arndt, V, Augustinsson, A, Auvinen, PK, Freeman, LEB, Becher, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Brenner, H, Briceno, I, Brucker, SY, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Egan, KM, Evans, DG, Fasching, PA, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Han, SN, Hart, SN, Hartman, M, Heyworth, JS, Hoppe, R, Hopper, JL, Hunter, DJ, Ito, H, Jager, A, Jakimovska, M, Jakubowska, A, Janni, W, Kaaks, R, Kang, D, Kapoor, PM, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Mariapun, S, Matsuo, K, Mavroudis, D, Milne, RL, Muranen, TA, Newman, WG, Noh, D-Y, Nordestgaard, BG, Obi, N, Olshan, AF, Olsson, H, Park-Simon, T-W, Petridis, C, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rashid, MU, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schwentner, L, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Tamimi, RM, Tapper, W, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Wang, SS, Williams, JA, Winqvist, R, Wolk, A, Wu, AH, Yoo, K-Y, Yu, J-C, Zheng, W, Ziogas, A, Yang, XR, Eliassen, AH, Holmes, MD, Garcia-Closas, M, Teo, SH, Schmidt, MK, and Chang-Claude, J
Abstract: BACKGROUND: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking. CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
Published: 2021

4. Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

Author: Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Cowper-Sal Lari, R, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, Dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guénel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Perez, JIA, Menéndez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collée, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnæs, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, García-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Brauch, H, Brüning, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Dörk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, González-Neira, A, Pita, G, Rosario Alonso, M, Álvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, Dunning, AM, Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Cowper-Sal Lari, R, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, Dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guénel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Perez, JIA, Menéndez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collée, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnæs, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, García-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Brauch, H, Brüning, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Dörk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, González-Neira, A, Pita, G, Rosario Alonso, M, Álvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, and Dunning, AM
Abstract: This corrects the article DOI: 10.1038/ncomms5999.
Published: 2018

5. Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types

Author: Kar, SP, Beesley, J, Al Olama, AA, Michailidou, K, Tyrer, J, Kote-Jarai, ZA, Lawrenson, K, Lindstrom, S, Ramus, SJ, Thompson, DJ, Kibel, AS, Dansonka-Mieszkowska, A, Michael, A, Dieffenbach, AK, Gentry-Maharaj, A, Whittemore, AS, Wolk, A, Monteiro, A, Peixoto, A, Kierzek, A, Cox, A, Rudolph, A, Gonzalez-Neira, A, Wu, AH, Lindblom, A, Swerdlow, A, Ziogas, A, Ekici, AB, Burwinkel, B, Karlan, BY, Nordestgaard, BG, Blomqvist, C, Phelan, C, McLean, C, Pearce, CL, Vachon, C, Cybulski, C, Slavov, C, Stegmaier, C, Maier, C, Ambrosone, CB, Hogdall, CK, Teerlink, CC, Kang, D, Tessier, DC, Schaid, DJ, Stram, DO, Cramer, DW, Neal, DE, Eccles, D, Flesch-Janys, D, Velez Edwards, DR, Wokozorczyk, D, Levine, DA, Yannoukakos, D, Sawyer, EJ, Bandera, EV, Poole, EM, Goode, EL, Khusnutdinova, E, Hogdall, E, Song, F, Bruinsma, F, Heitz, F, Modugno, F, Hamdy, FC, Wiklund, F, Giles, GG, Olsson, H, Wildiers, H, and Ulmer, HU
Abstract: © 2016 American Association for Cancer Research. Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/ BCL2L11; rs7937840/11q12/ INCENP; rs1469713/19p13/ GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/ SMC2; rs8037137/15q26/ RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/ NSUN4; rs9375701/6q23/ L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers.
Published: 2016

6. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author: Gusev, A, Shi, H, Kichaev, G, Pomerantz, M, Li, F, Long, HW, Ingles, SA, Kittles, RA, Strom, SS, Rybicki, BA, Nemesure, B, Isaacs, WB, Zheng, W, Pettaway, CA, Yeboah, ED, Tettey, Y, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Chokkalingam, AP, John, EM, Murphy, AB, Signorello, LB, Carpten, J, Leske, MC, Wu, S-Y, Hennis, AJM, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Witte, JS, Casey, G, Kaggwa, S, Cook, MB, Stram, DO, Blot, WJ, Eeles, RA, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Southey, MC, Fitzgerald, LM, Gronberg, H, Wiklund, F, Aly, M, Henderson, BE, Schleutker, J, Wahlfors, T, Tammela, TLJ, Nordestgaard, BG, Key, TJ, Travis, RC, Neal, DE, Donovan, JL, Hamdy, FC, Pharoah, P, Pashayan, N, Khaw, K-T, Stanford, JL, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Maier, C, Vogel, W, Luedeke, M, Herkommer, K, Kibel, AS, Cybulski, C, Wokolorczyk, D, Kluzniak, W, Cannon-Albright, L, Teerlink, C, Brenner, H, Dieffenbach, AK, Arndt, V, Park, JY, Sellers, TA, Lin, H-Y, Slavov, C, Kaneva, R, Mitev, V, Batra, J, Spurdle, A, Clements, JA, Teixeira, MR, Pandha, H, Michael, A, Paulo, P, Maia, S, Kierzek, A, Conti, DV, Albanes, D, Berg, C, Berndt, SI, Campa, D, Crawford, ED, Diver, WR, Gapstur, SM, Gaziano, JM, Giovannucci, E, Hoover, R, Hunter, DJ, Johansson, M, Kraft, P, Le Marchand, L, Lindstrom, S, Navarro, C, Overvad, K, Riboli, E, Siddiq, A, Stevens, VL, Trichopoulos, D, Vineis, P, Yeager, M, Trynka, G, Raychaudhuri, S, Schumacher, FR, Price, AL, Freedman, ML, Haiman, CA, Pasaniuc, B, Cook, M, Guy, M, Govindasami, K, Leongamornlert, D, Sawyer, EJ, Wilkinson, R, Saunders, EJ, Tymrakiewicz, M, Dadaev, T, Morgan, A, Fisher, C, Hazel, S, Livni, N, Lophatananon, A, Pedersen, J, Hopper, JL, Adolfson, J, Stattin, P, Johansson, J-E, Cavalli-Bjoerkman, C, Karlsson, A, Broms, M, Auvinen, A, Kujala, P, Maeaettaenen, L, Murtola, T, Taari, K, Weischer, M, Nielsen, SF, Klarskov, P, Roder, A, Iversen, P, Wallinder, H, Gustafsson, S, Cox, A, Brown, P, George, A, Marsden, G, Lane, A, Davis, M, Tillmans, L, Riska, S, Wang, L, Rinckleb, A, Lubiski, J, Stegmaier, C, Pow-Sang, J, Park, H, Radlein, S, Rincon, M, Haley, J, Zachariah, B, Kachakova, D, Popov, E, Mitkova, A, Vlahova, A, Dikov, T, Christova, S, Heathcote, P, Wood, G, Malone, G, Saunders, P, Eckert, A, Yeadon, T, Kerr, K, Collins, A, Turner, M, Srinivasan, S, Kedda, M-A, Alexander, K, Omara, T, Wu, H, Henrique, R, Pinto, P, Santos, J, Barros-Silva, J, and Consortium, PRACTICAL
Subjects: urologic and male genital diseases
Abstract: Although genome-wide association studies have identified over 100 risk loci that explain ~33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
Published: 2016

7. Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author: Bolton, KL, Tyrer, J, Song, H, Ramus, SJ, Notaridou, M, Jones, C, Sher, T, Gentry-Maharaj, A, Wozniak, E, Tsai, Y-Y, Weidhaas, J, Paik, D, Van Den Berg, DJ, Stram, DO, Pearce, CL, Wu, AH, Brewster, W, Anton-Culver, H, Ziogas, A, Narod, SA, Levine, DA, Kaye, SB, Brown, R, Paul, J, Flanagan, J, Sieh, W, McGuire, V, Whittemore, AS, Campbell, I, Gore, ME, Lissowska, J, Yang, HP, Medrek, K, Gronwald, J, Lubinski, J, Jakubowska, A, Le, ND, Cook, LS, Kelemen, LE, Brooks-Wilson, A, Massuger, LFAG, Kiemeney, LA, Aben, KKH, van Altena, AM, Houlston, R, Tomlinson, I, Palmieri, RT, Moorman, PG, Schildkraut, J, Iversen, ES, Phelan, C, Vierkant, RA, Cunningham, JM, Goode, EL, Fridley, BL, Kruger-Kjaer, S, Blaeker, J, Hogdall, E, Hogdall, C, Gross, J, Karlan, BY, Ness, RB, Edwards, RP, Odunsi, K, Moyisch, KB, Baker, JA, Modugno, F, Heikkinenen, T, Butzow, R, Nevanlinna, H, Leminen, A, Bogdanova, N, Antonenkova, N, Doerk, T, Hillemanns, P, Dürst, M, Runnebaum, I, Thompson, PJ, Carney, ME, Goodman, MT, Lurie, G, Wang-Gohrke, S, Hein, R, Chang-Claude, J, Rossing, MA, Cushing-Haugen, KL, Doherty, J, Chen, C, Rafnar, T, Besenbacher, S, Sulem, P, Stefansson, K, Birrer, MJ, Terry, KL, Hernandez, D, Cramer, DW, Vergote, I, Amant, F, Lambrechts, D, Despierre, E, Fasching, PA, Beckmann, MW, Thiel, FC, Ekici, AB, Chen, X, Australian Ovarian Cancer Study Group, Johnatty, SE, Webb, PM, Beesley, J, Chanock, S, Garcia-Closas, M, Sellers, T, Easton, DF, Berchuck, A, Chenevix-Trench, G, Pharoah, PDP, and Gayther, SA
Subjects: Australian Ovarian Cancer Study Group
Published: 2016

8. Two susceptibility loci identified for prostate cancer aggressiveness

Author: Berndt, Si, Wang, Z, Yeager, M, Alavanja, Mc, Albanes, D, Amundadottir, L, Andriole, G, Beane Freeman, L, Campa, D, Cancel-Tassin, G, Canzian, F, Cornu, Jn, Cussenot, O, Diver, Wr, Gapstur, Sm, Grönberg, H, Haiman, Ca, Henderson, B, Hutchinson, A, Hunter, Dj, Key, Tj, Kolb, S, Koutros, S, Kraft, P, Le Marchand, L, Lindström, S, Machiela, Mj, Ostrander, Ea, Riboli, E, Schumacher, F, Siddiq, A, Stanford, Jl, Stevens, Vl, Travis, Rc, Tsilidis, Kk, Virtamo, J, Weinstein, S, Wilkund, F, Xu, J, Lilly Zheng, S, Yu, K, Wheeler, W, Zhang, H, African, Ancestry Prostate Cancer GWAS Consortium, Sampson, J, Black, A, Jacobs, K, Hoover, Rn, Tucker, M, Chanock, Sj. Ingles SA, Kittles, Ra, Strom, Ss, Rybicki, Ba, Nemesure, B, Isaacs, Wb, Zheng, W, Pettaway, Ca, Yeboah, Ed, Tettey, Y, Biritwum, Rb, Adjei, Aa, Tay, E, Truelove, A, Niwa, S, Chokkalingam, Ap, John, Em, Murphy, Ab, Signorello, Lb, Carpten, J, Leske, Mc, Wu, Sy, Hennis, Aj, Neslund-Dudas, C, Hsing, Aw, Chu, L, Goodman, Pj, Klein, Ea, Witte, Js, Casey, G, Kaggwa, S, Cook, Mb, Stram, Do, and Blot, Wj.
Subjects: Oncology, Male, Aging, GLEASON SCORE, LINKAGE SCAN, General Physics and Astronomy, Genome-wide association study, Disease, Bioinformatics, Prostate cancer, SEQUENCE VARIANTS, Medicine, 2.1 Biological and endogenous factors, GTPASE-ACTIVATING PROTEIN, Aetiology, POPULATION, Cancer, RISK, education.field_of_study, African Ancestry Prostate Cancer GWAS Consortium, Multidisciplinary, Prostate Cancer, 3. Good health, Multidisciplinary Sciences, Science & Technology - Other Topics, Urologic Diseases, medicine.medical_specialty, Population, Article, General Biochemistry, Genetics and Molecular Biology, GENOME-WIDE ASSOCIATION, BASE-LINE CHARACTERISTICS, COHORT, METAANALYSIS, Internal medicine, Genetics, SNP, Humans, Neoplasm Invasiveness, Genetic Predisposition to Disease, education, Pathological, Science & Technology, business.industry, Vascular disease, Prevention, Human Genome, Case-control study, Prostatic Neoplasms, General Chemistry, medicine.disease, Genetic Loci, Case-Control Studies, Neoplasm Grading, business
Abstract: Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.
Published: 2015

9. Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)

Author: Darabi, H, Beesley, J, Droit, A, Kar, S, Nord, S, Marjaneh, MM, Soucy, P, Michailidou, K, Ghoussaini, M, Wahl, HF, Bolla, MK, Wang, Q, Dennis, J, Alonso, MR, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Benitez, J, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Chang-Claude, J, Choi, J-Y, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Doerk, T, Easton, DF, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Galle, E, Garcia-Closas, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hallberg, E, Hamann, U, Hartman, M, Hollestelle, A, Hopper, JL, Ito, H, Jakubowska, A, Johnson, N, Kang, D, Khan, S, Kosma, V-M, Kriege, M, Kristensen, V, Lambrechts, D, Le Marchand, L, Lee, SC, Lindblom, A, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Mayes, R, Mckay, J, Meindl, A, Milne, RL, Muir, K, Neuhausen, SL, Nevanlinna, H, Olswold, C, Orr, N, Peterlongo, P, Pita, G, Pylkaes, K, Rudolph, A, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Seynaeve, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Surowy, H, Swerdlow, A, Teo, SH, Tessier, DC, Tomlinson, I, Torres, D, Truong, T, Vachon, CM, Vincent, D, Winqvist, R, Wu, AH, Wu, P-E, Yip, CH, Zheng, W, Pharoah, PDP, Hall, P, Edwards, SL, Simard, J, French, JD, Chenevix-Trench, G, Dunning, AM, Darabi, H, Beesley, J, Droit, A, Kar, S, Nord, S, Marjaneh, MM, Soucy, P, Michailidou, K, Ghoussaini, M, Wahl, HF, Bolla, MK, Wang, Q, Dennis, J, Alonso, MR, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Benitez, J, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Chang-Claude, J, Choi, J-Y, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Doerk, T, Easton, DF, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Galle, E, Garcia-Closas, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hallberg, E, Hamann, U, Hartman, M, Hollestelle, A, Hopper, JL, Ito, H, Jakubowska, A, Johnson, N, Kang, D, Khan, S, Kosma, V-M, Kriege, M, Kristensen, V, Lambrechts, D, Le Marchand, L, Lee, SC, Lindblom, A, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Mayes, R, Mckay, J, Meindl, A, Milne, RL, Muir, K, Neuhausen, SL, Nevanlinna, H, Olswold, C, Orr, N, Peterlongo, P, Pita, G, Pylkaes, K, Rudolph, A, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Seynaeve, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Surowy, H, Swerdlow, A, Teo, SH, Tessier, DC, Tomlinson, I, Torres, D, Truong, T, Vachon, CM, Vincent, D, Winqvist, R, Wu, AH, Wu, P-E, Yip, CH, Zheng, W, Pharoah, PDP, Hall, P, Edwards, SL, Simard, J, French, JD, Chenevix-Trench, G, and Dunning, AM
Abstract: Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
Published: 2016

10. A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer

Author: Lee, AW, Bomkamp, A, Bandera, EV, Jensen, A, Ramus, SJ, Goodman, MT, Rossing, MA, Modugno, F, Moysich, KB, Chang-Claude, J, Rudolph, A, Gentry-Maharaj, A, Terry, KL, Gayther, SA, Cramer, DW, Doherty, JA, Schildkraut, JM, Kjaer, SK, Ness, RB, Menon, U, Berchuck, A, Mukherjee, B, Roman, L, Pharoah, PD, Chenevix-Trench, G, Olson, S, Hogdall, E, Wu, AH, Pike, MC, Stram, DO, Pearce, CL, Lee, AW, Bomkamp, A, Bandera, EV, Jensen, A, Ramus, SJ, Goodman, MT, Rossing, MA, Modugno, F, Moysich, KB, Chang-Claude, J, Rudolph, A, Gentry-Maharaj, A, Terry, KL, Gayther, SA, Cramer, DW, Doherty, JA, Schildkraut, JM, Kjaer, SK, Ness, RB, Menon, U, Berchuck, A, Mukherjee, B, Roman, L, Pharoah, PD, Chenevix-Trench, G, Olson, S, Hogdall, E, Wu, AH, Pike, MC, Stram, DO, and Pearce, CL
Abstract: Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non-users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19-1.91), which was stronger for long-term ET users of 10+ years (OR = 1.85, 95% CI 1.28-2.66, pint = 0.034). Non-users showed essentially no association (OR = 1.08, 95% CI 0.96-1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint = 0.021 and pint = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow-up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.
Published: 2016

11. Interactions between genetic variants and breast cancer risk factors in thebreast and prostate cancer cohort consortium

Author: Campa D, Kaaks R, Le Marchand L, Haiman CA, Travis RC, Berg CD, Buring JE, Chanock SJ, Diver WR, Dostal L, Fournier A, Hankinson SE, Henderson BE, Hoover RN, Isaacs C, Johansson M, Kolonel LN, Kraft P, Lee IM, McCarty CA, Overvad K, Peeters PH, Riboli E, Sanchez MJ, Schumacher FR, Skeie G, Stram DO, Thun MJ, Trichopoulos D, Zhang S, Ziegler RG, Hunter DJ, Lindström S, Canzian F., PANICO, SALVATORE, Campa, D, Kaaks, R, Le Marchand, L, Haiman, Ca, Travis, Rc, Berg, Cd, Buring, Je, Chanock, Sj, Diver, Wr, Dostal, L, Fournier, A, Hankinson, Se, Henderson, Be, Hoover, Rn, Isaacs, C, Johansson, M, Kolonel, Ln, Kraft, P, Lee, Im, Mccarty, Ca, Overvad, K, Panico, Salvatore, Peeters, Ph, Riboli, E, Sanchez, Mj, Schumacher, Fr, Skeie, G, Stram, Do, Thun, Mj, Trichopoulos, D, Zhang, S, Ziegler, Rg, Hunter, Dj, Lindström, S, and Canzian, F.
Published: 2011

12. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

Author: Milne, RL, Burwinkel, B, Michailidou, K, Arias-Perez, JI, Zamora, MP, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Pita, G, Alonso, MR, Dennis, J, Wang, Q (Qing), Bolla, MK, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Ko, YD, Brauch, H, Hamann, U, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Li, JM, Brand, JS, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Lambrechts, D, Peuteman, G, Christiaens, MR, Smeets, A, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Hartman, M, Hui, M, Lim, WY, Chan, CW, Marme, F, Yang, RX, Bugert, P, Lindblom, A, Margolin, S, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Bojesen, SE, Nordestgaard, BG, Flyger, H, Hooning, Maartje, Kriege, Mieke, van den Ouweland, Ans, Koppert, Linetta, Fletcher, O, Johnson, N, dos-Santos-Silva, I, Peto, J, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, JR, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Cox, A, Cross, SS, Reed, MWR, Schmidt, MK (Marjanka), Broeks, A, Cornelissen, S, Braaf, L, Kang, D, Choi, JY, Park, SK, Noh, DY, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Radice, P, Peterlongo, P, Azzollini, J, Barile, M, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, WT, Shen, CY, Hsiung, CN, Yu, JC, Hou, MF, Guenel, P, Sanchez, M, Mulot, C, Blot, W, Cai, QY, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Bogdanova, N, Dork, T, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Shu, XO, Lu, W, Gao, YT, Zhang, B, Couch, FJ, Toland, AE, Yannoukakos, D, Sangrajrang, S, Mckay, J, Wang, XS, Olson, JE, Vachon, C, Purrington, K, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Ahmed, S (Shahana), Shah, M, Pharoah, PDP, Hall, P, Giles, GG, Benitez, J, Dunning, AM, Chenevix-Trench, G, Easton, DF, Clinical Genetics, Cardiothoracic Surgery, Medical Oncology, and Surgery
Subjects: SDG 3 - Good Health and Well-being
Abstract: Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 x 10 26], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 x 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 x 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 x 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 x 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
Published: 2014

13. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author: Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Gapstur, SM, Gaudet, MM, Diver, WR, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Berg, CD, Chanock, SJ, Figueroa, J, Hoover, RN, Lambrechts, D, Neven, P, Wildiers, H, van Limbergen, E, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Waisfisz, Q, Meijers-Heijboer, H, Adank, MA, van der Luijt, RB, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Yoo, K-Y, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Guenel, P, Truong, T, Mulot, C, Sanchez, M, Burwinkel, B, Marme, F, Surowy, H, Sohn, C, Wu, AH, Tseng, C-C, Van den Berg, D, Stram, DO, Gonzalez-Neira, A, Benitez, J, Zamora, MP, Arias Perez, JI, Shu, X-O, Lu, W, Gao, Y-T, Cai, H, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Taib, NAM, Tan, G-H, Hooning, MJ, Hollestelle, A, Martens, JWM, Collee, JM, Blot, W, Signorello, LB, Cai, Q, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Shen, C-Y, Hsiung, C-N, Wu, P-E, Hou, M-F, Kristensen, VN, Nord, S, Alnaes, GIG, Giles, GG, Milne, RL, McLean, C, Canzian, F, Trichopoulos, D, Peeters, P, Lund, E, Sund, M, Khaw, K-T, Gunter, MJ, Palli, D, Mortensen, LM, Dossus, L, Huerta, J-M, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Chia, KS, Chan, CW, Fasching, PA, Hein, A, Beckmann, MW, Haeberle, L, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Ashworth, A, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Brinton, L, Garcia-Closas, M, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Brauch, H, Hamann, U, Bruening, T, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Bogdanova, NV, Doerk, T, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska, K, Huzarski, T, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Kabisch, M, Torres, D, Neuhausen, SL, Anton-Culver, H, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Tessier, DC, Vincent, D, Bacot, F, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Simard, J, Pharoah, PPDP, Kraft, P, Dunning, AM, Chenevix-Trench, G, Hall, P, Easton, DF, Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Gapstur, SM, Gaudet, MM, Diver, WR, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Berg, CD, Chanock, SJ, Figueroa, J, Hoover, RN, Lambrechts, D, Neven, P, Wildiers, H, van Limbergen, E, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Waisfisz, Q, Meijers-Heijboer, H, Adank, MA, van der Luijt, RB, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Yoo, K-Y, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Guenel, P, Truong, T, Mulot, C, Sanchez, M, Burwinkel, B, Marme, F, Surowy, H, Sohn, C, Wu, AH, Tseng, C-C, Van den Berg, D, Stram, DO, Gonzalez-Neira, A, Benitez, J, Zamora, MP, Arias Perez, JI, Shu, X-O, Lu, W, Gao, Y-T, Cai, H, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Taib, NAM, Tan, G-H, Hooning, MJ, Hollestelle, A, Martens, JWM, Collee, JM, Blot, W, Signorello, LB, Cai, Q, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Shen, C-Y, Hsiung, C-N, Wu, P-E, Hou, M-F, Kristensen, VN, Nord, S, Alnaes, GIG, Giles, GG, Milne, RL, McLean, C, Canzian, F, Trichopoulos, D, Peeters, P, Lund, E, Sund, M, Khaw, K-T, Gunter, MJ, Palli, D, Mortensen, LM, Dossus, L, Huerta, J-M, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Chia, KS, Chan, CW, Fasching, PA, Hein, A, Beckmann, MW, Haeberle, L, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Ashworth, A, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Brinton, L, Garcia-Closas, M, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Brauch, H, Hamann, U, Bruening, T, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Bogdanova, NV, Doerk, T, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska, K, Huzarski, T, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Kabisch, M, Torres, D, Neuhausen, SL, Anton-Culver, H, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Tessier, DC, Vincent, D, Bacot, F, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Simard, J, Pharoah, PPDP, Kraft, P, Dunning, AM, Chenevix-Trench, G, Hall, P, and Easton, DF
Abstract: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
Published: 2015

14. Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

Author: Glubb, DM, Maranian, MJ, Michailidou, K, Pooley, KA, Meyer, KB, Kar, S, Carlebur, S, O'Reilly, M, Betts, JA, Hillman, KM, Kaufmann, S, Beesley, J, Canisius, S, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Schmidt, MK (Marjanka), Broeks, A, Hogervorst, FB, van der Schoot, CE, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Ruebner, M, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Pharoah, PDP, Bolla, MK, Wang, Q (Qing), Dennis, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Burwinkel, B, Marme, F, Yang, RX, Surowy, H, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Gonzelez-Neira, A, Benitez, J, Zamora, MP, Perez, JIA, Anton-Culver, H, Neuhausen, SL, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Schmutzler, RK, Brauch, H, Ko, YD, Bruning, T, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Matsuo, K, Ito, H, Iwata, H, Tanaka, H, Dork, T, Bogdanova, NV, Helbig, S, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Lambrechts, D, Zhao, H (Hui), Weltens, C, van Limbergen, E, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Seibold, P, Radice, P, Peterlongo, P, Barile, M, Capra, F, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Giles, GG, Milne, RL, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Teo, SH, Yip, CH, See, MH, Cornes, B, Cheng, CY (Ching-Yu), Ikram, Kamran, Kristensen, V, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, van Asperen, CJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Klevebring, D, Darabi, H, Eriksson, M, Hooning, Maartje, Hollestelle, Antoinette, Martens, John, Collee, Margriet, Hall, P, Li, JM, Humphreys, K, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MWR, Blot, W, Signorello, LB, Cai, QY, Shah, M, Ghoussaini, M, Kang, D, Choi, JY, Park, SK, Noh, DY, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Olswold, C, Slager, S, Toland, AE, Yannoukakos, D, Shen, CY, Wu, PE, Yu, JC, Hou, MF, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S (Shahana), Healey, CS, Brown, MA, Ponder, BAJ, Chenevix-Trench, G, Thompson, DJ, Edwards, SL, Easton, DF, Dunning, AM, French, JD, Glubb, DM, Maranian, MJ, Michailidou, K, Pooley, KA, Meyer, KB, Kar, S, Carlebur, S, O'Reilly, M, Betts, JA, Hillman, KM, Kaufmann, S, Beesley, J, Canisius, S, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Schmidt, MK (Marjanka), Broeks, A, Hogervorst, FB, van der Schoot, CE, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Ruebner, M, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Pharoah, PDP, Bolla, MK, Wang, Q (Qing), Dennis, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Burwinkel, B, Marme, F, Yang, RX, Surowy, H, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Gonzelez-Neira, A, Benitez, J, Zamora, MP, Perez, JIA, Anton-Culver, H, Neuhausen, SL, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Schmutzler, RK, Brauch, H, Ko, YD, Bruning, T, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Matsuo, K, Ito, H, Iwata, H, Tanaka, H, Dork, T, Bogdanova, NV, Helbig, S, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Lambrechts, D, Zhao, H (Hui), Weltens, C, van Limbergen, E, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Seibold, P, Radice, P, Peterlongo, P, Barile, M, Capra, F, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Giles, GG, Milne, RL, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Teo, SH, Yip, CH, See, MH, Cornes, B, Cheng, CY (Ching-Yu), Ikram, Kamran, Kristensen, V, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, RAEM, Seynaeve, Caroline, van Asperen, CJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Klevebring, D, Darabi, H, Eriksson, M, Hooning, Maartje, Hollestelle, Antoinette, Martens, John, Collee, Margriet, Hall, P, Li, JM, Humphreys, K, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MWR, Blot, W, Signorello, LB, Cai, QY, Shah, M, Ghoussaini, M, Kang, D, Choi, JY, Park, SK, Noh, DY, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Olswold, C, Slager, S, Toland, AE, Yannoukakos, D, Shen, CY, Wu, PE, Yu, JC, Hou, MF, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S (Shahana), Healey, CS, Brown, MA, Ponder, BAJ, Chenevix-Trench, G, Thompson, DJ, Edwards, SL, Easton, DF, Dunning, AM, and French, JD
Abstract: Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER-: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, p(trend) = 5.7 3 10(-44)) and estrogen-receptor-negative (ER-: OR = 1.10, 95% CI = 1.05-1.15, p(trend) = 3.0 x 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [p(cond) = 1.61 x 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER-: OR = 0.90, 95% CI = 0.87-0.93, p(cond) = 1.4 x 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
Published: 2015

15. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer

Author: Haiman, CA, Chen, GK, Vachon, CM, Canzian, F, Dunning, A, Millikan, RC, Wang, X, Ademuyiwa, F, Ahmed, S, Ambrosone, CB, Baglietto, L, Balleine, R, Bandera, EV, Beckmann, MW, Berg, CD, Bernstein, L, Blomqvist, C, Blot, WJ, Brauch, H, Buring, JE, Carey, LA, Carpenter, JE, Chang-Claude, J, Chanock, SJ, Chasman, DI, Clarke, CL, Cox, A, Cross, SS, Deming, SL, Diasio, RB, Dimopoulos, AM, Driver, WR, Duennebier, T, Durcan, L, Eccles, D, Edlund, CK, Ekici, AB, Fasching, PA, Feigelson, HS, Flesch-Janys, D, Fostira, F, Foersti, A, Fountzilas, G, Gerty, SM, Giles, GG, Godwin, AK, Goodfellow, P, Graham, N, Greco, D, Hamann, U, Hankinson, SE, Hartmann, A, Hein, R, Heinz, J, Holbrook, A, Hoover, RN, Hu, JJ, Hunter, DJ, Ingles, SA, Irwanto, A, Ivanovich, J, John, EM, Johnson, N, Jukkola-Vuorinen, A, Kaaks, R, Ko, Y-D, Kolonel, LN, Konstantopoulou, I, Kosma, V-M, Kulkarni, S, Lambrechts, D, Lee, AM, Le Marchand, L, Lesnick, T, Liu, J, Lindstrom, S, Mannermaa, A, Margolin, S, Martin, NG, Miron, P, Montgomery, GW, Nevanlinna, H, Nickels, S, Nyante, S, Olswold, C, Palmer, J, Pathak, H, Pectasides, D, Perou, CM, Peto, J, Pharoah, PDP, Pooler, LC, Press, MF, Pylkas, K, Rebbeck, TR, Rodriguez-Gil, JL, Rosenberg, L, Ross, E, Ruediger, T, Silva, IDS, Sawyer, E, Schmidt, MK, Schulz-Wendtland, R, Schumacher, F, Severi, G, Sheng, X, Signorello, LB, Sinn, H-P, Stevens, KN, Southey, MC, Tapper, WJ, Tomlinson, I, Hogervorst, FBL, Wauters, E, Weaver, J, Wildiers, H, Winqvist, R, Van Den Berg, D, Wan, P, Xia, LY, Yannoukakos, D, Zheng, W, Ziegler, RG, Siddiq, A, Slager, SL, Stram, DO, Easton, D, Kraft, P, Henderson, BE, Couch, FJ, and Gene, EIBC
Abstract: Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10−10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10−9), particularly in younger women (
Published: 2011

16. Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author: Bolton, KL, Tyrer, J, Song, H, Ramus, SJ, Notaridou, M, Jones, C, Sher, T, Gentry-Maharaj, A, Wozniak, E, Tsai, YY, Weidhaas, J, Paik, D, Van Den Berg, DJ, Stram, DO, Pearce, CL, Wu, AH, Brewster, W, Anton-Culver, H, Ziogas, A, Narod, SA, Levine, DA, Kaye, SB, Brown, R, Paul, J, Flanagan, J, Sieh, W, McGuire, V, Whittemore, AS, Campbell, I, Gore, ME, Lissowska, J, Yang, HP, Medrek, K, Gronwald, J, Lubinski, J, Jakubowska, A, Le, ND, Cook, LS, Kelemen, LE, Brook-Wilson, A, Massuger, LFAG, Kiemeney, LA, Aben, KKH, Van Altena, AM, Houlston, R, Tomlinson, I, Palmieri, RT, Moorman, PG, Schildkraut, J, Iversen, ES, Phelan, C, Vierkant, RA, Cunningham, JM, Goode, EL, Fridley, BL, Kruger-Kjaer, S, Blaeker, J, Hogdall, E, Hogdall, C, Gross, J, Karlan, BY, Ness, RB, Edwards, RP, Odunsi, K, Moyisch, KB, Baker, JA, Modugno, F, Heikkinenen, T, Butzow, R, Nevanlinna, H, Leminen, A, Bogdanova, N, Antonenkova, N, Doerk, T, Hillemanns, P, Dürst, M, Runnebaum, I, Thompson, PJ, Carney, ME, Goodman, MT, Lurie, G, Wang-Gohrke, S, Hein, R, Chang-Claude, J, Rossing, MA, Cushing-Haugen, KL, Doherty, J, Chen, C, Rafnar, T, Besenbacher, S, Sulem, P, Stefansson, K, Birrer, MJ, Terry, KL, Hernandez, D, Cramer, DW, and Vergote, I
Subjects: endocrine system diseases, female genital diseases and pregnancy complications
Abstract: Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5×10-4and P = 6×10-4, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3×10-9and P = 4×10-11, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development. © 2010 Nature America, Inc. All rights reserved.
Published: 2010

17. Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians.

Author: Chen, P, Takeuchi, F, Lee, J-Y, Li, H, Wu, J-Y, Liang, J, Long, J, Tabara, Y, Goodarzi, MO, Pereira, MA, Kim, YJ, Go, MJ, Stram, DO, Vithana, E, Khor, C-C, Liu, J, Liao, J, Ye, X, Wang, Y, Lu, L, Young, TL, Lee, J, Thai, AC, Cheng, C-Y, van Dam, RM, Friedlander, Y, Heng, C-K, Koh, W-P, Chen, C-H, Chang, L-C, Pan, W-H, Qi, Q, Isono, M, Zheng, W, Cai, Q, Gao, Y, Yamamoto, K, Ohnaka, K, Takayanagi, R, Kita, Y, Ueshima, H, Hsiung, CA, Cui, J, Sheu, WH-H, Rotter, JI, Chen, Y-DI, Hsu, C, Okada, Y, Kubo, M, Takahashi, A, Tanaka, T, van Rooij, FJA, Ganesh, SK, Huang, J, Huang, T, Yuan, J, Hwang, J-Y, CHARGE Hematology Working Group, Gross, MD, Assimes, TL, Miki, T, Shu, X-O, Qi, L, Chen, Y-T, Lin, X, Aung, T, Wong, T-Y, Teo, Y-Y, Kim, B-J, Kato, N, Tai, E-S, Chen, P, Takeuchi, F, Lee, J-Y, Li, H, Wu, J-Y, Liang, J, Long, J, Tabara, Y, Goodarzi, MO, Pereira, MA, Kim, YJ, Go, MJ, Stram, DO, Vithana, E, Khor, C-C, Liu, J, Liao, J, Ye, X, Wang, Y, Lu, L, Young, TL, Lee, J, Thai, AC, Cheng, C-Y, van Dam, RM, Friedlander, Y, Heng, C-K, Koh, W-P, Chen, C-H, Chang, L-C, Pan, W-H, Qi, Q, Isono, M, Zheng, W, Cai, Q, Gao, Y, Yamamoto, K, Ohnaka, K, Takayanagi, R, Kita, Y, Ueshima, H, Hsiung, CA, Cui, J, Sheu, WH-H, Rotter, JI, Chen, Y-DI, Hsu, C, Okada, Y, Kubo, M, Takahashi, A, Tanaka, T, van Rooij, FJA, Ganesh, SK, Huang, J, Huang, T, Yuan, J, Hwang, J-Y, CHARGE Hematology Working Group, Gross, MD, Assimes, TL, Miki, T, Shu, X-O, Qi, L, Chen, Y-T, Lin, X, Aung, T, Wong, T-Y, Teo, Y-Y, Kim, B-J, Kato, N, and Tai, E-S
Abstract: Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10(-23)], HBS1L/MYB [8.5 × 10(-15)], MYO9B [9.0 × 10(-12)], and CYBA [1.1 × 10(-8)] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.
Published: 2014

18. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Author: Al Olama, AA, Kote-Jarai, Z, Berndt, SI, Conti, DV, Schumacher, F, Han, Y, Benlloch, S, Hazelett, DJ, Wang, Z, Saunders, E, Leongamornlert, D, Lindstrom, S, Jugurnauth-Little, S, Dadaev, T, Tymrakiewicz, M, Stram, DO, Rand, K, Wan, P, Stram, A, Sheng, X, Pooler, LC, Park, K, Xia, L, Tyrer, J, Kolonel, LN, Le Marchand, L, Hoover, RN, Machiela, MJ, Yeager, M, Burdette, L, Chung, CC, Hutchinson, A, Yu, K, Goh, C, Ahmed, M, Govindasami, K, Guy, M, Tammela, TLJ, Auvinen, A, Wahlfors, T, Schleutker, J, Visakorpi, T, Leinonen, KA, Xu, J, Aly, M, Donovan, J, Travis, RC, Key, TJ, Siddiq, A, Canzian, F, Khaw, K-T, Takahashi, A, Kubo, M, Pharoah, P, Pashayan, N, Weischer, M, Nordestgaard, BG, Nielsen, SF, Klarskov, P, Roder, MA, Iversen, P, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Stanford, JL, Kolb, S, Holt, S, Knudsen, B, Coll, AH, Gapstur, SM, Diver, WR, Stevens, VL, Maier, C, Luedeke, M, Herkommer, K, Rinckleb, AE, Strom, SS, Pettaway, C, Yeboah, ED, Tettey, Y, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Choklcalingam, AP, Cannon-Albright, L, Cybulski, C, Wokolorczyk, D, Kluzniak, W, Park, J, Sellers, T, Lin, H-Y, Isaacs, WB, Partin, AW, Brenner, H, Dieffenbach, AK, Stegmaier, C, Chen, C, Giovannucci, EL, Ma, J, Stampfer, M, Penney, KL, Mucci, L, John, EM, Ingles, SA, Kittles, RA, Murphy, AB, Pandha, H, Michael, A, Kierzek, AM, Blot, W, Signorello, LB, Zheng, W, Albanes, D, Virtamo, J, Weinstein, S, Nemesure, B, Carpten, J, Leske, C, Wu, S-Y, Hennis, A, Kibel, AS, Rybicki, BA, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Zheng, SL, Batra, J, Clements, J, Spurdle, A, Teixeira, MR, Paulo, P, Maia, S, Slavov, C, Kaneva, R, Mitev, V, Witte, JS, Casey, G, Gillanders, EM, Seminara, D, Riboli, E, Hamdy, FC, Coetzee, GA, Li, Q, Freedman, ML, Hunter, DJ, Muir, K, Gronberg, H, Nea, DE, Southey, M, Giles, GG, Severi, G, Cook, MB, Nakagawa, H, Wiklund, F, Kraft, P, Chanock, SJ, Henderson, BE, Easton, DF, Eeles, RA, Haiman, CA, Al Olama, AA, Kote-Jarai, Z, Berndt, SI, Conti, DV, Schumacher, F, Han, Y, Benlloch, S, Hazelett, DJ, Wang, Z, Saunders, E, Leongamornlert, D, Lindstrom, S, Jugurnauth-Little, S, Dadaev, T, Tymrakiewicz, M, Stram, DO, Rand, K, Wan, P, Stram, A, Sheng, X, Pooler, LC, Park, K, Xia, L, Tyrer, J, Kolonel, LN, Le Marchand, L, Hoover, RN, Machiela, MJ, Yeager, M, Burdette, L, Chung, CC, Hutchinson, A, Yu, K, Goh, C, Ahmed, M, Govindasami, K, Guy, M, Tammela, TLJ, Auvinen, A, Wahlfors, T, Schleutker, J, Visakorpi, T, Leinonen, KA, Xu, J, Aly, M, Donovan, J, Travis, RC, Key, TJ, Siddiq, A, Canzian, F, Khaw, K-T, Takahashi, A, Kubo, M, Pharoah, P, Pashayan, N, Weischer, M, Nordestgaard, BG, Nielsen, SF, Klarskov, P, Roder, MA, Iversen, P, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Stanford, JL, Kolb, S, Holt, S, Knudsen, B, Coll, AH, Gapstur, SM, Diver, WR, Stevens, VL, Maier, C, Luedeke, M, Herkommer, K, Rinckleb, AE, Strom, SS, Pettaway, C, Yeboah, ED, Tettey, Y, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Choklcalingam, AP, Cannon-Albright, L, Cybulski, C, Wokolorczyk, D, Kluzniak, W, Park, J, Sellers, T, Lin, H-Y, Isaacs, WB, Partin, AW, Brenner, H, Dieffenbach, AK, Stegmaier, C, Chen, C, Giovannucci, EL, Ma, J, Stampfer, M, Penney, KL, Mucci, L, John, EM, Ingles, SA, Kittles, RA, Murphy, AB, Pandha, H, Michael, A, Kierzek, AM, Blot, W, Signorello, LB, Zheng, W, Albanes, D, Virtamo, J, Weinstein, S, Nemesure, B, Carpten, J, Leske, C, Wu, S-Y, Hennis, A, Kibel, AS, Rybicki, BA, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Zheng, SL, Batra, J, Clements, J, Spurdle, A, Teixeira, MR, Paulo, P, Maia, S, Slavov, C, Kaneva, R, Mitev, V, Witte, JS, Casey, G, Gillanders, EM, Seminara, D, Riboli, E, Hamdy, FC, Coetzee, GA, Li, Q, Freedman, ML, Hunter, DJ, Muir, K, Gronberg, H, Nea, DE, Southey, M, Giles, GG, Severi, G, Cook, MB, Nakagawa, H, Wiklund, F, Kraft, P, Chanock, SJ, Henderson, BE, Easton, DF, Eeles, RA, and Haiman, CA
Abstract: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
Published: 2014

19. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Author: Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Lari, RC-S, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collee, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnaes, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Brauch, H, Bruening, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Doerk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, Dunning, AM, Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Lari, RC-S, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collee, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnaes, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Brauch, H, Bruening, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Doerk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, and Dunning, AM
Abstract: GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
Published: 2014

20. Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A

Author: Wang, H, Burnett, T, Kono, S, Haiman, CA, Iwasaki, M, Wilkens, LR, Loo, LWM, Van den Berg, D, Kolonel, LN, Henderson, BE, Keku, TO, Sandler, RS, Signorello, LB, Blot, WJ, Newcomb, PA, Pande, M, Amos, CI, West, DW, Bezieau, S, Berndt, SI, Zanke, BW, Hsu, L, Lindor, NM, Haile, RW, Hopper, JL, Jenkins, MA, Gallinger, S, Casey, G, Stenzel, SL, Schumacher, FR, Peters, U, Gruber, SB, Tsugane, S, Stram, DO, Le Marchand, L, Wang, H, Burnett, T, Kono, S, Haiman, CA, Iwasaki, M, Wilkens, LR, Loo, LWM, Van den Berg, D, Kolonel, LN, Henderson, BE, Keku, TO, Sandler, RS, Signorello, LB, Blot, WJ, Newcomb, PA, Pande, M, Amos, CI, West, DW, Bezieau, S, Berndt, SI, Zanke, BW, Hsu, L, Lindor, NM, Haile, RW, Hopper, JL, Jenkins, MA, Gallinger, S, Casey, G, Stenzel, SL, Schumacher, FR, Peters, U, Gruber, SB, Tsugane, S, Stram, DO, and Le Marchand, L
Abstract: The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P<5 × 10(-8)) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.4 × 10(-9)), providing additional insight into the aetiology of CRC and highlighting the value of association mapping in diverse populations.
Published: 2014

21. FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Author: Agarwal, D, Pineda, S, Michailidou, K, Herranz, J, Pita, G, Moreno, LT, Alonso, MR, Dennis, J, Wang, Q, Bolla, MK, Meyer, KB, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Lindblom, A, Margolin, S, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Matsuo, K, Ito, H, Iwata, H, Kondo, N, Hartman, M, Hui, M, Lim, WY, Iau, PT-C, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, W-T, Brauch, H, Bruening, T, Hamann, U, Dunning, AM, Shah, M, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Schmidt, MK, Broeks, A, Rosenberg, EH, van't Veer, LJ, Fasching, PA, Renner, SP, Ekici, AB, Beckmann, MW, Shen, C-Y, Hsiung, C-N, Yu, J-C, Hou, M-F, Blot, W, Cai, Q, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Cox, A, Brock, IW, Reed, MWR, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, J, Shu, X-O, Lu, W, Gao, Y-T, Zhang, B, Radice, P, Peterlongo, P, Manoukian, S, Mariette, F, Sangrajrang, S, Mckay, J, Couch, FJ, Toland, AE, Yannoukakos, D, Fletcher, O, Johnson, N, dos Santos Silva, I, Peto, J, Marme, F, Burwinkel, B, Guenel, P, Truong, T, Sanchez, M, Mulot, C, Bojesen, SE, Nordestgaard, BG, Flyer, H, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Lambrechts, D, Yesilyurt, BT, Floris, G, Leunen, K, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Wang, X, Olson, JE, Vachon, C, Purrington, K, Giles, GG, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Hooning, MJ, Kriege, M, Collee, JM, Tilanus-Linthorst, M, Li, J, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Bogdanova, N, Doerk, T, Hall, P, Chenevix-Trench, G, Easton, DF, Pharoah, PDP, Arias-Perez, JI, Zamora, P, Benitez, J, Milne, RL, Agarwal, D, Pineda, S, Michailidou, K, Herranz, J, Pita, G, Moreno, LT, Alonso, MR, Dennis, J, Wang, Q, Bolla, MK, Meyer, KB, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Lindblom, A, Margolin, S, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Matsuo, K, Ito, H, Iwata, H, Kondo, N, Hartman, M, Hui, M, Lim, WY, Iau, PT-C, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, W-T, Brauch, H, Bruening, T, Hamann, U, Dunning, AM, Shah, M, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Schmidt, MK, Broeks, A, Rosenberg, EH, van't Veer, LJ, Fasching, PA, Renner, SP, Ekici, AB, Beckmann, MW, Shen, C-Y, Hsiung, C-N, Yu, J-C, Hou, M-F, Blot, W, Cai, Q, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Cox, A, Brock, IW, Reed, MWR, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, J, Shu, X-O, Lu, W, Gao, Y-T, Zhang, B, Radice, P, Peterlongo, P, Manoukian, S, Mariette, F, Sangrajrang, S, Mckay, J, Couch, FJ, Toland, AE, Yannoukakos, D, Fletcher, O, Johnson, N, dos Santos Silva, I, Peto, J, Marme, F, Burwinkel, B, Guenel, P, Truong, T, Sanchez, M, Mulot, C, Bojesen, SE, Nordestgaard, BG, Flyer, H, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Lambrechts, D, Yesilyurt, BT, Floris, G, Leunen, K, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Wang, X, Olson, JE, Vachon, C, Purrington, K, Giles, GG, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Hooning, MJ, Kriege, M, Collee, JM, Tilanus-Linthorst, M, Li, J, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Bogdanova, N, Doerk, T, Hall, P, Chenevix-Trench, G, Easton, DF, Pharoah, PDP, Arias-Perez, JI, Zamora, P, Benitez, J, and Milne, RL
Abstract: BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
Published: 2014

22. Joint effects of known type 2 diabetes susceptibility loci in genome-wide association study of Singapore Chinese: The Singapore Chinese health study

Author: Chen, Z, Pereira, MA, Seielstad, M, Koh, WP, Tai, ES, Teo, YY, Liu, J, Hsu, C, Wang, R, Odegaard, AO, Thyagarajan, B, Koratkar, R, Yuan, JM, Gross, MD, Stram, DO, Chen, Z, Pereira, MA, Seielstad, M, Koh, WP, Tai, ES, Teo, YY, Liu, J, Hsu, C, Wang, R, Odegaard, AO, Thyagarajan, B, Koratkar, R, Yuan, JM, Gross, MD, and Stram, DO
Abstract: Background: Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study. Methods: 2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r2>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ±100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis. Results: Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p<0.05) for 15 SNPs, while 32 more were directionally consistent with previous reports. Risk score was a significant predictor with a 2.03 fold higher risk CI (1.69-2.44) of T2D comparing the highest to lowest quintile of risk allele burden (p = 5.72×10-14). Two improved SNPs around index rs10923931 and 5 new candidate SNPs around indices rs10965250 and rs1111875 passed simple Bonferroni corrections for significance in conditional analysis. Nonetheless, only a small fraction (2.3% on the disease liability scale) of T2D burden in Singapore is explained by these SNPs. Conclusions: While diabetes risk in Singapore Chinese involves genetic variants, most disease risk remains unexplained. Further genetic work is ongoing in the Singapore Chinese population to identify unique common variants not already seen in earlier studies. However rapid increases in T2D risk have occurred in recent decades in this population, indicating that dynamic environmental influences and possibly gene by environment
Published: 2014

23. Haplotypes of the estrogen receptor beta gene and breast cancer risk

Author: Cox, DG, Bretsky, P, Kraft, P, Pharoah, P, Albanes, D, Altshuler, D, Amiano, P, Berglund, G, Boeing, H, Buring, J, Burtt, N, Calle, EE, Canzian, F, Chanock, S, Clavel-Chapelon, F, Colditz, GA, Feigelson, HS, Haiman, CA, Hankinson, SE, Hirschhorn, J, Henderson, BE, Hoover, R, Hunter, DJ, Kaaks, R, Kolonel, L, LeMarchand, L, Lund, E, Palli, D, Peeters, PH, Pike, MC, Riboli, E, Stram, DO, Thun, M, Tjonneland, A, Travis, RC, Trichopoulos, D, and Yeager, M
Abstract: Exposure to exogenous (oral contraceptives, postmenopausal hormone therapy) and endogenous (number of ovulatory cycles, adiposity) steroid hormones is associated with breast cancer risk. Breast cancer risk associated with these exposures could hypothetically be modified by genes in the steroid hormone synthesis, metabolism and signaling pathways. Estrogen receptors are the first step along the path of signaling cell growth and development upon stimulation with estrogens. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium has systematically selected haplotype tagging SNPs in genes along the steroid hormone synthesis, metabolism and binding pathways, including the estrogen receptor beta (ESR2) gene. Four htSNPs tag the 6 major (>5% frequency) haplotypes of the ESR2 gene. These polymorphisms have been genotyped in 5,789 breast cancer cases and 7,761 controls nested within the American Cancer Society Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study and Women's Health Study cohorts. None of the SNPs were independently associated with breast cancer risk. One haplotype of the ESR2 gene was associated with breast cancer risk before correction for multiple testing (OR 1.17, 95% CI 1.07-1.28, p = 0.0007). This haplotype remained associated with breast cancer risk after adjustment for multiple testing using a permutation procedure. There was no statistically significant heterogeneity in SNP or haplotype odds ratios across cohorts. These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women.
Published: 2008

24. Haplotype analysis of the HSD17B1 gene and risk of breast cancer: A comprehensive approach to multicenter analyses of prospective cohort studies

Author: Feigelson, HS Cox, DG Cann, HM Wacholder, S Kaaks, R and Henderson, BE Albanes, D Altshuler, D Berglund, G and Berrino, F Bingham, S Buring, JE Burtt, NP Calle, EE and Chanock, SJ Clavel-Chapelon, F Colditz, G Diver, WR and Freedman, ML Haiman, CA Hankinson, SE Hayes, RB and Hirschhorn, JN Hunter, D Kolonel, LN Kraft, P and LeMarchand, L Linseisen, J Modi, W Navarro, C Peeters, PH Pike, MC Riboli, E Setiawan, VW Stram, DO Thomas, G Thun, MJ Tjonneland, A Trichopoulos, D
Abstract: The 17 beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X-2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study.
Published: 2006

25. Genetic variation in the HSD17B1 gene and risk of prostate cancer

Author: Kraft, P Pharoah, P Chanock, SJ Albanes, D Kolonel, LN and Hayes, RB Altshuler, D Andriole, G Berg, C Boeing, H and Burtt, NP Bueno-de-Mesquita, B Calle, EE Cann, H and Canzian, F Chen, YC Crawford, DE Dunning, AM Feigelson, HS Freedman, ML Gaziano, JM Giovannucci, E Gonzalez, CA and Haiman, CA Hallmans, G Henderson, BE Hirschhorn, JN and Hunter, DJ Kaaks, R Key, T Le Marchand, L Ma, J and Overvad, K Palli, D Pike, MC Riboli, E Rodriguez, C and Setiawan, WV Stampfer, MJ Stram, DO Thomas, G Thun, MJ and Travis, R Trichopoulou, A Virtamo, J Wacholder, S
Abstract: Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17p-hydroxysteroid clehydrogenase 1, an enzyme that converts clihydroepiandrosterone to the testosterone precursor Delta 5-androsterone-3 beta, 17 beta-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.
Published: 2005

26. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Author: Shen, H, Fridley, BL, Song, H, Lawrenson, K, Cunningham, JM, Ramus, SJ, Cicek, MS, Tyrer, J, Stram, D, Larson, MC, Koebel, M, Ziogas, A, Zheng, W, Yang, HP, Wu, AH, Wozniak, EL, Woo, YL, Winterhoff, B, Wik, E, Whittemore, AS, Wentzensen, N, Weber, RP, Vitonis, AF, Vincent, D, Vierkant, RA, Vergote, I, Van Den Berg, D, Van Altena, AM, Tworoger, SS, Thompson, PJ, Tessier, DC, Terry, KL, Teo, S-H, Templeman, C, Stram, DO, Southey, MC, Sieh, W, Siddiqui, N, Shvetsov, YB, Shu, X-O, Shridhar, V, Wang-Gohrke, S, Severi, G, Schwaab, I, Salvesen, HB, Rzepecka, IK, Runnebaum, IB, Rossing, MA, Rodriguez-Rodriguez, L, Risch, HA, Renner, SP, Poole, EM, Pike, MC, Phelan, CM, Pelttari, LM, Pejovic, T, Paul, J, Orlow, I, Omar, SZ, Olson, SH, Odunsi, K, Nickels, S, Nevanlinna, H, Ness, RB, Narod, SA, Nakanishi, T, Moysich, KB, Monteiro, ANA, Moes-Sosnowska, J, Modugno, F, Menon, U, McLaughlin, JR, McGuire, V, Matsuo, K, Adenan, NAM, Massuger, LFAG, Lurie, G, Lundvall, L, Lubinski, J, Lissowska, J, Levine, DA, Leminen, A, Lee, AW, Le, ND, Lambrechts, S, Lambrechts, D, Kupryjanczyk, J, Krakstad, C, Konecny, GE, Kjaer, SK, Kiemeney, LA, Kelemen, LE, Keeney, GL, Karlan, BY, Karevan, R, Kalli, KR, Kajiyama, H, Ji, B-T, Jensen, A, Jakubowska, A, Iversen, E, Hosono, S, Hogdall, CK, Hogdall, E, Hoatlin, M, Hillemanns, P, Heitz, F, Hein, R, Harter, P, Halle, MK, Hall, P, Gronwald, J, Gore, M, Goodman, MT, Giles, GG, Gentry-Maharaj, A, Garcia-Closas, M, Flanagan, JM, Fasching, PA, Ekici, AB, Edwards, R, Eccles, D, Easton, DF, Duerst, M, du Bois, A, Doerk, T, Doherty, JA, Despierre, E, Dansonka-Mieszkowska, A, Cybulski, C, Cramer, DW, Cook, LS, Chen, X, Charbonneau, B, Chang-Claude, J, Campbell, I, Butzow, R, Bunker, CH, Brueggmann, D, Brown, R, Brooks-Wilson, A, Brinton, LA, Bogdanova, N, Block, MS, Benjamin, E, Beesley, J, Beckmann, MW, Bandera, EV, Baglietto, L, Bacot, F, Armasu, SM, Antonenkova, N, Anton-Culver, H, Aben, KK, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Schildkraut, JM, Sellers, TA, Huntsman, D, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Pharoah, PDP, Laird, PW, Goode, EL, Pearce, CL, Shen, H, Fridley, BL, Song, H, Lawrenson, K, Cunningham, JM, Ramus, SJ, Cicek, MS, Tyrer, J, Stram, D, Larson, MC, Koebel, M, Ziogas, A, Zheng, W, Yang, HP, Wu, AH, Wozniak, EL, Woo, YL, Winterhoff, B, Wik, E, Whittemore, AS, Wentzensen, N, Weber, RP, Vitonis, AF, Vincent, D, Vierkant, RA, Vergote, I, Van Den Berg, D, Van Altena, AM, Tworoger, SS, Thompson, PJ, Tessier, DC, Terry, KL, Teo, S-H, Templeman, C, Stram, DO, Southey, MC, Sieh, W, Siddiqui, N, Shvetsov, YB, Shu, X-O, Shridhar, V, Wang-Gohrke, S, Severi, G, Schwaab, I, Salvesen, HB, Rzepecka, IK, Runnebaum, IB, Rossing, MA, Rodriguez-Rodriguez, L, Risch, HA, Renner, SP, Poole, EM, Pike, MC, Phelan, CM, Pelttari, LM, Pejovic, T, Paul, J, Orlow, I, Omar, SZ, Olson, SH, Odunsi, K, Nickels, S, Nevanlinna, H, Ness, RB, Narod, SA, Nakanishi, T, Moysich, KB, Monteiro, ANA, Moes-Sosnowska, J, Modugno, F, Menon, U, McLaughlin, JR, McGuire, V, Matsuo, K, Adenan, NAM, Massuger, LFAG, Lurie, G, Lundvall, L, Lubinski, J, Lissowska, J, Levine, DA, Leminen, A, Lee, AW, Le, ND, Lambrechts, S, Lambrechts, D, Kupryjanczyk, J, Krakstad, C, Konecny, GE, Kjaer, SK, Kiemeney, LA, Kelemen, LE, Keeney, GL, Karlan, BY, Karevan, R, Kalli, KR, Kajiyama, H, Ji, B-T, Jensen, A, Jakubowska, A, Iversen, E, Hosono, S, Hogdall, CK, Hogdall, E, Hoatlin, M, Hillemanns, P, Heitz, F, Hein, R, Harter, P, Halle, MK, Hall, P, Gronwald, J, Gore, M, Goodman, MT, Giles, GG, Gentry-Maharaj, A, Garcia-Closas, M, Flanagan, JM, Fasching, PA, Ekici, AB, Edwards, R, Eccles, D, Easton, DF, Duerst, M, du Bois, A, Doerk, T, Doherty, JA, Despierre, E, Dansonka-Mieszkowska, A, Cybulski, C, Cramer, DW, Cook, LS, Chen, X, Charbonneau, B, Chang-Claude, J, Campbell, I, Butzow, R, Bunker, CH, Brueggmann, D, Brown, R, Brooks-Wilson, A, Brinton, LA, Bogdanova, N, Block, MS, Benjamin, E, Beesley, J, Beckmann, MW, Bandera, EV, Baglietto, L, Bacot, F, Armasu, SM, Antonenkova, N, Anton-Culver, H, Aben, KK, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Schildkraut, JM, Sellers, TA, Huntsman, D, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Pharoah, PDP, Laird, PW, Goode, EL, and Pearce, CL
Abstract: HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
Published: 2013

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

Author: Dubé, M-P, Lindstrom, S, Schumacher, F, Siddiq, A, Travis, RC, Campa, D, Berndt, SI, Diver, WR, Severi, G, Allen, N, Andriole, G, Bueno-de-Mesquita, B, Chanock, SJ, Crawford, D, Gaziano, JM, Giles, GG, Giovannucci, E, Guo, C, Haiman, CA, Hayes, RB, Halkjaer, J, Hunter, DJ, Johansson, M, Kaaks, R, Kolonel, LN, Navarro, C, Riboli, E, Sacerdote, C, Stampfer, M, Stram, DO, Thun, MJ, Trichopoulos, D, Virtamo, J, Weinstein, SJ, Yeager, M, Henderson, B, Ma, J, Le Marchand, L, Albanes, D, Kraft, P, Dubé, M-P, Lindstrom, S, Schumacher, F, Siddiq, A, Travis, RC, Campa, D, Berndt, SI, Diver, WR, Severi, G, Allen, N, Andriole, G, Bueno-de-Mesquita, B, Chanock, SJ, Crawford, D, Gaziano, JM, Giles, GG, Giovannucci, E, Guo, C, Haiman, CA, Hayes, RB, Halkjaer, J, Hunter, DJ, Johansson, M, Kaaks, R, Kolonel, LN, Navarro, C, Riboli, E, Sacerdote, C, Stampfer, M, Stram, DO, Thun, MJ, Trichopoulos, D, Virtamo, J, Weinstein, SJ, Yeager, M, Henderson, B, Ma, J, Le Marchand, L, Albanes, D, and Kraft, P
Abstract: Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10⁻²⁸). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade < 8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.
Published: 2011

28. Identification, replication, and fine-mapping of loci associated with adult height in individuals of African ancestry

Author: N'Diaye, A, Chen, GK, Palmer, CD, Ge, B, Tayo, B, Mathias, RA, Ding, J, Nalls, MA, Adeyemo, A, Adoue, V, Ambrosone, CB, Atwood, L, Bandera, EV, Becker, LC, Berndt, SI, Bernstein, L, Blot, WJ, Boerwinkle, E, Britton, A, Casey, G, Chanock, SJ, Demerath, E, Deming, SL, Diver, WR, Fox, C, Harris, TB, Hernandez, DG, Hu, JJ, Ingles, SA, John, EM, Johnson, C, Keating, B, Kittles, RA, Kolonel, LN, Kritchevsky, SB, Marchand, L, Lohman, K, Liu, J, Millikan, RC, Murphy, A, Musani, S, Neslund-Dudas, C, North, KE, Nyante, S, Ogunniyi, A, Ostrander, EA, Papanicolaou, G, Patel, S, Pettaway, CA, Press, MF, Redline, S, Rodriguez-Gil, JL, Rotimi, C, Rybicki, BA, Salako, B, Schreiner, PJ, Signorello, LB, Singleton, AB, Stanford, JL, Stram, AH, Stram, DO, Strom, SS, Suktitipat, B, Thun, MJ, Witte, JS, Yanek, LR, Ziegler, RG, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Evans, MK, Liu, Y, Becker, DM, Cooper, RS, Pastinen, T, Henderson, BE, Hirschhorn, JN, Lettre, G, Haiman, CA, N'Diaye, A, Chen, GK, Palmer, CD, Ge, B, Tayo, B, Mathias, RA, Ding, J, Nalls, MA, Adeyemo, A, Adoue, V, Ambrosone, CB, Atwood, L, Bandera, EV, Becker, LC, Berndt, SI, Bernstein, L, Blot, WJ, Boerwinkle, E, Britton, A, Casey, G, Chanock, SJ, Demerath, E, Deming, SL, Diver, WR, Fox, C, Harris, TB, Hernandez, DG, Hu, JJ, Ingles, SA, John, EM, Johnson, C, Keating, B, Kittles, RA, Kolonel, LN, Kritchevsky, SB, Marchand, L, Lohman, K, Liu, J, Millikan, RC, Murphy, A, Musani, S, Neslund-Dudas, C, North, KE, Nyante, S, Ogunniyi, A, Ostrander, EA, Papanicolaou, G, Patel, S, Pettaway, CA, Press, MF, Redline, S, Rodriguez-Gil, JL, Rotimi, C, Rybicki, BA, Salako, B, Schreiner, PJ, Signorello, LB, Singleton, AB, Stanford, JL, Stram, AH, Stram, DO, Strom, SS, Suktitipat, B, Thun, MJ, Witte, JS, Yanek, LR, Ziegler, RG, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Evans, MK, Liu, Y, Becker, DM, Cooper, RS, Pastinen, T, Henderson, BE, Hirschhorn, JN, Lettre, G, and Haiman, CA
Abstract: Adult height is a classic polygenic trait of high heritability (h 2 ~0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ~10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10 -12 and 2p14-rs4315565, P = 1.2×10 -8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10 -4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits. © 2011 N'Diaye et al.
Published: 2011

29. Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility 'Hot-Spot'

Author: Dermitzakis, ET, Johnatty, SE, Beesley, J, Chen, X, Macgregor, S, Duffy, DL, Spurdle, AB, deFazio, A, Gava, N, Webb, PM, Rossing, MA, Doherty, JA, Goodman, MT, Lurie, G, Thompson, PJ, Wilkens, LR, Ness, RB, Moysich, KB, Chang-Claude, J, Wang-Gohrke, S, Cramer, DW, Terry, KL, Hankinson, SE, Tworoger, SS, Garcia-Closas, M, Yang, H, Lissowska, J, Chanock, SJ, Pharoah, PD, Song, H, Whitemore, AS, Pearce, CL, Stram, DO, Wu, AH, Pike, MC, Gayther, SA, Ramus, SJ, Menon, U, Gentry-Maharaj, A, Anton-Culver, H, Ziogas, A, Hogdall, E, Kjaer, SK, Hogdall, C, Berchuck, A, Schildkraut, JM, Iversen, ES, Moorman, PG, Phelan, CM, Sellers, TA, Cunningham, JM, Vierkant, RA, Rider, DN, Goode, EL, Haviv, I, Chenevix-Trench, G, Dermitzakis, ET, Johnatty, SE, Beesley, J, Chen, X, Macgregor, S, Duffy, DL, Spurdle, AB, deFazio, A, Gava, N, Webb, PM, Rossing, MA, Doherty, JA, Goodman, MT, Lurie, G, Thompson, PJ, Wilkens, LR, Ness, RB, Moysich, KB, Chang-Claude, J, Wang-Gohrke, S, Cramer, DW, Terry, KL, Hankinson, SE, Tworoger, SS, Garcia-Closas, M, Yang, H, Lissowska, J, Chanock, SJ, Pharoah, PD, Song, H, Whitemore, AS, Pearce, CL, Stram, DO, Wu, AH, Pike, MC, Gayther, SA, Ramus, SJ, Menon, U, Gentry-Maharaj, A, Anton-Culver, H, Ziogas, A, Hogdall, E, Kjaer, SK, Hogdall, C, Berchuck, A, Schildkraut, JM, Iversen, ES, Moorman, PG, Phelan, CM, Sellers, TA, Cunningham, JM, Vierkant, RA, Rider, DN, Goode, EL, Haviv, I, and Chenevix-Trench, G
Abstract: We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n=1,233 serous invasive cases; n=3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele>or=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.
Published: 2010

30. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics

Author: Leal, SM, Garcia-Closas, M, Hall, P, Nevanlinna, H, Pooley, K, Morrison, J, Richesson, DA, Bojesen, SE, Nordestgaard, BG, Axelsson, CK, Arias, JI, Milne, RL, Ribas, G, Gonzalez-Neira, A, Benitez, J, Zamora, P, Brauch, H, Justenhoven, C, Hamann, U, Ko, Y-D, Bruening, T, Haas, S, Doerk, T, Schuermann, P, Hillemanns, P, Bogdanova, N, Bremer, M, Karstens, JH, Fagerholm, R, Aaltonen, K, Aittomaki, K, Von Smitten, K, Blomqvist, C, Mannermaa, A, Uusitupa, M, Eskelinen, M, Tengstrom, M, Kosma, V-M, Kataja, V, Chenevix-Trench, G, Spurdle, AB, Beesley, J, Chen, X, Devilee, P, Van Asperen, CJ, Jacobi, CE, Tollenaar, RAEM, Huijts, PEA, Klijn, JGM, Chang-Claude, J, Kropp, S, Slanger, T, Flesch-Janys, D, Mutschelknauss, E, Salazar, R, Wang-Gohrke, S, Couch, F, Goode, EL, Olson, JE, Vachon, C, Fredericksen, ZS, Giles, GG, Baglietto, L, Severi, G, Hopper, JL, English, DR, Southey, MC, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, Stram, DO, Hunter, DJ, Hankinson, SE, Cox, DG, Tamimi, R, Kraft, P, Sherman, ME, Chanock, SJ, Lissowska, J, Brinton, LA, Peplonska, B, Hooning, MJ, Meijers-Heijboer, H, Collee, JM, Van den Ouweland, A, Uitterlinden, AG, Liu, J, Lin, LY, Yuqing, L, Humphreys, K, Czene, K, Cox, A, Balasubramanian, SP, Cross, SS, Reed, MWR, Blows, F, Driver, K, Dunning, A, Tyrer, J, Ponder, BAJ, Sangrajrang, S, Brennan, P, Mckay, J, Odefrey, F, Gabrieau, V, Sigurdson, A, Doody, M, Struewing, JP, Alexander, B, Easton, DF, Pharoah, PD, Leal, SM, Garcia-Closas, M, Hall, P, Nevanlinna, H, Pooley, K, Morrison, J, Richesson, DA, Bojesen, SE, Nordestgaard, BG, Axelsson, CK, Arias, JI, Milne, RL, Ribas, G, Gonzalez-Neira, A, Benitez, J, Zamora, P, Brauch, H, Justenhoven, C, Hamann, U, Ko, Y-D, Bruening, T, Haas, S, Doerk, T, Schuermann, P, Hillemanns, P, Bogdanova, N, Bremer, M, Karstens, JH, Fagerholm, R, Aaltonen, K, Aittomaki, K, Von Smitten, K, Blomqvist, C, Mannermaa, A, Uusitupa, M, Eskelinen, M, Tengstrom, M, Kosma, V-M, Kataja, V, Chenevix-Trench, G, Spurdle, AB, Beesley, J, Chen, X, Devilee, P, Van Asperen, CJ, Jacobi, CE, Tollenaar, RAEM, Huijts, PEA, Klijn, JGM, Chang-Claude, J, Kropp, S, Slanger, T, Flesch-Janys, D, Mutschelknauss, E, Salazar, R, Wang-Gohrke, S, Couch, F, Goode, EL, Olson, JE, Vachon, C, Fredericksen, ZS, Giles, GG, Baglietto, L, Severi, G, Hopper, JL, English, DR, Southey, MC, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, Stram, DO, Hunter, DJ, Hankinson, SE, Cox, DG, Tamimi, R, Kraft, P, Sherman, ME, Chanock, SJ, Lissowska, J, Brinton, LA, Peplonska, B, Hooning, MJ, Meijers-Heijboer, H, Collee, JM, Van den Ouweland, A, Uitterlinden, AG, Liu, J, Lin, LY, Yuqing, L, Humphreys, K, Czene, K, Cox, A, Balasubramanian, SP, Cross, SS, Reed, MWR, Blows, F, Driver, K, Dunning, A, Tyrer, J, Ponder, BAJ, Sangrajrang, S, Brennan, P, Mckay, J, Odefrey, F, Gabrieau, V, Sigurdson, A, Doody, M, Struewing, JP, Alexander, B, Easton, DF, and Pharoah, PD
Abstract: A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding
Published: 2008

31. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics

Author: Garcia-Closas, M, Hall, P, Nevanlinna, H, Pooley, KA, Morrison, J, Richesson, DA, Bojesen, SE, Nordestgaard, BG, Axelsson, CK, Arias, JI, Milne, RL, Ribas, G, Gonzalez-Neira, A, Benitez, J, Zamora, P, Brauch, H, Justenhoven, C, Hamann, U, Ko, YD, Bruening, T, Haas, S, Dork, T, Schurmann, P, Hillemanns, P, Bogdanova, N, Bremer, M, Karstens, JH, Fagerholm, R, Aaltonen, K, Aittomaki, K, von Smitten, K, Blomqvist, C, Mannermaa, A, Uusitupa, M, Eskelinen, M, Tengstrom, M, Kosma, VM, Kataja, V, Chenevix-Trench, G, Spurdle, AB, Beeslev, J, Chen, X, Devilee, P, van Asperen, CJ, Jacobi, CE, Tollenaar, RA, Huijts, PE, Klijn, Jan, Chang-Claude, J, Kropp, S, Slanger, T, Flesch-Janys, D, Mutschelknauss, E, Salazar, R, Wang-Gohrke, S, Couch, F, Goode, EL, Olson, JE, Vachon, C, Fredericksen, ZS, Giles, GG, Baglietto, L, Severi, G, Hopper, JL, English, DR, Southey, M, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, Stram, DO, Hunter, DJ, Hankinson, SE, Cox, DG, Tamimi, R, van Kraft, PJA (Peter), Sherman, M, Chanock, S, Lissowska, J, Brinton, L, Peplonska, B, Hooning, Maartje, Meijers-Heijboer, EJ, Collee, Margriet, van den Ouweland, Ans, Uitterlinden, André, Liu, Jun, Lin, L, Yuqing, L, Humphreys, K, Czene, K, Cox, A, Balasubramanian, SP, Cross, SS, Reed, MWR, Blows, F, Driver, K, Dunning, AJ, Tyrer, J, Garcia-Closas, M, Hall, P, Nevanlinna, H, Pooley, KA, Morrison, J, Richesson, DA, Bojesen, SE, Nordestgaard, BG, Axelsson, CK, Arias, JI, Milne, RL, Ribas, G, Gonzalez-Neira, A, Benitez, J, Zamora, P, Brauch, H, Justenhoven, C, Hamann, U, Ko, YD, Bruening, T, Haas, S, Dork, T, Schurmann, P, Hillemanns, P, Bogdanova, N, Bremer, M, Karstens, JH, Fagerholm, R, Aaltonen, K, Aittomaki, K, von Smitten, K, Blomqvist, C, Mannermaa, A, Uusitupa, M, Eskelinen, M, Tengstrom, M, Kosma, VM, Kataja, V, Chenevix-Trench, G, Spurdle, AB, Beeslev, J, Chen, X, Devilee, P, van Asperen, CJ, Jacobi, CE, Tollenaar, RA, Huijts, PE, Klijn, Jan, Chang-Claude, J, Kropp, S, Slanger, T, Flesch-Janys, D, Mutschelknauss, E, Salazar, R, Wang-Gohrke, S, Couch, F, Goode, EL, Olson, JE, Vachon, C, Fredericksen, ZS, Giles, GG, Baglietto, L, Severi, G, Hopper, JL, English, DR, Southey, M, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, Stram, DO, Hunter, DJ, Hankinson, SE, Cox, DG, Tamimi, R, van Kraft, PJA (Peter), Sherman, M, Chanock, S, Lissowska, J, Brinton, L, Peplonska, B, Hooning, Maartje, Meijers-Heijboer, EJ, Collee, Margriet, van den Ouweland, Ans, Uitterlinden, André, Liu, Jun, Lin, L, Yuqing, L, Humphreys, K, Czene, K, Cox, A, Balasubramanian, SP, Cross, SS, Reed, MWR, Blows, F, Driver, K, Dunning, AJ, and Tyrer, J
Published: 2008

32. Effects of Vehicle Exhaust in Aged Adults Riding on Los Angeles Freeways.

Author: Cascio, WE, primary, Katwa, LC, additional, Linn, WS, additional, Stram, DO, additional, Zhu, Y, additional, Cascio, JL, additional, and Hinds, WC, additional
Published: 2009
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33. Age-specific effects of hormone therapy use on overall mortality and ischemic heart disease mortality among women in the California Teachers Study.

Author: Stram DO, Liu Y, Henderson KD, Sullivan-Halley J, Luo J, Saxena T, Reynolds P, Chang ET, Neuhausen SL, Horn-Ross PL, Bernstein L, Ursin G, Stram, Daniel O, Liu, Yuan, Henderson, Katherine D, Sullivan-Halley, Jane, Luo, Jianning, Saxena, Tanmai, Reynolds, Peggy, and Chang, Ellen T
Published: 2011
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34. Nonsteroidal anti-inflammatory drugs: effects on mortality after colorectal cancer diagnosis.

Author: Zell JA, Ziogas A, Bernstein L, Clarke CA, Deapen D, Largent JA, Neuhausen SL, Stram DO, Ursin G, Anton-Culver H, Zell, Jason A, Ziogas, Argyrios, Bernstein, Leslie, Clarke, Christina A, Deapen, Dennis, Largent, Joan A, Neuhausen, Susan L, Stram, Daniel O, Ursin, Giske, and Anton-Culver, Hoda
Abstract: Background: Nonsteroidal anti-inflammatory drug (NSAID) use has been associated with a decreased colorectal cancer (CRC) risk. However, to the best of the authors' knowledge, the effects of NSAID on clinical outcomes after CRC diagnosis are not well defined. The authors investigated the association between prediagnosis NSAID use and mortality after CRC diagnosis among women in the California Teachers Study cohort.Methods: Women aged <85 years participating in the California Teachers Study, without a prior CRC diagnosis at baseline (1995-1996), and who were diagnosed with CRC during follow-up through December 2005, were eligible for analysis of the association between prediagnosis NSAID use and mortality. NSAID use (including aspirin and ibuprofen) was collected through a self-administered questionnaire. Cancer occurrence was identified through California Cancer Registry linkage. Multivariate Cox proportional hazards regression models were used to estimate hazards ratios (HR) for death and 95% confidence intervals (95% CIs).Results: Among 621 CRC patients who were identified, 64% reported no prediagnosis regular NSAID use, 17% reported use of 1 to 6 days/week, and 20% reported daily use. A duration of NSAID use <5 years was reported by 17% of patients and a use of >or=5 years was reported by 18%. Regular prediagnosis NSAID use (1-3 days/week, 4-6 days/week, and daily) versus none was associated with improved overall survival (OS) (HR, 0.71; 95% CI, 0.53-0.95) and CRC-specific survival (HR, 0.58; 95% CI 0.40-0.84) after adjustment for clinically relevant factors. Prediagnosis NSAID use >or=5 years (vs none) was found to be associated with improved OS (HR, 0.55; 95% CI, 0.37-0.84) and CRC-specific survival (HR, 0.40; 95% CI, 0.23-0.71) in adjusted analyses.Conclusions: When used regularly or over a prolonged duration before CRC diagnosis, NSAIDs are associated with decreased mortality among female CRC patients. [ABSTRACT FROM AUTHOR]
Published: 2009
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35. Calcium, vitamin D, and dairy porduct intake and porstate cancer risk: the multiethnic cohort study.

Author: Park S, Murphy SP, Wilkens LR, Stram DO, Henderson BE, and Kolonel LN
Abstract: High intakes of calcium and dairy products have been suggested to be related to prostate cancer risk. Such associations were examined in the Multiethnic Cohort Study (1993-2002) among 82,483 men who completed a detailed quantitative food frequency questionnaire. During a mean follow-up of 8 years, 4,404 total cases of prostate cancer were identified. In Cox proportional hazards models, no association was found between calcium and vitamin D intake and total, advanced, or high-grade prostate cancer risk, whether for total intake, intake from foods, or intake from supplements, among all male participants or among nonusers of supplemental calcium. No association of calcium or vitamin D intake was seen across racial/ethnic groups. In analyses of food groups, dairy product and total milk consumption were not associated with prostate cancer risk. However, low-/nonfat milk was related to an increased risk and whole milk to a decreased risk of total prostate cancer; after stratification, these effects were limited to localized or low-grade tumors. Although the findings from this study do not support an association between the intakes of calcium and vitamin D and prostate cancer risk, they do suggest that an association with milk consumption may vary by fat content, particularly for early forms of this cancer. [ABSTRACT FROM AUTHOR]
Published: 2007
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36. Risk factors for renal cell cancer: the multiethnic cohort.

Author: Setiawan VW, Stram DO, Nomura AM, Kolonel LN, and Henderson BE
Abstract: The association of body size, lifestyle, and medical conditions with renal cell cancer risk was examined among 161,126 Hawaii-Los Angeles Multiethnic Cohort participants (1993-2002). After 8.3 years of follow-up, 347 renal cell cancer cases (220 men, 127 women) were identified. Renal cell cancer risk increased with increasing body mass index in men (multivariate relative risk (RR) = 1.06 per unit of body mass index, p = 0.001) and women (RR = 1.07, p < 0.0001). The relative risks associated with being obese compared with being lean were 1.76 (95% confidence interval (CI): 1.20, 2.58) for men and 2.27 (95% CI: 1.37, 3.74) for women. Hypertension was associated with renal cell cancer (RR(men) = 1.42, 95% CI: 1.07, 1.87; RR(women) = 1.58, 95% CI: 1.09, 2.28). Smoking was confirmed to be a risk factor for both sexes. Among women, diuretic use was associated with increased risk (RR = 1.63, 95% CI: 1.04, 2.57), whereas physical activity was associated with reduced risk (p(trend) = 0.027). Alcohol consumption was inversely associated with risk for men (p(trend) = 0.045). Compared with nondrinkers, men who drank >/=1 drinks/day had a 31% lower risk (95% CI: 0.49, 0.96). Results show that body mass index, smoking, and hypertension are risk factors for renal cell cancer in both sexes. [ABSTRACT FROM AUTHOR]
Published: 2007
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37. Beta-cryptoxanthin and lung cancer in Shanghai, China -- an examination of potential confounding with cigarette smoking using urinary cotinine as a biomarker for true tobacco exposure.

Author: Stram DO, Yuan J, Chan KK, Gao Y, Ross RK, and Yu MC
Abstract: Diet may be a modifier of smoking-related cancer risk, with protective effects of intake of fruits and vegetables and associated antioxidants found in many observational studies. We previously reported serum Beta-Cryptoxanthin levels being inversely associated with smoking-related lung cancer incidence in a cohort of Chinese men. We noted, however, that serum Beta-Cryptoxanthinn is negatively correlated with smoking. Since self-reports of smoking intensity undoubtedly contain errors, this negative correlation indicates a potential bias in assessing the effects of Beta-Cryptoxanthin, due to confounding with the unmeasured (residual) portion of cigarette exposure. We evaluated cotinine levels in pre-diagnostic spot urine samples to attempt to improve smoking assessment. We noted that urinary cotinine levels correlated significantly with cigarette consumption overall and that cotinine was strongly predictive of lung cancer risk. Urinary cotinine, however, was not as strong a predictor of lung cancer risk in current smokers as were self-reports of cigarette consumption and cotinine remained only a marginally significant predictor of lung cancer risk after adjustment for self-reports. An apparent benefit of Beta-Cryptoxanthin remained evident when including both urinary cotinine and self-reported cigarette consumption and cotinine in the statistical model. However, we conclude that cotinine measured from a single spot urine seems to have only limited value in augmenting self-reports of cigarette consumption so that, at present, the apparent protective effects of Beta-Cryptoxanthinn, as seen in our own study, should continue to be regarded as unproven. We believe that future epidemiological evaluation of the association between Beta-Cryptoxanthin (and other antioxidants) and reduced lung cancer risk must utilize improved biomarkers to augment smokers' own self-reports of smoking amount. [ABSTRACT FROM AUTHOR]
Published: 2007
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38. Long-term recreational physical activity and risk of invasive and in situ breast cancer: the California teachers study.

Author: Dallal CM, Sullivan-Halley J, Ross RK, Wang Y, Deapen D, Horn-Ross PL, Reynolds P, Stram DO, Clarke CA, Anton-Culver H, Ziogas A, Peel D, West DW, Wright W, and Bernstein L
Published: 2007
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39. Ethnic and racial differences in the smoking-related risk of lung cancer.

Author: Haiman CA, Stram DO, Wilkens LR, Pike MC, Kolonel LN, Henderson BE, and Le Marchand L
Published: 2006

40. A controlled 2-mo dietary fat reduction and soy food supplementation study in postmenopausal women.

Author: Wu AH, Stanczyk FZ, Martinez C, Tseng C, Hendrich S, Murphy P, Chaikittisilpa S, Stram DO, and Pike MC
Abstract: BACKGROUND: Low intake of dietary fat and high intake of soy foods have been suggested to partly explain the lower breast cancer rates in Asia, perhaps because of lower endogenous estrogens. OBJECTIVE: The objective was to assess the hormonal and nonhormonal effects of diets resembling an Asian diet in terms of total fat and soy food contents. DESIGN: Fifty-seven postmenopausal women participated in a randomized, controlled, dietary intervention study. The subjects consumed a very-low-fat diet (VLFD; 11% of energy as fat), a Step I diet (25% of energy as fat) supplemented with soy food (SFD; 50 mg isoflavones/d), or a control Step I diet (CD; 27% of energy as fat) with no soy food. All diets were prepared at the General Clinical Research Center of the University of Southern California. Serum hormones and other markers were measured at baseline and every 2 wk during the 8 wk of intervention. RESULTS: There were no significant differences in total estradiol and sex hormone binding globulin at the completion of the intervention between women in the SFD and VLFD groups and those in the CD group. Serum insulin decreased significantly in the SFD group, and leptin decreased significantly in the SFD and VLFD groups; however, these changes did not differ significantly from the changes in the CD group. CONCLUSIONS: This study does not provide evidence that ingestion of soy food or a VLFD significantly reduces estrogen concentrations in postmenopausal women. However, short-term changes in diet may have significant and beneficial effects on blood insulin and leptin concentrations. Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]
Published: 2005

41. Correlation of dietary intake and colorectal cancer incidence among Mexican-American migrants: the Multiethnic Cohort Study.

Author: Monroe KR, Hankin JH, Pike MC, Henderson BE, Stram DO, Park S, Nomura AMY, Wilkens LR, and Kolonel LN
Abstract: Studies of migrants, along with geographic and temporal variations in incidence, indicate that colorectal cancer is especially sensitive to changes in environmental factors, including, most importantly, diet. The goal of this research was to examine the changes in dietary practices that may be consistent with the changing incidence of colorectal cancer in the Los Angeles Mexican-American population. Cancer incidence and dietary intake data were available for over 35,000 Latinos of Mexican national origin currently participating in the prospective Multiethnic Cohort Study, representing the largest sample of Mexican-origin Latinos of any such study in the United States. The dataset is unique in that changes in cancer rates and in dietary behaviors across three generations could be examined. Most of the change in colorectal cancer rates occurred between the first and second generations, and, correspondingly, nearly all the dietary change also occurred between the first and second generations. Although some food traditions were retained by Mexican Americans, the dietary changes due to acculturation were significant and support an association between colorectal cancer risk and certain dietary components, notably, alcohol as a risk factor and nonstarch polysaccharides and vegetables as protective factors. [ABSTRACT FROM AUTHOR]
Published: 2003
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42. Risk factors for cardiovascular and cerebrovascular death among African Americans and Hispanics in Los Angeles, California.

Author: Henderson SO, Bretsky P, Henderson BE, and Stram DO
Published: 2001

43. Singapore Chinese health study: development, validation, and calibration of the Quantitative Food Frequency Questionnaire.

Author: Hankin JH, Stram DO, Arakawa K, Park S, Low S, Lee H, and Yu MC
Abstract: This report describes the development and validation/calibration of a structured food frequency questionnaire for use in a large-scale cohort study of diet and health in Chinese men and women aged 45-74 years in Singapore, the development of a food composition database for analysis of the dietary data, and the results of the dietary validation/calibration study. The present calibration study comparing estimated intakes from 24-hour recalls with those from the food frequency questionnaires revealed correlations of 0.24-0.79 for energy and nutrients among the Singapore Chinese, which are comparable to the correlation coefficients reported in calibration studies of other populations. We also report on the nutritional profiles of Singapore Chinese on the basis of results of 1,880 24-hour dietary recalls conducted on 1,022 (425 men and 597 women) cohort subjects. Comparisons with age-adjusted corresponding values for US whites and blacks show distinct differences in dietary intakes between the Singapore and US populations. The Singapore cohort will be followed prospectively to identify dietary associations with cancer risk and other health outcomes. [ABSTRACT FROM AUTHOR]
Published: 2001
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44. Meta-analysis: dietary fat intake, serum estrogen levels, and the risk of breast cancer.

Author: Wu AH, Pike MC, Stram DO, Wu, A H, Pike, M C, and Stram, D O
Abstract: Background: There is compelling evidence that estrogens influence breast cancer risk. Since the mid-1980s, dietary fat intervention studies have been conducted to investigate the effect of fat intake on endogenous estrogen levels. To further our understanding of the possible relationship between dietary fat and breast cancer, we conducted a meta-analysis of dietary fat intervention studies that investigated serum estradiol levels, and we reviewed the nature of the evidence provided by prospective analytic studies of fat consumption and breast cancer risk.Methods: A computerized search of the English language literature on estrogen/estradiol and dietary fat intervention studies published from January 1966 through June 1998 was conducted using the MEDLINE database. Pooled estimates were derived from the change in estradiol levels associated with fat reduction from 13 studies. Analyses were conducted separately for premenopausal and postmenopausal women and in both groups combined.Results and Conclusions: Statistically significant reductions in serum estradiol levels of -7.4% (95% confidence interval [CI] = -11.7% to -2.9%) among premenopausal women and -23.0% (95% CI = -27.7% to -18.1%) among postmenopausal women were observed, with an overall -13.4% (95% CI = -16.6% to -10.1%) reduction observed. The greatest reductions occurred in two studies in which dietary fat was reduced to 10%-12% of calories compared with 18%-25% of calories in the other studies. A statistically significant reduction in estradiol levels of -6.6% (95% CI = -10.3% to -2.7%) remained after exclusion of these two studies. Review of prospective analytic epidemiologic studies that allowed for dietary measurement error suggests that the possibility that reducing fat consumption below 20% of calories will reduce breast cancer risk cannot be excluded.Implications: Dietary fat reduction can result in a lowering of serum estradiol levels and such dietary modification may still offer an approach to breast cancer prevention. [ABSTRACT FROM AUTHOR]
Published: 1999
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45. Association analysis identifies 65 new breast cancer risk loci

Author: Michailidou, K, Lindström, S, Dennis, J, Beesley, J, Hui, S, Kar, S, Lemaçon, A, Soucy, P, Glubb, D, Rostamianfar, A, Bolla, MK, Wang, Q, Tyrer, J, Dicks, E, Lee, A, Wang, Z, Allen, J, Keeman, R, Eilber, U, French, JD, Qing Chen, X, Fachal, L, McCue, K, McCart Reed, AE, Ghoussaini, M, Carroll, JS, Jiang, X, Finucane, H, Adams, M, Adank, MA, Ahsan, H, Aittomäki, K, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Arun, B, Auer, PL, Bacot, F, Barrdahl, M, Baynes, C, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Brinton, L, Broberg, P, Brock, IW, Broeks, A, Brooks-Wilson, A, Brucker, SY, Brüning, T, Burwinkel, B, Butterbach, K, Cai, Q, Cai, H, Caldés, T, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chan, TL, David Cheng, T-Y, Seng Chia, K, Choi, J-Y, Christiansen, H, Clarke, CL, NBCS Collaborators, Collée, M, Conroy, DM, Cordina-Duverger, E, Cornelissen, S, Cox, DG, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Devilee, P, Doheny, KF, Dörk, T, Dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Elvira, M, Engel, C, Eriksson, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fritschi, L, Gaborieau, V, Gabrielson, M, Gago-Dominguez, M, Gao, Y-T, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grenaker Alnæs, GI, Grip, M, Gronwald, J, Grundy, A, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hamel, N, Hankinson, S, Harrington, P, Hart, SN, Hartikainen, JM, Hartman, M, Hein, A, Heyworth, J, Hicks, B, Hillemanns, P, Ho, DN, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Hou, M-F, Hsiung, C-N, Huang, G, Humphreys, K, Ishiguro, J, Ito, H, Iwasaki, M, Iwata, H, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, K, Jones, M, Jukkola-Vuorinen, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kang, D, Kasuga, Y, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, JI, Kim, S-W, Knight, JA, Kosma, V-M, Kristensen, VN, Krüger, U, Kwong, A, Lambrechts, D, Le Marchand, L, Lee, E, Lee, MH, Lee, JW, Neng Lee, C, Lejbkowicz, F, Li, J, Lilyquist, J, Lindblom, A, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lophatananon, A, Lubinski, J, Luccarini, C, Lux, MP, Ma, ESK, MacInnis, RJ, Maishman, T, Makalic, E, Malone, KE, Kostovska, IM, Mannermaa, A, Manoukian, S, Manson, JE, Margolin, S, Mariapun, S, Martinez, ME, Matsuo, K, Mavroudis, D, McKay, J, McLean, C, Meijers-Heijboer, H, Meindl, A, Menéndez, P, Menon, U, Meyer, J, Miao, H, Miller, N, Taib, NAM, Muir, K, Mulligan, AM, Mulot, C, Neuhausen, SL, Nevanlinna, H, Neven, P, Nielsen, SF, Noh, D-Y, Nordestgaard, BG, Norman, A, Olopade, OI, Olson, JE, Olsson, H, Olswold, C, Orr, N, Pankratz, VS, Park, SK, Park-Simon, T-W, Lloyd, R, Perez, JIA, Peterlongo, P, Peto, J, Phillips, K-A, Pinchev, M, Plaseska-Karanfilska, D, Prentice, R, Presneau, N, Prokofyeva, D, Pugh, E, Pylkäs, K, Rack, B, Radice, P, Rahman, N, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Romm, J, Ruddy, KJ, Rüdiger, T, Rudolph, A, Ruebner, M, Rutgers, EJT, Saloustros, E, Sandler, DP, Sangrajrang, S, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schürmann, P, Scott, RJ, Scott, C, Seal, S, Seynaeve, C, Shah, M, Sharma, P, Shen, C-Y, Sheng, G, Sherman, ME, Shrubsole, MJ, Shu, X-O, Smeets, A, Sohn, C, Southey, MC, Spinelli, JJ, Stegmaier, C, Stewart-Brown, S, Stone, J, Stram, DO, Surowy, H, Swerdlow, A, Tamimi, R, Taylor, JA, Tengström, M, Teo, SH, Beth Terry, M, Tessier, DC, Thanasitthichai, S, Thöne, K, Tollenaar, RAEM, Tomlinson, I, Tong, L, Torres, D, Truong, T, Tseng, C-C, Tsugane, S, Ulmer, H-U, Ursin, G, Untch, M, Vachon, C, Van Asperen, CJ, Van Den Berg, D, Van Den Ouweland, AMW, Van Der Kolk, L, Van Der Luijt, RB, Vincent, D, Vollenweider, J, Waisfisz, Q, Wang-Gohrke, S, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Wu, AH, Xia, L, Yamaji, T, Yang, XR, Har Yip, C, Yoo, K-Y, Yu, J-C, Zheng, W, Zheng, Y, Zhu, B, Ziogas, A, Ziv, E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani, Antoniou, AC, Droit, A, Andrulis, IL, Amos, CI, Couch, FJ, Pharoah, PDP, Chang-Claude, J, Hall, P, Hunter, DJ, Milne, RL, García-Closas, M, Schmidt, MK, Chanock, SJ, Dunning, AM, Edwards, SL, Bader, GD, Chenevix-Trench, G, Simard, J, Kraft, P, and Easton, DF
Subjects: ConFab/AOCS Investigators, ABCTB Investigators, skin and connective tissue diseases, 3. Good health, NBCS Collaborators
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

46. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

Author: Wheeler, E, Leong, A, Liu, C-T, Hivert, M-F, Strawbridge, RJ, Podmore, C, Li, M, Yao, J, Sim, X, Hong, J, Chu, AY, Zhang, W, Wang, X, Chen, P, Maruthur, NM, Porneala, BC, Sharp, SJ, Jia, Y, Kabagambe, EK, Chang, L-C, Chen, W-M, Elks, CE, Evans, DS, Fan, Q, Giulianini, F, Go, MJ, Hottenga, J-J, Hu, Y, Jackson, AU, Kanoni, S, Kim, YJ, Kleber, ME, Ladenvall, C, Lecoeur, C, Lim, S-H, Lu, Y, Mahajan, A, Marzi, C, Nalls, MA, Navarro, P, Nolte, IM, Rose, LM, Rybin, DV, Sanna, S, Shi, Y, Stram, DO, Takeuchi, F, Tan, SP, Van Der Most, PJ, Van Vliet-Ostaptchouk, JV, Wong, A, Yengo, L, Zhao, W, Goel, A, Martinez Larrad, MT, Radke, D, Salo, P, Tanaka, T, Van Iperen, EPA, Abecasis, G, Afaq, S, Alizadeh, BZ, Bertoni, AG, Bonnefond, A, Böttcher, Y, Bottinger, EP, Campbell, H, Carlson, OD, Chen, C-H, Cho, YS, Garvey, WT, Gieger, C, Goodarzi, MO, Grallert, H, Hamsten, A, Hartman, CA, Herder, C, Hsiung, CA, Huang, J, Igase, M, Isono, M, Katsuya, T, Khor, C-C, Kiess, W, Kohara, K, Kovacs, P, Lee, J, Lee, W-J, Lehne, B, Li, H, Liu, J, Lobbens, S, Luan, J, Lyssenko, V, Meitinger, T, Miki, T, Miljkovic, I, Moon, S, Mulas, A, Müller, G, Müller-Nurasyid, M, Nagaraja, R, Nauck, M, Pankow, JS, Polasek, O, Prokopenko, I, Ramos, PS, Rasmussen-Torvik, L, Rathmann, W, Rich, SS, Robertson, NR, Roden, M, Roussel, R, Rudan, I, Scott, RA, Scott, WR, Sennblad, B, Siscovick, DS, Strauch, K, Sun, L, Swertz, M, Tajuddin, SM, Taylor, KD, Teo, Y-Y, Tham, YC, Tönjes, A, Wareham, NJ, Willemsen, G, Wilsgaard, T, Hingorani, AD, EPIC-CVD Consortium, EPIC-InterAct Consortium, Lifelines Cohort Study, Egan, J, Ferrucci, L, Hovingh, GK, Jula, A, Kivimaki, M, Kumari, M, Njølstad, I, Palmer, CNA, Serrano Ríos, M, Stumvoll, M, Watkins, H, Aung, T, Blüher, M, Boehnke, M, Boomsma, DI, Bornstein, Chambers, JC, Chasman, DI, Chen, Y-DI, Chen, Y-T, Cheng, C-Y, Cucca, F, De Geus, EJC, Deloukas, P, Evans, MK, Fornage, M, Friedlander, Y, Froguel, P, Groop, L, Gross, MD, Harris, TB, Hayward, C, Heng, C-K, Ingelsson, E, Kato, N, Kim, B-J, Koh, W-P, Kooner, JS, Körner, A, Kuh, D, Kuusisto, J, Laakso, M, Lin, X, Liu, Y, Loos, RJF, Magnusson, PKE, März, W, McCarthy, MI, Oldehinkel, AJ, Ong, KK, Pedersen, NL, Pereira, MA, Peters, A, Ridker, PM, Sabanayagam, C, Sale, M, Saleheen, D, Saltevo, J, Schwarz, PE, Sheu, WHH, Snieder, H, Spector, TD, Tabara, Y, Tuomilehto, J, Van Dam, RM, Wilson, JG, Wilson, JF, Wolffenbuttel, BHR, Wong, TY, Wu, J-Y, Yuan, J-M, Zonderman, AB, Soranzo, N, Guo, X, Roberts, DJ, Florez, JC, Sladek, R, Dupuis, J, Morris, AP, Tai, E-S, Selvin, E, Rotter, JI, Langenberg, C, Barroso, I, and Meigs, JB
Subjects: Hemoglobin A, Glycosylated, endocrine system diseases, Diabetes Mellitus, Type 2, phenotype, genetic variation, nutritional and metabolic diseases, humans, 3. Good health, Genome-Wide Association Study, risk
Abstract: BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

47. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author: Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, BOCS, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Gapstur, SM, Gaudet, MM, Diver, WR, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Berg, CD, Chanock, SJ, Figueroa, J, Hoover, RN, Lambrechts, D, Neven, P, Wildiers, H, van Limbergen, E, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Waisfisz, Q, Meijers-Heijboer, H, Adank, MA, van der Luijt, RB, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, JY, Park, SK, Yoo, KY, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Guénel, P, Truong, T, Mulot, C, Sanchez, M, Burwinkel, B, Marme, F, Surowy, H, Sohn, C, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, González-Neira, A, Benitez, J, Zamora, MP, Perez, JI, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MW, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, ConFab Investigators, AOCS Group, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Taib, NA, Tan, GH, Hooning, MJ, Hollestelle, A, Martens, JW, Collée, JM, Blot, W, Signorello, LB, Cai, Q, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Shen, CY, Hsiung, CN, Wu, PE, Hou, MF, Kristensen, VN, Nord, S, Alnaes, GI, NBCS, Giles, GG, Milne, RL, McLean, C, Canzian, F, Trichopoulos, D, Peeters, P, Lund, E, Sund, M, Khaw, KT, Gunter, MJ, Palli, D, Mortensen, LM, Dossus, L, Huerta, JM, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Chia, KS, Chan, CW, Fasching, PA, Hein, A, Beckmann, MW, Haeberle, L, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Ashworth, A, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Brinton, L, Garcia-Closas, M, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Brauch, H, Hamann, U, Brüning, T, GENICA Network, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Bogdanova, NV, Dörk, T, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Devilee, P, Tollenaar, RA, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska, K, Huzarski, T, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Kabisch, M, Torres, D, Neuhausen, SL, Anton-Culver, H, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Tessier, DC, Vincent, D, Bacot, F, Pita, G, Alonso, MR, Álvarez, N, Herrero, D, Simard, J, Pharoah, PP, Kraft, P, Dunning, AM, Chenevix-Trench, G, Hall, P, Easton, DF, Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, BOCS, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Gapstur, SM, Gaudet, MM, Diver, WR, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Berg, CD, Chanock, SJ, Figueroa, J, Hoover, RN, Lambrechts, D, Neven, P, Wildiers, H, van Limbergen, E, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Waisfisz, Q, Meijers-Heijboer, H, Adank, MA, van der Luijt, RB, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, JY, Park, SK, Yoo, KY, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Guénel, P, Truong, T, Mulot, C, Sanchez, M, Burwinkel, B, Marme, F, Surowy, H, Sohn, C, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, González-Neira, A, Benitez, J, Zamora, MP, Perez, JI, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MW, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, ConFab Investigators, AOCS Group, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Taib, NA, Tan, GH, Hooning, MJ, Hollestelle, A, Martens, JW, Collée, JM, Blot, W, Signorello, LB, Cai, Q, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Shen, CY, Hsiung, CN, Wu, PE, Hou, MF, Kristensen, VN, Nord, S, Alnaes, GI, NBCS, Giles, GG, Milne, RL, McLean, C, Canzian, F, Trichopoulos, D, Peeters, P, Lund, E, Sund, M, Khaw, KT, Gunter, MJ, Palli, D, Mortensen, LM, Dossus, L, Huerta, JM, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Chia, KS, Chan, CW, Fasching, PA, Hein, A, Beckmann, MW, Haeberle, L, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Ashworth, A, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Brinton, L, Garcia-Closas, M, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Brauch, H, Hamann, U, Brüning, T, GENICA Network, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Bogdanova, NV, Dörk, T, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Devilee, P, Tollenaar, RA, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska, K, Huzarski, T, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Kabisch, M, Torres, D, Neuhausen, SL, Anton-Culver, H, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Tessier, DC, Vincent, D, Bacot, F, Pita, G, Alonso, MR, Álvarez, N, Herrero, D, Simard, J, Pharoah, PP, Kraft, P, Dunning, AM, Chenevix-Trench, G, Hall, P, and Easton, DF

48. RESPONSE: re: meta-analysis: dietary fat intake, serum estrogen levels, and the risk of breast cancer.

Author: Wu, AH, Stram, DO, and C Pike M
Published: 2000

49. RESPONSE: Re: Meta-analysis: Dietary Fat Intake, Serum Estrogen Levels, and the Risk of Breast Cancer.

Author: Wu, AH, Stram, DO, and Pike, MC
Published: 1999
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50. 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

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