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1. Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer

Author: Wichert, K, Hoppe, R, Ickstadt, K, Behrens, T, Winter, S, Herold, R, Terschueren, C, Lo, W-Y, Guenel, P, Truong, T, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Lush, M, Andrulis, IL, Brenner, H, Chang-Claude, J, Cox, A, Cross, SS, Czene, K, Eriksson, M, Figueroa, JD, Garcia-Closas, M, Goldberg, MS, Hamann, U, He, W, Holleczek, B, Hopper, JL, Jakubowska, A, Ko, Y-D, Lubinski, J, Mulligan, AM, Obi, N, Rhenius, V, Shah, M, Shu, X-O, Simard, J, Southey, MC, Zheng, W, Dunning, AM, Pharoah, PDP, Hall, P, Easton, DF, Bruening, T, Brauch, H, Harth, V, Rabstein, S, Wichert, K, Hoppe, R, Ickstadt, K, Behrens, T, Winter, S, Herold, R, Terschueren, C, Lo, W-Y, Guenel, P, Truong, T, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Lush, M, Andrulis, IL, Brenner, H, Chang-Claude, J, Cox, A, Cross, SS, Czene, K, Eriksson, M, Figueroa, JD, Garcia-Closas, M, Goldberg, MS, Hamann, U, He, W, Holleczek, B, Hopper, JL, Jakubowska, A, Ko, Y-D, Lubinski, J, Mulligan, AM, Obi, N, Rhenius, V, Shah, M, Shu, X-O, Simard, J, Southey, MC, Zheng, W, Dunning, AM, Pharoah, PDP, Hall, P, Easton, DF, Bruening, T, Brauch, H, Harth, V, and Rabstein, S
Abstract: Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation.
Published: 2023

2. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

Author: Morra, A, Schreurs, MAC, Andrulis, IL, Anton-Culver, H, Augustinsson, A, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brauch, H, Broeks, A, Buys, SS, Camp, NJ, Castelao, JE, Cessna, MH, Chang-Claude, J, Chung, WK, Collaborators, N, Colonna, SV, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dörk, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Evans, DG, Fasching, PA, Fehm, TN, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, Genkinger, J, Grassmann, F, Gündert, M, Hahnen, E, Haiman, CA, Hamann, U, Harrington, PA, Hartikainen, JM, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Investigators, A, Investigators, K, Jakubowska, A, Janni, W, Jernström, H, John, EM, Johnson, N, Jones, ME, Kristensen, VN, Kurian, AW, Lambrechts, D, Marchand, LL, Lindblom, A, Lubiński, J, Lux, MP, Mannermaa, A, Mavroudis, D, Mulligan, AM, Muranen, TA, Nevanlinna, H, Nevelsteen, I, Neven, P, Newman, WG, Obi, N, Offit, K, Olshan, AF, Park-Simon, T-W, Patel, AV, Peterlongo, P, Phillips, K-A, Plaseska-Karanfilska, D, Polley, EC, Presneau, N, Pylkäs, K, Rack, B, Radice, P, Rashid, MU, Rhenius, V, Robson, M, Romero, A, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schuetze, S, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Tapper, WJ, Teras, LR, Tollenaar, RAEM, Tomczyk, K, Tomlinson, I, Troester, MA, Vachon, CM, van Veen, EM, Wang, Q, Wendt, C, Wildiers, H, Winqvist, R, Ziogas, A, Hall, P, Pharoah, PDP, Adank, MA, Hollestelle, A, Schmidt, MK, Hooning, MJ, Morra, A, Schreurs, MAC, Andrulis, IL, Anton-Culver, H, Augustinsson, A, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brauch, H, Broeks, A, Buys, SS, Camp, NJ, Castelao, JE, Cessna, MH, Chang-Claude, J, Chung, WK, Collaborators, N, Colonna, SV, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dörk, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Evans, DG, Fasching, PA, Fehm, TN, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, Genkinger, J, Grassmann, F, Gündert, M, Hahnen, E, Haiman, CA, Hamann, U, Harrington, PA, Hartikainen, JM, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Investigators, A, Investigators, K, Jakubowska, A, Janni, W, Jernström, H, John, EM, Johnson, N, Jones, ME, Kristensen, VN, Kurian, AW, Lambrechts, D, Marchand, LL, Lindblom, A, Lubiński, J, Lux, MP, Mannermaa, A, Mavroudis, D, Mulligan, AM, Muranen, TA, Nevanlinna, H, Nevelsteen, I, Neven, P, Newman, WG, Obi, N, Offit, K, Olshan, AF, Park-Simon, T-W, Patel, AV, Peterlongo, P, Phillips, K-A, Plaseska-Karanfilska, D, Polley, EC, Presneau, N, Pylkäs, K, Rack, B, Radice, P, Rashid, MU, Rhenius, V, Robson, M, Romero, A, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schuetze, S, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Tapper, WJ, Teras, LR, Tollenaar, RAEM, Tomczyk, K, Tomlinson, I, Troester, MA, Vachon, CM, van Veen, EM, Wang, Q, Wendt, C, Wildiers, H, Winqvist, R, Ziogas, A, Hall, P, Pharoah, PDP, Adank, MA, Hollestelle, A, Schmidt, MK, and Hooning, MJ
Abstract: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09-1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words).
Published: 2023

3. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

Author: Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, NV, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Doerk, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Guendert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, Y-D, Kristensen, VN, Lindblom, A, Lissowska, J, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, MI, Rashid, MU, Rhenius, V, Rookus, MA, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sironen, R, Southey, MC, Suvanto, M, Tollenaar, RAEM, Tomlinson, I, Truong, T, van der Kolk, LE, van Veen, EM, Wappenschmidt, B, Yang, XR, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Lush, M, Michailidou, K, Pharoah, PDP, Wang, Q, Adank, MA, Schmidt, MK, Andrulis, IL, Chang-Claude, J, Nevanlinna, H, Chenevix-Trench, G, Evans, DG, Milne, RL, Radice, P, Peterlongo, P, Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, NV, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Doerk, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Guendert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, Y-D, Kristensen, VN, Lindblom, A, Lissowska, J, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, MI, Rashid, MU, Rhenius, V, Rookus, MA, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sironen, R, Southey, MC, Suvanto, M, Tollenaar, RAEM, Tomlinson, I, Truong, T, van der Kolk, LE, van Veen, EM, Wappenschmidt, B, Yang, XR, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Lush, M, Michailidou, K, Pharoah, PDP, Wang, Q, Adank, MA, Schmidt, MK, Andrulis, IL, Chang-Claude, J, Nevanlinna, H, Chenevix-Trench, G, Evans, DG, Milne, RL, Radice, P, and Peterlongo, P
Abstract: Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.
Published: 2023

4. Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes

Author: Mavaddat, N, Dorling, L, Carvalho, S, Allen, J, Gonzalez-Neira, A, Keeman, R, Bolla, MK, Dennis, J, Wang, Q, Ahearn, TU, Andrulis, IL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Briceno, I, Bruning, T, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Christiansen, H, Czene, K, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Geisler, J, Giles, GG, Guenel, P, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Hartikainen, JM, Hartman, M, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, EK, Kristensen, VN, Li, J, Lim, SH, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Taib, NAM, Morra, A, Muir, K, Obi, N, Osorio, A, Park-Simon, T-W, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Thorne, H, Tomlinson, I, Torres, D, Truong, T, Yip, CH, Spurdle, AB, Vreeswijk, MPG, Dunning, AM, Garcia-Closas, M, Pharoah, PDP, Kvist, A, Muranen, TA, Nevanlinna, H, Teo, SH, Devilee, P, Schmidt, MK, Easton, DF, Mavaddat, N, Dorling, L, Carvalho, S, Allen, J, Gonzalez-Neira, A, Keeman, R, Bolla, MK, Dennis, J, Wang, Q, Ahearn, TU, Andrulis, IL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Briceno, I, Bruning, T, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Christiansen, H, Czene, K, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Geisler, J, Giles, GG, Guenel, P, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Hartikainen, JM, Hartman, M, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, EK, Kristensen, VN, Li, J, Lim, SH, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Taib, NAM, Morra, A, Muir, K, Obi, N, Osorio, A, Park-Simon, T-W, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Thorne, H, Tomlinson, I, Torres, D, Truong, T, Yip, CH, Spurdle, AB, Vreeswijk, MPG, Dunning, AM, Garcia-Closas, M, Pharoah, PDP, Kvist, A, Muranen, TA, Nevanlinna, H, Teo, SH, Devilee, P, Schmidt, MK, and Easton, DF
Abstract: IMPORTANCE: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subt
Published: 2022

5. Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Author: Grootes, I, Keeman, R, Blows, FM, Milne, RL, Giles, GG, Swerdlow, AJ, Fasching, PA, Abubakar, M, Andrulis, IL, Anton-Culver, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Bonanni, B, Briceno, I, Burwinkel, B, Camp, NJ, Castelao, JE, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Ernst, K, Evans, DG, Figueroa, JD, Fink, V, Floris, G, Fox, S, Gabrielson, M, Gago-Dominguez, M, Garcia-Saenz, JA, Gonzalez-Neira, A, Haeberle, L, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hein, A, Hooning, MJ, Hou, M-F, Howell, SJ, Ito, H, Jakubowska, A, Janni, W, John, EM, Jung, A, Kang, D, Kristensen, VN, Kwong, A, Lambrechts, D, Li, J, Manoochehri, M, Margolin, S, Matsuo, K, Taib, NAM, Mulligan, AM, Nevanlinna, H, Newman, WG, Offit, K, Osorio, A, Park, SK, Park-Simon, T-W, Patel, A, Presneau, N, Pylkas, K, Rack, B, Radice, P, Rennert, G, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schochter, F, Schoemaker, MJ, Shen, C-Y, Shibli, R, Sinn, P, Tapper, WJ, Tawfiq, E, Teo, SH, Teras, LR, Torres, D, Vachon, CM, van Deurzen, CHM, Wendt, C, Williams, JA, Winqvist, R, Elwood, M, Schmidt, MK, Pharoah, PDP, Grootes, I, Keeman, R, Blows, FM, Milne, RL, Giles, GG, Swerdlow, AJ, Fasching, PA, Abubakar, M, Andrulis, IL, Anton-Culver, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Bonanni, B, Briceno, I, Burwinkel, B, Camp, NJ, Castelao, JE, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Ernst, K, Evans, DG, Figueroa, JD, Fink, V, Floris, G, Fox, S, Gabrielson, M, Gago-Dominguez, M, Garcia-Saenz, JA, Gonzalez-Neira, A, Haeberle, L, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hein, A, Hooning, MJ, Hou, M-F, Howell, SJ, Ito, H, Jakubowska, A, Janni, W, John, EM, Jung, A, Kang, D, Kristensen, VN, Kwong, A, Lambrechts, D, Li, J, Manoochehri, M, Margolin, S, Matsuo, K, Taib, NAM, Mulligan, AM, Nevanlinna, H, Newman, WG, Offit, K, Osorio, A, Park, SK, Park-Simon, T-W, Patel, A, Presneau, N, Pylkas, K, Rack, B, Radice, P, Rennert, G, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schochter, F, Schoemaker, MJ, Shen, C-Y, Shibli, R, Sinn, P, Tapper, WJ, Tawfiq, E, Teo, SH, Teras, LR, Torres, D, Vachon, CM, van Deurzen, CHM, Wendt, C, Williams, JA, Winqvist, R, Elwood, M, Schmidt, MK, and Pharoah, PDP
Abstract: BACKGROUND: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2). METHOD: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance. RESULTS: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted. CONCLUSION: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.
Published: 2022

6. Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies

Author: Jung, AY, Ahearn, TU, Behrens, S, Middha, P, Bolla, MK, Wang, Q, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Becher, H, Brenner, H, Canzian, F, Carey, LA, Consortium, C, Czene, K, Eliassen, AH, Eriksson, M, Evans, DG, Figueroa, JD, Fritschi, L, Gabrielson, M, Giles, GG, Guenel, P, Hadjisavvas, A, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Huesing, A, Kaaks, R, Kosma, V-M, Koutros, S, Kraft, P, Lacey, J, Le Marchand, L, Lissowska, J, Loizidou, MA, Mannermaa, A, Maurer, T, Murphy, RA, Olshan, AF, Olsson, H, Patel, A, Perou, CM, Rennert, G, Shibli, R, Shu, X-O, Southey, MC, Stone, J, Tamimi, RM, Teras, LR, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Wolk, A, Wu, AH, Yang, XR, Zheng, W, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Chatterjee, N, Schmidt, MK, Garcia-Closas, M, Chang-Claude, J, Jung, AY, Ahearn, TU, Behrens, S, Middha, P, Bolla, MK, Wang, Q, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Becher, H, Brenner, H, Canzian, F, Carey, LA, Consortium, C, Czene, K, Eliassen, AH, Eriksson, M, Evans, DG, Figueroa, JD, Fritschi, L, Gabrielson, M, Giles, GG, Guenel, P, Hadjisavvas, A, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Huesing, A, Kaaks, R, Kosma, V-M, Koutros, S, Kraft, P, Lacey, J, Le Marchand, L, Lissowska, J, Loizidou, MA, Mannermaa, A, Maurer, T, Murphy, RA, Olshan, AF, Olsson, H, Patel, A, Perou, CM, Rennert, G, Shibli, R, Shu, X-O, Southey, MC, Stone, J, Tamimi, RM, Teras, LR, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Wolk, A, Wu, AH, Yang, XR, Zheng, W, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Chatterjee, N, Schmidt, MK, Garcia-Closas, M, and Chang-Claude, J
Abstract: BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all
Published: 2022

7. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ∼200,000 patients

Author: Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, Schmidt, MK, Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, and Schmidt, MK
Abstract: BACKGROUND: Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. METHODS: We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. RESULTS: The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56-0.74) versus 0.63 (95%PI 0.54-0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34-2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.
Published: 2022

8. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ∼ 200,000 patients (vol 24, 69, 2022)

Author: Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, Schmidt, MK, Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, and Schmidt, MK
Published: 2022

9. The impact of the Covid-19 pandemic on breast cancer early detection and screening

Author: Figueroa, JD, Gray, E, Pashayan, N, Deandrea, S, Karch, A, Vale, DB, Elder, K, Procopio, P, Ravesteyn, NTV, Mutabi, M, Canfell, K, Nickson, C, Figueroa, JD, Gray, E, Pashayan, N, Deandrea, S, Karch, A, Vale, DB, Elder, K, Procopio, P, Ravesteyn, NTV, Mutabi, M, Canfell, K, and Nickson, C
Abstract: The COVID-19 pandemic affects mortality and morbidity, with disruptions expected to continue for some time, with access to timely cancer-related services a concern. For breast cancer, early detection and treatment is key to improved survival and longer-term quality of life. Health services generally have been strained and in many settings with population breast mammography screening, efforts to diagnose and treat breast cancers earlier have been paused or have had reduced capacity. The resulting delays to diagnosis and treatment may lead to more intensive treatment requirements and, potentially, increased mortality. Modelled evaluations can support responses to the pandemic by estimating short- and long-term outcomes for various scenarios. Multiple calibrated and validated models exist for breast cancer screening, and some have been applied in 2020 to estimate the impact of breast screening disruptions and compare options for recovery, in a range of international settings. On behalf of the Covid and Cancer Modelling Consortium (CCGMC) Working Group 2 (Breast Cancer), we summarize and provide examples of such in a range of settings internationally, and propose priorities for future modelling exercises. International expert collaborations from the CCGMC Working Group 2 (Breast Cancer) will conduct analyses and modelling studies needed to inform key stakeholders recovery efforts in order to mitigate the impact of the pandemic on early diagnosis and treatment of breast cancer.
Published: 2021

10. Abstract P3-06-17: Unlocking the transcriptomic potential of formalin-fixed paraffin embedded breast cancer tissues for high-throughput genomic analysis

Author: Turnbull, AK, primary, Selli, C, additional, Martinez-Perez, C, additional, Fernando, A, additional, Renshaw, L, additional, Keys, J, additional, Figueroa, JD, additional, He, X, additional, Tanioka, M, additional, Munro, A, additional, Murphy, L, additional, Fawkes, A, additional, Clark, R, additional, Coutts, A, additional, Perou, CM, additional, Carey, LA, additional, Dixon, JM, additional, and Sims, AH, additional
Published: 2019
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11. Interaktion von vier genetischen Risikovarianten für das Harnblasenkarzinom

Author: Selinski, S, Blaszkewicz, M, Ickstadt, K, Gerullis, H, Otto, T, Roth, E, Volkert, F, Ovsiannikov, D, Moormann, O, Banfi, G, Nyirady, P, Vermeulen, SH, Garcia-Closas, M, Figueroa, JD, Johnson, A, Karagas, MR, Kogevinas, M, Malats, N, Schwenn, M, Silverman, DT, Koutros, S, Rothman, N, Kiemeney, LA, Hengstler, JG, Golka, K, Selinski, S, Blaszkewicz, M, Ickstadt, K, Gerullis, H, Otto, T, Roth, E, Volkert, F, Ovsiannikov, D, Moormann, O, Banfi, G, Nyirady, P, Vermeulen, SH, Garcia-Closas, M, Figueroa, JD, Johnson, A, Karagas, MR, Kogevinas, M, Malats, N, Schwenn, M, Silverman, DT, Koutros, S, Rothman, N, Kiemeney, LA, Hengstler, JG, and Golka, K
Published: 2018

12. E-cadherin breast tumor expression, risk factors and survival: Pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium

Author: Horne, HN, Oh, H, Sherman, ME, Palakal, M, Hewitt, SM, Schmidt, MK, Milne, RL, Hardisson, D, Benitez, J, Blomqvist, C, Bolla, MK, Brenner, H, Chang-Claude, J, Cora, R, Couch, FJ, Cuk, K, Devilee, P, Easton, DF, Eccles, DM, Eilber, U, Hartikainen, JM, Heikkila, P, Holleczek, B, Hooning, MJ, Jones, M, Keeman, R, Mannermaa, A, Martens, JWM, Muranen, TA, Nevanlinna, H, Olson, JE, Orr, N, Perez, JIA, Pharoah, PDP, Ruddy, KJ, Saum, K-U, Schoemaker, MJ, Seynaeve, C, Sironen, R, Smit, VTHBM, Swerdlow, AJ, Tengstrom, M, Thomas, AS, Timmermans, AM, Tollenaar, RAEM, Troester, MA, van Asperen, CJ, van Deurzen, CHM, Van Leeuwen, FF, Van'tVeer, LJ, Garcia-Closas, M, Figueroa, JD, Horne, HN, Oh, H, Sherman, ME, Palakal, M, Hewitt, SM, Schmidt, MK, Milne, RL, Hardisson, D, Benitez, J, Blomqvist, C, Bolla, MK, Brenner, H, Chang-Claude, J, Cora, R, Couch, FJ, Cuk, K, Devilee, P, Easton, DF, Eccles, DM, Eilber, U, Hartikainen, JM, Heikkila, P, Holleczek, B, Hooning, MJ, Jones, M, Keeman, R, Mannermaa, A, Martens, JWM, Muranen, TA, Nevanlinna, H, Olson, JE, Orr, N, Perez, JIA, Pharoah, PDP, Ruddy, KJ, Saum, K-U, Schoemaker, MJ, Seynaeve, C, Sironen, R, Smit, VTHBM, Swerdlow, AJ, Tengstrom, M, Thomas, AS, Timmermans, AM, Tollenaar, RAEM, Troester, MA, van Asperen, CJ, van Deurzen, CHM, Van Leeuwen, FF, Van'tVeer, LJ, Garcia-Closas, M, and Figueroa, JD
Abstract: E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, >2 cm, and HER2-negative. Loss of E-cadherin expression (score < 100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.
Published: 2018

13. E-cadherin breast tumor expression, risk factors and survival: Pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium

Author: Horne, H N, Oh, H, Sherman, ME, Palakal, M, Hewitt, SM, Schmidt, MK (Marjanka), Milne, RL, Hardisson, D, Benitez, J, Blomqvist, C, Bolla, MK, Brenner, H, Chang-Claude, J, Cora, R, Couch, FJ, Cuk, K, Devilee, P, Easton, DF, Eccles, DM, Eilber, U, Hartikainen, JM, Heikkila, P, Holleczek, B, Hooning, Maartje, Jones, M, Keeman, R, Mannermaa, A, Martens, John, Muranen, TA, Nevanlinna, H, Olson, JE, Orr, N, Perez, JIA, Pharoah, PDP, Ruddy, KJ, Saum, KU, Schoemaker, MJ, Seynaeve, Caroline, Sironen, R, Smit, V, Swerdlow, AJ, Tengstrom, M, Thomas, AS, Timmermans, Mieke, Tollenaar, R, Troester, MA, van Asperen, CJ, van Deurzen, Carolien, Van Leeuwen, FF, Van'tVeer, LJ, Garcia-Closas, M, Figueroa, JD, Horne, H N, Oh, H, Sherman, ME, Palakal, M, Hewitt, SM, Schmidt, MK (Marjanka), Milne, RL, Hardisson, D, Benitez, J, Blomqvist, C, Bolla, MK, Brenner, H, Chang-Claude, J, Cora, R, Couch, FJ, Cuk, K, Devilee, P, Easton, DF, Eccles, DM, Eilber, U, Hartikainen, JM, Heikkila, P, Holleczek, B, Hooning, Maartje, Jones, M, Keeman, R, Mannermaa, A, Martens, John, Muranen, TA, Nevanlinna, H, Olson, JE, Orr, N, Perez, JIA, Pharoah, PDP, Ruddy, KJ, Saum, KU, Schoemaker, MJ, Seynaeve, Caroline, Sironen, R, Smit, V, Swerdlow, AJ, Tengstrom, M, Thomas, AS, Timmermans, Mieke, Tollenaar, R, Troester, MA, van Asperen, CJ, van Deurzen, Carolien, Van Leeuwen, FF, Van'tVeer, LJ, Garcia-Closas, M, and Figueroa, JD
Published: 2018

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

Author: Machiela, MJ, Zhou, W, Karlins, E, Sampson, JN, Freedman, ND, Yang, Q, Hicks, B, Dagnall, C, Hautman, C, Jacobs, KB, Abnet, CC, Aldrich, MC, Amos, C, Amundadottir, LT, Arslan, AA, Beane-Freeman, LE, Berndt, SI, Black, A, Blot, WJ, Bock, CH, Bracci, PM, Brinton, LA, Bueno-de-Mesquita, HB, Burdett, L, Buring, JE, Butler, MA, Canzian, F, Carreon, T, Chaffee, KG, Chang, I-S, Chatterjee, N, Chen, C, Chen, K, Chung, CC, Cook, LS, Bou, MC, Cullen, M, Davis, FG, De Vivo, I, Ding, T, Doherty, J, Duell, EJ, Epstein, CG, Fan, J-H, Figueroa, JD, Fraumeni, JF, Friedenreich, CM, Fuchs, CS, Gallinger, S, Gao, Y-T, Gapstur, SM, Garcia-Closas, M, Gaudet, MM, Gaziano, JM, Giles, GG, Gillanders, EM, Giovannucci, EL, Goldin, L, Goldstein, AM, Haiman, CA, Hallmans, G, Hankinson, SE, Harris, CC, Henriksson, R, Holly, EA, Hong, Y-C, Hoover, RN, Hsiung, CA, Hu, N, Hu, W, Hunter, DJ, Hutchinson, A, Jenab, M, Johansen, C, Khaw, K-T, Kim, HN, Kim, YH, Kim, YT, Klein, AP, Klein, R, Koh, W-P, Kolonel, LN, Kooperberg, C, Kraft, P, Krogh, V, Kurtz, RC, LaCroix, A, Lan, Q, Landi, MT, Le Marchand, L, Li, D, Liang, X, Liao, LM, Lin, D, Liu, J, Lissowska, J, Lu, L, Magliocco, AM, Malats, N, Matsuo, K, McNeill, LH, McWilliams, RR, Melin, BS, Mirabello, L, Moore, L, Olson, SH, Orlow, I, Park, JY, Patino-Garcia, A, Peplonska, B, Peters, U, Petersen, GM, Pooler, L, Prescott, J, Prokunina-Olsson, L, Purdue, MP, Qiao, Y-L, Rajaraman, P, Real, FX, Riboli, E, Risch, HA, Rodriguez-Santiago, B, Ruder, AM, Savage, SA, Schumacher, F, Schwartz, AG, Schwartz, KL, Seow, A, Setiawan, VW, Severi, G, Shen, H, Sheng, X, Shin, M-H, Shu, X-O, Silverman, DT, Spitz, MR, Stevens, VL, Stolzenberg-Solomon, R, Stram, D, Tang, Z-Z, Taylor, PR, Teras, LR, Tobias, GS, Van den Berg, D, Visvanathan, K, Wacholder, S, Wang, J-C, Wang, Z, Wentzensen, N, Wheeler, W, White, E, Wiencke, JK, Wolpin, BM, Wong, MP, Wu, C, Wu, T, Wu, X, Wu, Y-L, Wunder, JS, Xia, L, Yang, HP, Yang, P-C, Yu, K, Zanetti, KA, Zeleniuch-Jacquotte, A, Zheng, W, Zhou, B, Ziegler, RG, Perez-Jurado, LA, Caporaso, NE, Rothman, N, Tucker, M, Dean, MC, Yeager, M, Chanock, SJ, Machiela, MJ, Zhou, W, Karlins, E, Sampson, JN, Freedman, ND, Yang, Q, Hicks, B, Dagnall, C, Hautman, C, Jacobs, KB, Abnet, CC, Aldrich, MC, Amos, C, Amundadottir, LT, Arslan, AA, Beane-Freeman, LE, Berndt, SI, Black, A, Blot, WJ, Bock, CH, Bracci, PM, Brinton, LA, Bueno-de-Mesquita, HB, Burdett, L, Buring, JE, Butler, MA, Canzian, F, Carreon, T, Chaffee, KG, Chang, I-S, Chatterjee, N, Chen, C, Chen, K, Chung, CC, Cook, LS, Bou, MC, Cullen, M, Davis, FG, De Vivo, I, Ding, T, Doherty, J, Duell, EJ, Epstein, CG, Fan, J-H, Figueroa, JD, Fraumeni, JF, Friedenreich, CM, Fuchs, CS, Gallinger, S, Gao, Y-T, Gapstur, SM, Garcia-Closas, M, Gaudet, MM, Gaziano, JM, Giles, GG, Gillanders, EM, Giovannucci, EL, Goldin, L, Goldstein, AM, Haiman, CA, Hallmans, G, Hankinson, SE, Harris, CC, Henriksson, R, Holly, EA, Hong, Y-C, Hoover, RN, Hsiung, CA, Hu, N, Hu, W, Hunter, DJ, Hutchinson, A, Jenab, M, Johansen, C, Khaw, K-T, Kim, HN, Kim, YH, Kim, YT, Klein, AP, Klein, R, Koh, W-P, Kolonel, LN, Kooperberg, C, Kraft, P, Krogh, V, Kurtz, RC, LaCroix, A, Lan, Q, Landi, MT, Le Marchand, L, Li, D, Liang, X, Liao, LM, Lin, D, Liu, J, Lissowska, J, Lu, L, Magliocco, AM, Malats, N, Matsuo, K, McNeill, LH, McWilliams, RR, Melin, BS, Mirabello, L, Moore, L, Olson, SH, Orlow, I, Park, JY, Patino-Garcia, A, Peplonska, B, Peters, U, Petersen, GM, Pooler, L, Prescott, J, Prokunina-Olsson, L, Purdue, MP, Qiao, Y-L, Rajaraman, P, Real, FX, Riboli, E, Risch, HA, Rodriguez-Santiago, B, Ruder, AM, Savage, SA, Schumacher, F, Schwartz, AG, Schwartz, KL, Seow, A, Setiawan, VW, Severi, G, Shen, H, Sheng, X, Shin, M-H, Shu, X-O, Silverman, DT, Spitz, MR, Stevens, VL, Stolzenberg-Solomon, R, Stram, D, Tang, Z-Z, Taylor, PR, Teras, LR, Tobias, GS, Van den Berg, D, Visvanathan, K, Wacholder, S, Wang, J-C, Wang, Z, Wentzensen, N, Wheeler, W, White, E, Wiencke, JK, Wolpin, BM, Wong, MP, Wu, C, Wu, T, Wu, X, Wu, Y-L, Wunder, JS, Xia, L, Yang, HP, Yang, P-C, Yu, K, Zanetti, KA, Zeleniuch-Jacquotte, A, Zheng, W, Zhou, B, Ziegler, RG, Perez-Jurado, LA, Caporaso, NE, Rothman, N, Tucker, M, Dean, MC, Yeager, M, and Chanock, SJ
Abstract: To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
Published: 2016

15. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

Author: Horne, H N, Chung, C C, Zhang, H, Yu, Carol, Prokunina-Olsson, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Hopper, JL, Southey, MC, Schmidt, MK (Marjanka), Broeks, A, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Fletcher, O, Johnson, N, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guenel, P, Truong, T, Bojesen, SE, Flyger, H, Benitez, J, Gonzalez-Neira, A, Anton-Culver, H, Neuhausen, SL, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Nevanlinna, H, Khan, Salima, Matsuo, K, Iwata, H, Dork, T, Bogdanova, NV, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, VM, Chenevix-Trench, G, Wu, AH, den Berg, D V, Smeets, A, Zhao, H, Chang-Claude, J, Rudolph, A, Radice, P, Barile, M, Couch, FJ, Vachon, C, Giles, GG, Milne, RL, Haiman, CA, Le Marchand, L, Goldberg, MS, Teo, SH, Taib, NAM, Kristensen, V, Borresen-Dale, AL, Zheng, W, Shrubsole, M, Winqvist, R, Jukkola-Vuorinen, A, Andrulis, IL, Knight, JA, Devilee, P, Seynaeve, Caroline, Garcia-Closas, M, Czene, K, Darabi, H, Hollestelle, Antoinette, Martens, John, Li, JM, Lu, W, Shu, XO, Cox, A, Cross, SS, Blot, W, Cai, QY, Shah, M, Luccarini, C, Baynes, C, Harrington, P, Kang, D, Choi, JY, Hartman, M, Chia, KS, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, Sangrajrang, S, Brennan, P, Slager, S, Yannoukakos, D, Shen, CY, Hou, MF, Swerdlow, A, Orr, N, Simard, J, Hall, P, Pharoah, PDP, Easton, DF, Chanock, SJ, Dunning, AM, Figueroa, JD, Horne, H N, Chung, C C, Zhang, H, Yu, Carol, Prokunina-Olsson, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Hopper, JL, Southey, MC, Schmidt, MK (Marjanka), Broeks, A, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Fletcher, O, Johnson, N, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guenel, P, Truong, T, Bojesen, SE, Flyger, H, Benitez, J, Gonzalez-Neira, A, Anton-Culver, H, Neuhausen, SL, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Nevanlinna, H, Khan, Salima, Matsuo, K, Iwata, H, Dork, T, Bogdanova, NV, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, VM, Chenevix-Trench, G, Wu, AH, den Berg, D V, Smeets, A, Zhao, H, Chang-Claude, J, Rudolph, A, Radice, P, Barile, M, Couch, FJ, Vachon, C, Giles, GG, Milne, RL, Haiman, CA, Le Marchand, L, Goldberg, MS, Teo, SH, Taib, NAM, Kristensen, V, Borresen-Dale, AL, Zheng, W, Shrubsole, M, Winqvist, R, Jukkola-Vuorinen, A, Andrulis, IL, Knight, JA, Devilee, P, Seynaeve, Caroline, Garcia-Closas, M, Czene, K, Darabi, H, Hollestelle, Antoinette, Martens, John, Li, JM, Lu, W, Shu, XO, Cox, A, Cross, SS, Blot, W, Cai, QY, Shah, M, Luccarini, C, Baynes, C, Harrington, P, Kang, D, Choi, JY, Hartman, M, Chia, KS, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, Sangrajrang, S, Brennan, P, Slager, S, Yannoukakos, D, Shen, CY, Hou, MF, Swerdlow, A, Orr, N, Simard, J, Hall, P, Pharoah, PDP, Easton, DF, Chanock, SJ, Dunning, AM, and Figueroa, JD
Published: 2016

16. Magnetic Resonance Imaging Tracking of Distal Inflammatory Changes following Mild Traumatic Brain Injury (mTBI) in rats

Author: Gillham, SB, primary, Figueroa, JD, additional, and Bartnik, B, additional
Published: 2016
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17. Abstract P5-02-04: Plasma autoantibodies associated with basal-like breast cancers

Author: Wang (Student), J, primary, Figueroa, JD, additional, Wallstrom, G, additional, Barker, K, additional, Park, JG, additional, Demirkan, G, additional, Lissowska, J, additional, Anderson, K, additional, Qiu, J, additional, and LaBaer, J, additional
Published: 2016
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18. Genome-wide association study identifies multiple loci associated with bladder cancer risk

Author: Figueroa, JD, Ye, Y, Siddiq, A, Garcia-Closas, M, Chatterjee, N, Prokunina-Olsson, L, Cortessis, VK, Kooperberg, C, Cussenot, O, Benhamou, S, Prescott, J, Porru, S, Dinney, CP, Malats, N, Baris, D, Purdue, M, Jacobs, EJ, Albanes, D, Wang, Z, Deng, X, Chung, CC, Tang, W, Bueno-De-Mesquita, HB, Trichopoulos, D, Ljungberg, B, Clavel-Chapelon, F, Weiderpass, E, Krogh, V, Dorronsoro, M, Travis, R, Tjonneland, A, Brenan, P, Chang-Claude, J, Riboli, E, Conti, D, Gago Dominguez, Manuela, Stern, MC, Pike, MC, Van den Berg, D, Yuan, JM, Hohensee, C, Rodabough, R, Cancel-Tassin, G, Roupret, M, Comperat, E, Chen, C, De Vivo, I, Giovannucci, E, Hunter, DJ, Kraft, P, Lindstrom, S, Carta, A, Pavanello, S, Arici, C, Mastrangelo, G, Kamat, AM, Lerner, SP, Grossman, HB, Lin, J, Gu, J, Pu, X, Hutchinson, A, Burdette, L, Wheeler, W, Kogevinas, M, Tardon, A, Serra, C, Carrato, A, Garcia-Closas, R, Lloreta, J, Schwenn, M, Karagas, MR, Johnson, A, Schned, A, Armenti, KR, Hosain, GM, Andriole, G, Grubb, R, Black, A, Diver, WR, Gapstur, SM, Weinstein, SJ, Virtamo, J, Haiman, CA, Landi, MT, Caporaso, N, Fraumeni, JF, Vineis, P, Wu, X, Silverman, DT, Chanock, S, and Rothman, N
Subjects: Risk, Genotype, Meta-Analysis as Topic, Urinary Bladder Neoplasms, Genetic Loci, Case-Control Studies, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Genome-Wide Association Study
Abstract: Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 x 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 x 10(-9)) and rs907611 on 11p15.5 (P = 4.11 x 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 x 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 x 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
Published: 2014

19. 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

20. Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the International Consortium of Bladder Cancer

Author: Stern, Mc, Lin, J, Figueroa, Jd, Kelsey, Kt, Kiltie, Ae, Yuan, J. M., Matullo, G, Fletcher, T, Benhamou, S, Taylor, Ja, Placidi, Donatella, Zhang, Zf, Steineck, G, Rothman, N, Kogevinas, M, Silverman, D, Malatas, N, Chanock, S, Wu, X, KARAGAS MR ANDREW AS, Nelson, Hh, Bishop, Dt, Sak, Sc, Choudhury, A, Barrett, Jh, Elliot, F, Corral, R, Joshi, Ad, GAGO DOMINGUEZ, M, Cortessis, Vk, Xiang, Yb, Vineis, P, Sacerdote, C, Guarrera, S, Polidoro, S, Allione, A, Gurzau, E, Koppova, K, Kumar, R, Rudnai, P, Porru, Stefano, Carta, Angela, Campagna, Marcello, Arici, Cecilia, Park, Sl, and GARCIA CLOSAS, M.
Published: 2009

21. DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

Author: Perry, JRB, Hsu, Y-H, Chasman, DI, Johnson, AD, Elks, C, Albrecht, E, Andrulis, IL, Beesley, J, Berenson, GS, Bergmann, S, Bojesen, SE, Bolla, MK, Brown, J, Buring, JE, Campbell, H, Chang-Claude, J, Chenevix-Trench, G, Corre, T, Couch, FJ, Cox, A, Czene, K, D'adamo, AP, Davies, G, Deary, IJ, Dennis, J, Easton, DF, Engelhardt, EG, Eriksson, JG, Esko, T, Fasching, PA, Figueroa, JD, Flyger, H, Fraser, A, Garcia-Closas, M, Gasparini, P, Gieger, C, Giles, G, Guenel, P, Haegg, S, Hall, P, Hayward, C, Hopper, J, Ingelsson, E, Kardia, LR, Kasiman, K, Knight, JA, Lahti, J, Lawlor, DA, Magnusson, PKE, Margolin, S, Marsh, JA, Metspalu, A, Olson, JE, Pennell, CE, Polasek, O, Rahman, I, Ridker, PM, Robino, A, Rudan, I, Rudolph, A, Salumets, A, Schmidt, MK, Schoemaker, MJ, Smith, EN, Smith, JA, Southey, M, Stoeckl, D, Swerdlow, AJ, Thompson, DJ, Truong, T, Ulivi, S, Waldenberger, M, Wang, Q, Wild, S, Wilson, JF, Wright, AF, Zgaga, L, Ong, KK, Murabito, JM, Karasik, D, Murray, A, Perry, JRB, Hsu, Y-H, Chasman, DI, Johnson, AD, Elks, C, Albrecht, E, Andrulis, IL, Beesley, J, Berenson, GS, Bergmann, S, Bojesen, SE, Bolla, MK, Brown, J, Buring, JE, Campbell, H, Chang-Claude, J, Chenevix-Trench, G, Corre, T, Couch, FJ, Cox, A, Czene, K, D'adamo, AP, Davies, G, Deary, IJ, Dennis, J, Easton, DF, Engelhardt, EG, Eriksson, JG, Esko, T, Fasching, PA, Figueroa, JD, Flyger, H, Fraser, A, Garcia-Closas, M, Gasparini, P, Gieger, C, Giles, G, Guenel, P, Haegg, S, Hall, P, Hayward, C, Hopper, J, Ingelsson, E, Kardia, LR, Kasiman, K, Knight, JA, Lahti, J, Lawlor, DA, Magnusson, PKE, Margolin, S, Marsh, JA, Metspalu, A, Olson, JE, Pennell, CE, Polasek, O, Rahman, I, Ridker, PM, Robino, A, Rudan, I, Rudolph, A, Salumets, A, Schmidt, MK, Schoemaker, MJ, Smith, EN, Smith, JA, Southey, M, Stoeckl, D, Swerdlow, AJ, Thompson, DJ, Truong, T, Ulivi, S, Waldenberger, M, Wang, Q, Wild, S, Wilson, JF, Wright, AF, Zgaga, L, Ong, KK, Murabito, JM, Karasik, D, and Murray, A
Abstract: The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.
Published: 2014

22. Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

Author: Lindstroem, S, Thompson, DJ, Paterson, AD, Li, J, Gierach, GL, Scott, C, Stone, J, Douglas, JA, dos-Santos-Silva, I, Fernandez-Navarro, P, Verghase, J, Smith, P, Brown, J, Luben, R, Wareham, NJ, Loos, RJF, Heit, JA, Pankratz, VS, Norman, A, Goode, EL, Cunningham, JM, Deandrade, M, Vierkant, RA, Czene, K, Fasching, PA, Baglietto, L, Southey, MC, Giles, GG, Shah, KP, Chan, H-P, Helvie, MA, Beck, AH, Knoblauch, NW, Hazra, A, Hunter, DJ, Kraft, P, Pollan, M, Figueroa, JD, Couch, FJ, Hopper, JL, Hall, P, Easton, DF, Boyd, NF, Vachon, CM, Tamimi, RM, Lindstroem, S, Thompson, DJ, Paterson, AD, Li, J, Gierach, GL, Scott, C, Stone, J, Douglas, JA, dos-Santos-Silva, I, Fernandez-Navarro, P, Verghase, J, Smith, P, Brown, J, Luben, R, Wareham, NJ, Loos, RJF, Heit, JA, Pankratz, VS, Norman, A, Goode, EL, Cunningham, JM, Deandrade, M, Vierkant, RA, Czene, K, Fasching, PA, Baglietto, L, Southey, MC, Giles, GG, Shah, KP, Chan, H-P, Helvie, MA, Beck, AH, Knoblauch, NW, Hazra, A, Hunter, DJ, Kraft, P, Pollan, M, Figueroa, JD, Couch, FJ, Hopper, JL, Hall, P, Easton, DF, Boyd, NF, Vachon, CM, and Tamimi, RM
Abstract: Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5 × 10(-8)) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B and SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23 and TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease-susceptibility loci.
Published: 2014

23. 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

24. Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study

Author: Rudolph, A, Hein, R, Lindstroem, S, Beckmann, L, Behrens, S, Liu, J, Aschard, H, Bolla, MK, Wang, J, Truong, T, Cordina-Duverger, E, Menegaux, F, Bruening, T, Harth, V, Severi, G, Baglietto, L, Southey, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Eriksson, M, Humpreys, K, Darabi, H, Olson, JE, Stevens, KN, Vachon, CM, Knight, JA, Glendon, G, Mulligan, AM, Ashworth, A, Orr, N, Schoemaker, M, Webb, PM, Guenel, P, Brauch, H, Giles, G, Garcia-Closas, M, Czene, K, Chenevix-Trench, G, Couch, FJ, Andrulis, IL, Swerdlow, A, Hunter, DJ, Flesch-Janys, D, Easton, DF, Hall, P, Nevanlinna, H, Kraft, P, Chang-Claude, J, Rudolph, A, Hein, R, Lindstroem, S, Beckmann, L, Behrens, S, Liu, J, Aschard, H, Bolla, MK, Wang, J, Truong, T, Cordina-Duverger, E, Menegaux, F, Bruening, T, Harth, V, Severi, G, Baglietto, L, Southey, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Eriksson, M, Humpreys, K, Darabi, H, Olson, JE, Stevens, KN, Vachon, CM, Knight, JA, Glendon, G, Mulligan, AM, Ashworth, A, Orr, N, Schoemaker, M, Webb, PM, Guenel, P, Brauch, H, Giles, G, Garcia-Closas, M, Czene, K, Chenevix-Trench, G, Couch, FJ, Andrulis, IL, Swerdlow, A, Hunter, DJ, Flesch-Janys, D, Easton, DF, Hall, P, Nevanlinna, H, Kraft, P, and Chang-Claude, J
Abstract: Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case-control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) <3.0 × 10(-3) were selected for replication using pooled case-control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint≤8.9 × 10(-6)), two SNPs in SLC25A21 (combined Pint≤4.8 × 10(-5)), and three SNPs in PLCG2 (combined Pint≤4.5 × 10(-5)). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint≤2.7 × 10(-5)), one SNP in CD80 (combined Pint≤8.2 × 10(-6)), three SNPs on chr17 near TMEM132E (combined Pint≤2.2×10(-6)), and two SNPs on chr18 near SLC25A52 (combined Pint≤4.6 × 10(-5)). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.
Published: 2013

25. Genome-wide association analysis identifies three new breast cancer susceptibility loci

Author: Ghoussaini, M, Fletcher, O, Michailidou, K, Turnbull, C, Schmidt, MK, Dicks, E, Dennis, J, Wang, Q, Humphreys, MK, Luccarini, C, Baynes, C, Conroy, D, Maranian, M, Ahmed, S, Driver, K, Johnson, N, Orr, N, Silva, IDS, Waisfisz, Q, Meijers-Heijboer, H, Uitterlinden, AG, Rivadeneira, F, Hall, P, Czene, K, Irwanto, A, Liu, J, Nevanlinna, H, Aittomaki, K, Blomqvist, C, Meindl, A, Schmutzler, RK, Mueller-Myhsok, B, Lichtner, P, Chang-Claude, J, Hein, R, Nickels, S, Flesch-Janys, D, Tsimiklis, H, Makalic, E, Schmidt, D, Bui, M, Hopper, JL, Apicella, C, Park, DJ, Southey, M, Hunter, DJ, Chanock, SJ, Broeks, A, Verhoef, S, Hogervorst, FBL, Fasching, PA, Lux, MP, Beckmann, MW, Ekici, AB, Sawyer, E, Tomlinson, I, Kerin, M, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Truong, T, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Rosario Alonso, M, Gonzalez-Neira, A, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Justenhoven, C, Brauch, H, Bruening, T, Wang-Gohrke, S, Eilber, U, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Bogdanova, NV, Antonenkova, NN, Rogov, YI, Karstens, JH, Bermisheva, M, Prokofieva, D, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Lambrechts, D, Yesilyurt, BT, Floris, G, Leunen, K, Manoukian, S, Bonanni, B, Fortuzzi, S, Peterlongo, P, Couch, FJ, Wang, X, Stevens, K, Lee, A, Giles, GG, Baglietto, L, Severi, G, McLean, C, Alnaes, GG, Kristensen, V, Borrensen-Dale, A-L, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Glendon, G, Mulligan, AM, Devilee, P, van Asperen, CJ, Tollenaar, RAEM, Seynaeve, C, Figueroa, JD, Garcia-Closas, M, Brinton, L, Lissowska, J, Hooning, MJ, Hollestelle, A, Oldenburg, RA, van den Ouweland, AMW, Cox, A, Reed, MWR, Shah, M, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Jones, M, Schoemaker, M, Ashworth, A, Swerdlow, A, Beesley, J, Chen, X, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Chaiwerawattana, A, Kang, D, Yoo, K-Y, Noh, D-Y, Shen, C-Y, Yu, J-C, Wu, P-E, Hsiung, C-N, Perkins, A, Swann, R, Velentzis, L, Eccles, DM, Tapper, WJ, Gerty, SM, Graham, NJ, Ponder, BAJ, Chenevix-Trench, G, Pharoah, PDP, Lathrop, M, Dunning, AM, Rahman, N, Peto, J, Easton, DF, Ghoussaini, M, Fletcher, O, Michailidou, K, Turnbull, C, Schmidt, MK, Dicks, E, Dennis, J, Wang, Q, Humphreys, MK, Luccarini, C, Baynes, C, Conroy, D, Maranian, M, Ahmed, S, Driver, K, Johnson, N, Orr, N, Silva, IDS, Waisfisz, Q, Meijers-Heijboer, H, Uitterlinden, AG, Rivadeneira, F, Hall, P, Czene, K, Irwanto, A, Liu, J, Nevanlinna, H, Aittomaki, K, Blomqvist, C, Meindl, A, Schmutzler, RK, Mueller-Myhsok, B, Lichtner, P, Chang-Claude, J, Hein, R, Nickels, S, Flesch-Janys, D, Tsimiklis, H, Makalic, E, Schmidt, D, Bui, M, Hopper, JL, Apicella, C, Park, DJ, Southey, M, Hunter, DJ, Chanock, SJ, Broeks, A, Verhoef, S, Hogervorst, FBL, Fasching, PA, Lux, MP, Beckmann, MW, Ekici, AB, Sawyer, E, Tomlinson, I, Kerin, M, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Truong, T, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Rosario Alonso, M, Gonzalez-Neira, A, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Justenhoven, C, Brauch, H, Bruening, T, Wang-Gohrke, S, Eilber, U, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Bogdanova, NV, Antonenkova, NN, Rogov, YI, Karstens, JH, Bermisheva, M, Prokofieva, D, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Lambrechts, D, Yesilyurt, BT, Floris, G, Leunen, K, Manoukian, S, Bonanni, B, Fortuzzi, S, Peterlongo, P, Couch, FJ, Wang, X, Stevens, K, Lee, A, Giles, GG, Baglietto, L, Severi, G, McLean, C, Alnaes, GG, Kristensen, V, Borrensen-Dale, A-L, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Glendon, G, Mulligan, AM, Devilee, P, van Asperen, CJ, Tollenaar, RAEM, Seynaeve, C, Figueroa, JD, Garcia-Closas, M, Brinton, L, Lissowska, J, Hooning, MJ, Hollestelle, A, Oldenburg, RA, van den Ouweland, AMW, Cox, A, Reed, MWR, Shah, M, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Jones, M, Schoemaker, M, Ashworth, A, Swerdlow, A, Beesley, J, Chen, X, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Chaiwerawattana, A, Kang, D, Yoo, K-Y, Noh, D-Y, Shen, C-Y, Yu, J-C, Wu, P-E, Hsiung, C-N, Perkins, A, Swann, R, Velentzis, L, Eccles, DM, Tapper, WJ, Gerty, SM, Graham, NJ, Ponder, BAJ, Chenevix-Trench, G, Pharoah, PDP, Lathrop, M, Dunning, AM, Rahman, N, Peto, J, and Easton, DF
Abstract: Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
Published: 2012

26. Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

Author: Chan, KYK, Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, MK, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, IDS, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Truong, T, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Arias Perez, JI, Pilar Zamora, M, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, Y-D, Wang-Gohrke, S, Doerk, T, Schuermann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chen, X, Beesley, J, Lambrechts, D, Zhao, H, Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, A-L, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, JWM, Seynaeve, C, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, J, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S, Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, K-Y, Noh, D-Y, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Shen, C-Y, Yu, J-C, Hsu, H-M, Hou, M-F, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, Dunning, AM, Chan, KYK, Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, MK, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, IDS, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Truong, T, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Arias Perez, JI, Pilar Zamora, M, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, Y-D, Wang-Gohrke, S, Doerk, T, Schuermann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chen, X, Beesley, J, Lambrechts, D, Zhao, H, Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, A-L, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, JWM, Seynaeve, C, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, J, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S, Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, K-Y, Noh, D-Y, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Shen, C-Y, Yu, J-C, Hsu, H-M, Hou, M-F, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, and Dunning, AM
Abstract: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of
Published: 2012

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

Author: Jacobs, KB, Yeager, M, Zhou, W, Wacholder, S, Wang, Z, Rodriguez-Santiago, B, Hutchinson, A, Deng, X, Liu, C, Horner, M-J, Cullen, M, Epstein, CG, Burdett, L, Dean, MC, Chatterjee, N, Sampson, J, Chung, CC, Kovaks, J, Gapstur, SM, Stevens, VL, Teras, LT, Gaudet, MM, Albanes, D, Weinstein, SJ, Virtamo, J, Taylor, PR, Freedman, ND, Abnet, CC, Goldstein, AM, Hu, N, Yu, K, Yuan, J-M, Liao, L, Ding, T, Qiao, Y-L, Gao, Y-T, Koh, W-P, Xiang, Y-B, Tang, Z-Z, Fan, J-H, Aldrich, MC, Amos, C, Blot, WJ, Bock, CH, Gillanders, EM, Harris, CC, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, McNeill, LH, Rybicki, BA, Schwartz, AG, Signorello, LB, Spitz, MR, Wiencke, JK, Wrensch, M, Wu, X, Zanetti, KA, Ziegler, RG, Figueroa, JD, Garcia-Closas, M, Malats, N, Marenne, G, Prokunina-Olsson, L, Baris, D, Schwenn, M, Johnson, A, Landi, MT, Goldin, L, Consonni, D, Bertazzi, PA, Rotunno, M, Rajaraman, P, Andersson, U, Freeman, LEB, Berg, CD, Buring, JE, Butler, MA, Carreon, T, Feychting, M, Ahlbom, A, Gaziano, JM, Giles, GG, Hallmans, G, Hankinson, SE, Hartge, P, Henriksson, R, Inskip, PD, Johansen, C, Landgren, A, McKean-Cowdin, R, Michaud, DS, Melin, BS, Peters, U, Ruder, AM, Sesso, HD, Severi, G, Shu, X-O, Visvanathan, K, White, E, Wolk, A, Zeleniuch-Jacquotte, A, Zheng, W, Silverman, DT, Kogevinas, M, Gonzalez, JR, Villa, O, Li, D, Duell, EJ, Risch, HA, Olson, SH, Kooperberg, C, Wolpin, BM, Jiao, L, Hassan, M, Wheeler, W, Arslan, AA, Bueno-de-Mesquita, HB, Fuchs, CS, Gallinger, S, Gross, MD, Holly, EA, Klein, AP, LaCroix, A, Mandelson, MT, Petersen, G, Boutron-Ruault, M-C, Bracci, PM, Canzian, F, Chang, K, Cotterchio, M, Giovannucci, EL, Goggins, M, Bolton, JAH, Jenab, M, Khaw, K-T, Krogh, V, Kurtz, RC, McWilliams, RR, Mendelsohn, JB, Rabe, KG, Riboli, E, Tjonneland, A, Tobias, GS, Trichopoulos, D, Elena, JW, Yu, H, Amundadottir, L, Stolzenberg-Solomon, RZ, Kraft, P, Schumacher, F, Stram, D, Savage, SA, Mirabello, L, Andrulis, IL, Wunder, JS, Patino Garcia, A, Sierrasesumaga, L, Barkauskas, DA, Gorlick, RG, Purdue, M, Chow, W-H, Moore, LE, Schwartz, KL, Davis, FG, Hsing, AW, Berndt, SI, Black, A, Wentzensen, N, Brinton, LA, Lissowska, J, Peplonska, B, McGlynn, KA, Cook, MB, Graubard, BI, Kratz, CP, Greene, MH, Erickson, RL, Hunter, DJ, Thomas, G, Hoover, RN, Real, FX, Fraumeni, JF, Caporaso, NE, Tucker, M, Rothman, N, Perez-Jurado, LA, Chanock, SJ, Jacobs, KB, Yeager, M, Zhou, W, Wacholder, S, Wang, Z, Rodriguez-Santiago, B, Hutchinson, A, Deng, X, Liu, C, Horner, M-J, Cullen, M, Epstein, CG, Burdett, L, Dean, MC, Chatterjee, N, Sampson, J, Chung, CC, Kovaks, J, Gapstur, SM, Stevens, VL, Teras, LT, Gaudet, MM, Albanes, D, Weinstein, SJ, Virtamo, J, Taylor, PR, Freedman, ND, Abnet, CC, Goldstein, AM, Hu, N, Yu, K, Yuan, J-M, Liao, L, Ding, T, Qiao, Y-L, Gao, Y-T, Koh, W-P, Xiang, Y-B, Tang, Z-Z, Fan, J-H, Aldrich, MC, Amos, C, Blot, WJ, Bock, CH, Gillanders, EM, Harris, CC, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, McNeill, LH, Rybicki, BA, Schwartz, AG, Signorello, LB, Spitz, MR, Wiencke, JK, Wrensch, M, Wu, X, Zanetti, KA, Ziegler, RG, Figueroa, JD, Garcia-Closas, M, Malats, N, Marenne, G, Prokunina-Olsson, L, Baris, D, Schwenn, M, Johnson, A, Landi, MT, Goldin, L, Consonni, D, Bertazzi, PA, Rotunno, M, Rajaraman, P, Andersson, U, Freeman, LEB, Berg, CD, Buring, JE, Butler, MA, Carreon, T, Feychting, M, Ahlbom, A, Gaziano, JM, Giles, GG, Hallmans, G, Hankinson, SE, Hartge, P, Henriksson, R, Inskip, PD, Johansen, C, Landgren, A, McKean-Cowdin, R, Michaud, DS, Melin, BS, Peters, U, Ruder, AM, Sesso, HD, Severi, G, Shu, X-O, Visvanathan, K, White, E, Wolk, A, Zeleniuch-Jacquotte, A, Zheng, W, Silverman, DT, Kogevinas, M, Gonzalez, JR, Villa, O, Li, D, Duell, EJ, Risch, HA, Olson, SH, Kooperberg, C, Wolpin, BM, Jiao, L, Hassan, M, Wheeler, W, Arslan, AA, Bueno-de-Mesquita, HB, Fuchs, CS, Gallinger, S, Gross, MD, Holly, EA, Klein, AP, LaCroix, A, Mandelson, MT, Petersen, G, Boutron-Ruault, M-C, Bracci, PM, Canzian, F, Chang, K, Cotterchio, M, Giovannucci, EL, Goggins, M, Bolton, JAH, Jenab, M, Khaw, K-T, Krogh, V, Kurtz, RC, McWilliams, RR, Mendelsohn, JB, Rabe, KG, Riboli, E, Tjonneland, A, Tobias, GS, Trichopoulos, D, Elena, JW, Yu, H, Amundadottir, L, Stolzenberg-Solomon, RZ, Kraft, P, Schumacher, F, Stram, D, Savage, SA, Mirabello, L, Andrulis, IL, Wunder, JS, Patino Garcia, A, Sierrasesumaga, L, Barkauskas, DA, Gorlick, RG, Purdue, M, Chow, W-H, Moore, LE, Schwartz, KL, Davis, FG, Hsing, AW, Berndt, SI, Black, A, Wentzensen, N, Brinton, LA, Lissowska, J, Peplonska, B, McGlynn, KA, Cook, MB, Graubard, BI, Kratz, CP, Greene, MH, Erickson, RL, Hunter, DJ, Thomas, G, Hoover, RN, Real, FX, Fraumeni, JF, Caporaso, NE, Tucker, M, Rothman, N, Perez-Jurado, LA, and Chanock, SJ
Abstract: In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
Published: 2012

28. Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

Author: Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, Marjanka K, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, ID, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Perez, JIA, Zamora, MP, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Muller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, YD, Wang-Gohrke, S, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, J, Chen, XQ, Beesley, J, Lambrechts, D, Zhao, H (Hui), Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, XS, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, AL, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, John, Seynaeve, Caroline, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, JJ, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S (Shahana), Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, KY, Noh, DY, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Shen, CY, Yu, JC, Hsu, HM, Hou, MF, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, Dunning, AM, Truong, T, Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, Marjanka K, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, ID, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Perez, JIA, Zamora, MP, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Muller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, YD, Wang-Gohrke, S, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, J, Chen, XQ, Beesley, J, Lambrechts, D, Zhao, H (Hui), Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, XS, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, AL, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, John, Seynaeve, Caroline, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, JJ, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S (Shahana), Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, KY, Noh, DY, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Shen, CY, Yu, JC, Hsu, HM, Hou, MF, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, Dunning, AM, and Truong, T
Abstract: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6x10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8x10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2x10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8x10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8x10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3x10(-7), p(heterogeneity) = 5.1x10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
Published: 2012

29. Breast cancer susceptibility loci in association with age at menarche, age at natural menopause and the reproductive lifespan

Author: Warren Andersen, S, primary, Trentham-Dietz, A, additional, Gangnon, RE, additional, Hampton, JM, additional, Figueroa, JD, additional, Skinner, HG, additional, Engelman, CD, additional, Klein, BE, additional, Titus, LJ, additional, Egan, KM, additional, and Newcomb, PA, additional
Published: 2013
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30. Abstract P3-08-02: Common variants at 10p14 and 1p11.2 display heterogeneity in breast cancer associations by E-cadherin tumor tissue expression in two independent datasets

Author: Horne, HN, primary, Sherman, ME, additional, Garcia-Closas, M, additional, Pharoah, PD, additional, Blows, FM, additional, Yang, XR, additional, Lissowska, J, additional, Brinton, LA, additional, Chanock, SJ, additional, and Figueroa, JD, additional
Published: 2012
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31. Abstract P3-12-05: Genetic Variation in Prolactin and Prolactin Receptor, and Relationships with Serum Prolactin Levels and Breast Cancer Risk

Author: Nyante, SJ, primary, Faupel-Badger, JM, additional, Sherman, ME, additional, Gaudet, MM, additional, Falk, RT, additional, Andaya, AA, additional, Pfeiffer, RM, additional, Lissowska, J, additional, Brinton, LA, additional, Peplonska, B, additional, Vonderhaar, BK, additional, Chanock, SJ, additional, Garcia-Closas, M, additional, and Figueroa, JD., additional
Published: 2010
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32. 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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33. DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

Author: Jr, Perry, Yh, Hsu, Di, Chasman, Ad, Johnson, Elks C, Albrecht E, Il, Andrulis, Beesley J, Gs, Berenson, Bergmann S, Se, Bojesen, Mk, Bolla, Brown J, Je, Buring, Campbell H, Chang-Claude J, Chenevix-Trench G, Corre T, Fj, Couch, Cox A, Czene K, Adamo Ap, D., Davies G, Ij, Deary, Dennis J, Df, Easton, Eg, Engelhardt, Jg, Eriksson, Esko T, Fasching P, Jd, Figueroa, Flyger H, Fraser A, Garcia-Closas M, Gasparini P, Gieger C, Giles G, Guenel P, Hägg S, Hall P, Hayward C, Hopper J, Ingelsson E, kConFab investigators, Sl, Kardia, Kasiman K, Ja, Knight, Jari Lahti, Da, Lawlor, Pk, Magnusson, Margolin S, Ja, Marsh, Metspalu A, Je, Olson, Ce, Pennell, Polasek O, Rahman I, Pm, Ridker, Robino A, Rudan I, Rudolph A, Salumets A, Mk, Schmidt, Mj, Schoemaker, En, Smith, Ja, Smith, Southey M, Stöckl D, Aj, Swerdlow, Dj, Thompson, Truong T, Ulivi S, Waldenberger M, Wang Q, Wild S, Jf, Wilson, Af, Wright, Zgaga L, ReproGen Consortium, Kk, Ong, Jm, Murabito, Karasik D, Murray A, kConFab investigators, ReproGen Consortium, Perry, Jr, Hsu, Yh, Chasman, Di, Johnson, Ad, Elks, C, Albrecht, E, Andrulis, Il, Beesley, J, Berenson, G, Bergmann, S, Bojesen, Se, Bolla, Mk, Brown, J, Buring, Je, Campbell, H, Chang Claude, J, Chenevix Trench, G, Corre, T, Couch, Fj, Cox, A, Czene, K, D'Adamo, ADAMO PIO, Davies, G, Deary, Ij, Dennis, J, Easton, Df, Engelhardt, Eg, Eriksson, Jg, Esko, T, Fasching, Pa, Figueroa, Jd, Flyger, H, Fraser, A, Garcia Closas, M, Gasparini, Paolo, Gieger, C, Giles, G, Guenel, P, Hägg, S, Hall, P, Hayward, C, Hopper, J, Ingelsson, E, Kconfab, Investigator, Kardia, Sl, Kasiman, K, Knight, Ja, Lahti, J, Lawlor, Da, Magnusson, Pk, Margolin, S, Marsh, Ja, Metspalu, A, Olson, Je, Pennell, Ce, Polasek, O, Rahman, I, Ridker, Pm, Robino, Antonietta, Rudan, I, Rudolph, A, Salumets, A, Schmidt, Mk, Schoemaker, Mj, Smith, En, Smith, Ja, Southey, M, Stöckl, D, Swerdlow, Aj, Thompson, Dj, Truong, T, Ulivi, S, Waldenberger, M, Wang, Q, Wild, S, Wilson, Jf, Wright, Af, Zgaga, L, Consortium, R, Ong, Kk, Murabito, Jm, Karasik, D, and Murray, A.
Subjects: Association Studies Articles, Age Factors, Polymorphism, Single Nucleotide, age at menopause, GWAS, MSH6 gene, DNA-Binding Proteins, Medizinische Fakultät, Humans, Female, ddc:610, Menopause, Genome-Wide Association Study
Abstract: The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain
Published: 2013

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

Author: Rajesh Kumar, Gerald L. Andriole, Robert L. Grubb, Monica McGrath, Amanda Black, Manuela Gago-Dominguez, Margaret A. Knowles, Francisco X. Real, Nilanjan Chatterjee, Thorunn Rafnar, Kevin B. Jacobs, Silvia Polidoro, Debra T. Silverman, Sita H. Vermeulen, Manuel Sanchez, Núria Malats, Salvatore Panico, Amy Hutchinson, William Wheeler, Carmen Navarro, Montserrat Garcia-Closas, Carlotta Sacerdote, Gabriel Valdivia, Yi-Ping Fu, Kari Stefansson, Michelle A.T. Hildebrandt, Alessandra Allione, Katja K.H. Aben, Alison Johnson, W. Ryan Diver, Laurie Burdett, Sophia C.E. Bolick, David J. Hunter, Jarmo Virtamo, Jack A. Taylor, Ludmila Prokunina-Olsson, José I Sanz-Velez, Mark P. Purdue, Fulvio Ricceri, Elio Riboli, Maria Teresa Landi, Susan M. Gapstur, Søren Besenbacher, Joseph F. Fraumeni, Olivier Cussenot, J. Alfred Witjes, Victoria K. Cortessis, Paul Brennan, Tony Fletcher, David Van Den Berg, Börje Ljungberg, Lambertus A. Kiemeney, Dalsu Baris, Mark Teo, Zongli Xu, Geraldine Cancel-Tassin, Holger Dietrich, Zhaoming Wang, Maria D. Garcia-Prats, Françoise Clavel-Chapelon, Adonina Tardón, Paolo Vineis, Peter Rudnai, Margaret R. Karagas, Naomi E. Allen, H. Bas Bueno-de-Mesquita, Molly Schwenn, Jose I. Mayordomo, Ashley C. Godfrey, Manolis Kogevinas, Silvia Selinski, Stephen J. Chanock, Jonine D. Figueroa, Alan R. Schned, Stefano Porru, Mariana C. Stern, Demetrius Albanes, Simonetta Guarrera, Patrick Sulem, Immaculata De Vivo, Hushan Yang, Robert N. Hoover, Kvetoslava Koppova, Michael J. Thun, Malcolm C. Pike, Giuseppe Matullo, D T Bishop, Neil E. Caporaso, Klaus Golka, Eugen Gurzau, Colin P.N. Dinney, Josep Lloreta, Nathaniel Rothman, Eric J. Jacobs, Simone Benhamou, Alfredo Carrato, Federico Canzian, Xifeng Wu, Consol Serra, Anne Tjønneland, Jian-Min Yuan, Meredith Yeager, Reina García-Closas, Stephanie J. Weinstein, Jan G. Hengstler, Dimitrios Trichopoulos, Remco R. R. Makkinje, Anne E. Kiltie, Bogdan Czerniak, Meng Chen, Rothman, N, Garcia Closas, M, Chatterjee, N, Malats, N, Wu, X, Figueroa, Jd, Real, Fx, Van Den Berg, D, Matullo, G, Baris, D, Thun, M, Kiemeney, La, Vineis, P, De Vivo, I, Albanes, D, Purdue, Mp, Rafnar, T, Hildebrandt, Ma, Kiltie, Ae, Cussenot, O, Golka, K, Kumar, R, Taylor, Ja, Mayordomo, Ji, Jacobs, Kb, Kogevinas, M, Hutchinson, A, Wang, Z, Fu, Yp, Prokunina Olsson, L, Burdett, L, Yeager, M, Wheeler, W, Tardón, A, Serra, C, Carrato, A, García Closas, R, Lloreta, J, Johnson, A, Schwenn, M, Karagas, Mr, Schned, A, Andriole G., Jr, Grubb R., 3rd, Black, A, Jacobs, Ej, Diver, Wr, Gapstur, Sm, Weinstein, Sj, Virtamo, J, Cortessis, Vk, Gago Dominguez, M, Pike, Mc, Stern, Mc, Yuan, Jm, Hunter, Dj, Mcgrath, M, Dinney, Cp, Czerniak, B, Chen, M, Yang, H, Vermeulen, Sh, Aben, Kk, Witjes, Ja, Makkinje, Rr, Sulem, P, Besenbacher, S, Stefansson, K, Riboli, E, Brennan, P, Panico, Salvatore, Navarro, C, Allen, Ne, Bueno de Mesquita, Hb, Trichopoulos, D, Caporaso, Nicola, Landi, Mt, Canzian, F, Ljungberg, B, Tjonneland, A, Clavel Chapelon, F, Bishop, Dt, Teo, Mt, Knowles, Ma, Guarrera, S, Polidoro, S, Ricceri, F, Sacerdote, C, Allione, A, Cancel Tassin, G, Selinski, S, Hengstler, Jg, Dietrich, H, Fletcher, T, Rudnai, P, Gurzau, E, Koppova, K, Bolick, Sc, Godfrey, A, Xu, Z, Sanz Velez, Ji, D., García Prats M, Sanchez, M, Valdivia, G, Porru, S, Benhamou, S, Hoover, Rn, Fraumeni JF, Jr, Silverman, Dt, and Chanock, Sj
Subjects: Male, Arylamine N-Acetyltransferase, Chromosomes, Human, Pair 22, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], medicine.disease_cause, Genome-wide association studies, Risk Factors, genome-wide association, bladder cancer, Psychology, Genetics, Sex Characteristics, Incidence, Bladder cancer, Smoking, Chromosome Mapping, Single Nucleotide, Tag SNP, Europe, Chromosomes, Human, Pair 2, Pair 2, Female, Human, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Chromosomes, Article, Molecular epidemiology [NCEBP 1], Translational research [ONCOL 3], medicine, Humans, Family, Genetic Predisposition to Disease, Polymorphism, Pair 18, Pair 22, Genome-Wide Association Study, Neoplasm Staging, Spain, United States, Urinary Bladder Neoplasms, Cancer, Chromosome, medicine.disease, Evaluation of complex medical interventions [NCEBP 2], Carcinogenesis, Chromosomes, Human, Pair 18
Abstract: We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.
Published: 2010

35. Shifts in naturalistic behaviors induced by early social isolation stress are associated with adult binge-like eating in female rats.

Author: Simon TB, Sierra J, Williams A, Wright G, Rhee A, Horn J, Lou J, Sharafeddin F, Ontiveros-Ángel P, and Figueroa JD
Abstract: Binge eating (BE) is a highly pervasive maladaptive coping strategy in response to severe early life stress such as emotional and social neglect. BE is described as repeated episodes of uncontrolled eating and is tightly linked with comorbid mental health concerns. Despite social stressors occurring at a young age, the onset of BE typically does not occur until adulthood providing an interval for potential therapeutic intervention. Currently, our knowledge of longitudinal noninvasive digital biomarkers predictive of BE needs further development. Monitoring longitudinal impacts of adolescent social isolation stress on naturalistic behaviors in rats will enable the identification of noninvasive digital markers of disease progression to predict adult eating strategies. Recognizing adolescent naturalistic behaviors shaped by social stress informs our understanding of the underlying neurocircuits most effected. This study aimed to monitor and identify longitudinal behavioral shifts to enhance predictive capabilities in a rat model of social isolation stress-induced BE. We placed Paired ( n = 12) and Socially Isolated (SI, n = 12) female rats in observational home cages weekly for seven weeks to evaluate the effect of SI on 10 naturalistic behaviors. All 10 naturalistic behaviors were simultaneously detected and tracked using Noldus Ethovision XT automated recognition software. Composite phenotypic z-scores were calculated by standardizing all 10 behaviors. When transitioning into adulthood, all rats underwent conventional emotionality testing and were exposed to a Western-like high fat diet (WD, 43% kcal from fat) to evaluate BE. Longitudinal assessments revealed SI-induced shifts in adolescent phenotypic z-scores and that sniffing, unsupported rearing, jumping, and twitching were the most susceptible to SI. SI increased emotionality compared to the Paired controls. Finally, we identified adolescent twitching as a digital biomarker of adult WD consumption. Our findings suggest that home cage monitoring can detect disrupted naturalistic behaviors associated with maladaptive coping., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Simon, Sierra, Williams, Wright, Rhee, Horn, Lou, Sharafeddin, Ontiveros-Ángel and Figueroa.)
Published: 2024
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36. Impact of adolescent high-fat diet and psychosocial stress on neuroendocrine stress responses and binge eating behavior in adult male Lewis rats.

Author: Sierra J, Simon TB, Hilal DA, Torres YA, Santana JMS, and Figueroa JD
Abstract: Childhood obesity is a multifactorial disease affecting more than 160 million adolescents worldwide. Adolescent exposure to obesogenic environments, characterized by access to high-fat diets and stress, precipitates maladaptive eating habits in adulthood such as binge eating. Evidence suggests a strong association between Western-like high-saturated-fat (WD) food consumption and dysregulated hormone fluctuations. However, few studies have explored the long-term impact of adolescent WD and psychosocial stress on brain and behavior. This longitudinal study aimed to investigate the impact of adolescent exposure to an obesogenic diet on stress resiliency and increased susceptibility for binge-like eating behaviors. Adolescent male Lewis rats were given WD (41% fat; n=40) or control diet (CD, 16% fat; n=38) for 4 weeks before undergoing a stress paradigm of predator exposure and social instability (CDE, WDE, CDU, WDU; n=16/group). Subjects were provided intermittent WD access (24 h/week) to evaluate binge eating-like behavior in adulthood. Fecal corticosterone and testosterone were measured at four timepoints throughout adolescence and adulthood. WD rats exhibited increased body weight (p = 0.0217) and elevated testosterone in mid-adolescence (p=0.0312) and blunted stress-induced corticosterone response in mid-late adolescence (CDE:WDE, p=0.028). Adolescent hormone levels were negatively correlated with bingeing and explained the variability between adult rats expressing hyperphagic and hypophagic behaviors. These results demonstrate that exposure to WD in adolescence disrupts hormone fluctuations and stress responsivity, with effects persisting into adulthood. This underscores the importance of addressing obesogenic environments early to mitigate their lasting impact on hormone regulation and stress responsiveness., Competing Interests: Conflict of Interest Statement All authors report no financial interests or potential conflicts of interest.
Published: 2024
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37. Early-life obesogenic environment integrates immunometabolic and epigenetic signatures governing neuroinflammation.

Author: Ontiveros-Ángel P, Vega-Torres JD, Simon TB, Williams V, Inostroza-Nives Y, Alvarado-Crespo N, Gonzalez YV, Pompolius M, Katzka W, Lou J, Sharafeddin F, De la Peña I, Dong T, Gupta A, Viet CT, Febo M, Obenaus A, Nair A, and Figueroa JD
Abstract: Childhood overweight/obesity is associated with stress-related psychopathology, yet the pathways connecting childhood obesity to stress susceptibility are poorly understood. We employed a systems biology approach with 62 adolescent Lewis rats fed a Western-like high-saturated fat diet (WD, 41% kcal from fat) or a control diet (CD, 13% kcal from fat). A subset of rats underwent a 31-day model of predator exposures and social instability (PSS). Effects were assessed using behavioral tests, DTI (diffusion tensor imaging), NODDI (neurite orientation dispersion and density imaging), 16S rRNA gene sequencing for gut microbiome profiling, hippocampal microglia analysis, and targeted gene methylation. Parallel experiments on human microglia cells (HMC3) examined how palmitic acid influences cortisol-related inflammatory responses. Rats exposed to WD and PSS exhibited deficits in sociability, increased fear/anxiety-like behaviors, food consumption, and body weight. WD/PSS altered hippocampal microstructure (subiculum, CA1, dentate gyrus), and microbiome analysis showed a reduced abundance of members of the phylum Firmicutes . WD/PSS synergistically promoted neuroinflammatory changes in hippocampal microglia, linked with microbiome shifts and altered Fkbp5 expression/methylation. In HMC3, palmitate disrupted cortisol responses, affecting morphology, phagocytic markers, and cytokine release, partially mediated by FKBP5. This study identifies gene-environment interactions that influence microglia biology and may contribute to the connection between childhood obesity and stress-related psychopathology later in life., Competing Interests: The authors declare no conflicts of interest related to this work., (© 2024 The Authors.)
Published: 2024
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38. Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.

Author: Davidson AL, Michailidou K, Parsons MT, Fortuno C, Bolla MK, Wang Q, Dennis J, Naven M, Abubakar M, Ahearn TU, Alonso MR, Andrulis IL, Antoniou AC, Auvinen P, Behrens S, Bermisheva MA, Bogdanova NV, Bojesen SE, Brüning T, Byers HJ, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Collée JM, Czene K, Dörk T, Eriksson M, Evans DG, Fasching PA, Figueroa JD, Flyger H, Gago-Dominguez M, García-Closas M, Glendon G, González-Neira A, Grassmann F, Gronwald J, Guénel P, Hadjisavvas A, Haeberle L, Hall P, Hamann U, Hartman M, Ho PJ, Hooning MJ, Hoppe R, Howell A, Jakubowska A, Khusnutdinova EK, Kristensen VN, Li J, Lim J, Lindblom A, Liu J, Lophatananon A, Mannermaa A, Mavroudis DA, Mensenkamp AR, Milne RL, Muir KR, Newman WG, Obi N, Panayiotidis MI, Park SK, Park-Simon TW, Peterlongo P, Radice P, Rashid MU, Rhenius V, Saloustros E, Sawyer EJ, Schmidt MK, Seibold P, Shah M, Southey MC, Teo SH, Tomlinson I, Torres D, Truong T, van de Beek I, van der Hout AH, Wendt CC, Dunning AM, Pharoah PDP, Devilee P, Easton DF, James PA, and Spurdle AB
Subjects: Humans, Female, BRCA2 Protein genetics, BRCA1 Protein genetics, Fanconi Anemia Complementation Group N Protein genetics, Middle Aged, Mutation, Missense genetics, Adult, Tumor Suppressor Protein p53 genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Germ-Line Mutation genetics
Abstract: Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels., Competing Interests: Declaration of interests P.A.F. conducts research funded by Amgen, Novartis, and Pfizer. He received Honoraria from Roche, Novartis, and Pfizer. A.R.M. received funds from AstraZeneca for contribution to sponsored quality assessments and variant interpretation of VUSs in BRCA1 and BRCA2. The funds were paid to the institution., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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39. Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.

Author: Zanti M, O'Mahony DG, Parsons MT, Dorling L, Dennis J, Boddicker NJ, Chen W, Hu C, Naven M, Yiangou K, Ahearn TU, Ambrosone CB, Andrulis IL, Antoniou AC, Auer PL, Baynes C, Bodelon C, Bogdanova NV, Bojesen SE, Bolla MK, Brantley KD, Camp NJ, Campbell A, Castelao JE, Cessna MH, Chang-Claude J, Chen F, Chenevix-Trench G, Conroy DM, Czene K, De Nicolo A, Domchek SM, Dörk T, Dunning AM, Eliassen AH, Evans DG, Fasching PA, Figueroa JD, Flyger H, Gago-Dominguez M, García-Closas M, Glendon G, González-Neira A, Grassmann F, Hadjisavvas A, Haiman CA, Hamann U, Hart SN, Hartman MBA, Ho WK, Hodge JM, Hoppe R, Howell SJ, Jakubowska A, Khusnutdinova EK, Ko YD, Kraft P, Kristensen VN, Lacey JV, Li J, Lim GH, Lindström S, Lophatananon A, Luccarini C, Mannermaa A, Martinez ME, Mavroudis D, Milne RL, Muir K, Nathanson KL, Nuñez-Torres R, Obi N, Olson JE, Palmer JR, Panayiotidis MI, Patel AV, Pharoah PDP, Polley EC, Rashid MU, Ruddy KJ, Saloustros E, Sawyer EJ, Schmidt MK, Southey MC, Tan VK, Teo SH, Teras LR, Torres D, Trentham-Dietz A, Truong T, Vachon CM, Wang Q, Weitzel JN, Yadav S, Yao S, Zirpoli GR, Cline MS, Devilee P, Tavtigian SV, Goldgar DE, Couch FJ, Easton DF, Spurdle AB, and Michailidou K
Abstract: Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2 . This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.
Published: 2024
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40. Contribution of pre-diagnostic host factors to shaping the stromal microenvironment of breast cancer among sub-Saharan African women.

Author: Abubakar M, Ahearn TU, Duggan MA, Lawrence S, Adjei EK, Clegg-Lamptey JN, Yarney J, Wiafe-Addai B, Awuah B, Wiafe S, Nyarko K, Aitpillah FS, Ansong D, Hewitt SM, Brinton LA, Figueroa JD, Garcia-Closas M, Edusei L, and Titiloye N
Abstract: Background: The stromal microenvironment (SME) is integral to breast cancer (BC) biology, impacting metastatic proclivity and treatment response. Emerging data indicate that host factors may impact the SME, but the relationship between pre-diagnostic host factors and SME phenotype remains poorly characterized, particularly among women of African ancestry., Methods: We conducted a case-only analysis involving 792 BC patients (17-84 years) from the Ghana Breast Health Study (GBHS). High-accuracy machine-learning algorithms were applied to standard H&E-stained images to characterize SME phenotypes (including percent tumor-associated connective tissue stroma, Ta-CTS (%), and tumor-associated stromal cellular density, Ta-SCD (%)). Associations between pre-diagnostic host factors and SME phenotypes were assessed in multivariable linear regression models., Results: Decreasing Ta-CTS and increasing Ta-SCD were associated with aggressive, mostly high-grade tumors (p-value<0.001). Several pre-diagnostic host factors were associated with Ta-SCD independently of tumor characteristics. Compared with nulliparous women, parous women had higher levels of Ta-SCD [mean (standard deviation, SD) = 31.3% (7.6%) vs. 28.9% (7.1%); p-value=0.01]. Similarly, women with a positive family history of breast cancer had higher levels of Ta-SCD than those without family history [mean (SD) = 33.0% (7.5%)] vs. 30.9% (7.6%); p-value=0.03]. Conversely, increasing body size was associated with decreasing Ta-SCD [mean (SD) = 32.0% (7.4%), 31.3% (7.3%), and 29.0% (8.0%) for slight, average, and large body sizes, respectively, p-value=0.005]., Conclusions: Epidemiological risk factors were associated with varying degrees of stromal cellularity in tumors, independently of clinicopathological characteristics., Impact: The findings raise the possibility that epidemiological risk factors may partly influence tumor biology via the SME.
Published: 2024
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41. Early life adversity impacts alterations in brain structure and food addiction in individuals with high BMI.

Author: Ravichandran S, Sood R, Das I, Dong T, Figueroa JD, Yang J, Finger N, Vaughan A, Vora P, Selvaraj K, Labus JS, and Gupta A
Subjects: Humans, Female, Male, Adult, Adverse Childhood Experiences psychology, Reward, Young Adult, Middle Aged, Surveys and Questionnaires, Resilience, Psychological, Body Mass Index, Food Addiction psychology, Brain diagnostic imaging, Brain pathology, Brain physiopathology, Magnetic Resonance Imaging, Obesity psychology, Obesity pathology
Abstract: Obesity and food addiction are associated with distinct brain signatures related to reward processing, and early life adversity (ELA) also increases alterations in these same reward regions. However, the neural mechanisms underlying the effect of early life adversity on food addiction are unknown. Therefore, the aim of this study was to examine the interactions between ELA, food addiction, and brain morphometry in individuals with obesity. 114 participants with high body mass index (BMI) underwent structural MRIs, and completed several questionnaires (e.g., Yale Food Addiction Scale (YFAS), Brief Resilience Scale (BRS), Early Traumatic Inventory (ETI)). Freesurfer 6 was applied to generate the morphometry of brain regions. A multivariate pattern analysis was used to derive brain morphometry patterns associated with food addiction. General linear modeling and mediation analyses were conducted to examine the effects of ELA and resilience on food addiction in individuals with obesity. Statistical significance was determined at a level of p < 0.05. High levels of ELA showed a strong association between reward control brain signatures and food addiction (p = 0.03). Resilience positively mediated the effect of ELA on food addiction (B = 0.02, p = 0.038). Our findings suggest that food addiction is associated with brain signatures in motivation and reward processing regions indicative of dopaminergic dysregulation and inhibition of cognitive control regions. These mechanistic variabilities along with early life adversity suggest increased vulnerability to develop food addiction and obesity in adulthood, which can buffer by the neuroprotective effects of resilience, highlighting the value of incorporating cognitive appraisal into obesity therapeutic regimens., (© 2024. The Author(s).)
Published: 2024
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42. Role of the prefrontal cortical protease TACE/ADAM17 in neurobehavioral responses to chronic stress during adolescence.

Author: Sharafeddin F, Sierra J, Ghaly M, Simon TB, Ontiveros-Ángel P, Edelbach B, Febo M, Labus J, and Figueroa JD
Subjects: Animals, Male, Rats, Behavior, Animal physiology, Reflex, Startle physiology, Female, ADAM17 Protein metabolism, Prefrontal Cortex metabolism, Rats, Inbred Lew, Stress, Psychological physiopathology, Stress, Psychological metabolism
Abstract: Introduction: Chronic adolescent stress profoundly affects prefrontal cortical networks regulating top-down behavior control. However, the neurobiological pathways contributing to stress-induced alterations in the brain and behavior remain largely unknown. Chronic stress influences brain growth factors and immune responses, which may, in turn, disrupt the maturation and function of prefrontal cortical networks. The tumor necrosis factor alpha-converting enzyme/a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and inflammatory responses. This study aimed to determine the impact of stress on the prefrontal cortex and whether TACE/ADAM17 plays a role in these responses., Methods: We used a Lewis rat model that incorporates critical elements of chronic psychosocial stress, such as uncontrollability, unpredictability, lack of social support, and re-experiencing of trauma., Results: Chronic stress during adolescence reduced the acoustic startle reflex and social interactions while increasing extracellular free water content and TACE/ADAM17 mRNA levels in the medial prefrontal cortex. Chronic stress altered various ethological behavioral domains in the observation home cages (decreased ingestive behaviors and increased walking, grooming, and rearing behaviors). A group of rats was injected intracerebrally either with a novel Accell™ SMARTpool TACE/ADAM17 siRNA or a corresponding siRNA vehicle (control). The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Automated puncta quantification and analyses demonstrated that TACE/ADAM17 siRNA administration reduced TACE/ADAM17 mRNA levels in the medial prefrontal cortex (59% reduction relative to control). We found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited altered eating patterns (e.g., increased food intake and time in the feeding zone during the light cycle)., Conclusion: This study supports that the prefrontal cortex is sensitive to adolescent chronic stress and suggests that TACE/ADAM17 may be involved in the brain responses to stress., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)
Published: 2024
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43. Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease.

Author: Mullooly M, Fan S, Pfeiffer RM, Bowles EA, Duggan MA, Falk RT, Richert-Boe K, Glass AG, Kimes TM, Figueroa JD, Rohan TE, Abubakar M, and Gierach GL
Subjects: Female, Humans, Breast Density, Case-Control Studies, Risk Factors, Breast Neoplasms etiology, Breast Diseases complications
Abstract: Introduction: Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact future invasive breast cancer risk, but this has not been studied among women with BBD., Methods: We undertook a nested case-control study within a cohort of 15,395 women with BBD in Kaiser Permanente Northwest (KPNW; 1970-2012, followed through mid-2015). Cases (n = 261) developed invasive breast cancer > 1 year after BBD diagnosis, whereas controls (n = 249) did not have breast cancer by the case diagnosis date. Cases and controls were individually matched on BBD diagnosis age and plan membership duration. Standardized %MBD change (per 2 years), categorized as stable/any increase (≥ 0%), minimal decrease of less than 5% or a decrease greater than or equal to 5%, was determined from baseline and follow-up mammograms. Associations between MBD change and breast cancer risk were examined using adjusted unconditional logistic regression., Results: Overall, 64.5% (n = 329) of BBD patients had non-proliferative and 35.5% (n = 181) had proliferative disease with/without atypia. Women with an MBD decrease (≤ - 5%) were less likely to develop breast cancer (Odds Ratio (OR) 0.64; 95% Confidence Interval (CI) 0.38, 1.07) compared with women with minimal decreases. Associations were stronger among women ≥ 50 years at BBD diagnosis (OR 0.48; 95% CI 0.25, 0.92) and with proliferative BBD (OR 0.32; 95% CI 0.11, 0.99)., Discussion: Assessment of temporal MBD changes may inform risk monitoring among women with BBD, and strategies to actively reduce MBD may help decrease future breast cancer risk., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Published: 2024
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44. The enzymes of the oxidative phase of the pentose phosphate pathway as targets of reactive species: consequences for NADPH production.

Author: Fuentes-Lemus E, Reyes JS, Figueroa JD, Davies MJ, and López-Alarcón C
Subjects: NADP chemistry, NADP metabolism, Oxidation-Reduction, Oxidants, Pentose Phosphate Pathway physiology, Oxidative Stress
Abstract: The pentose phosphate pathway (PPP) is a key metabolic pathway. The oxidative phase of this process involves three reactions catalyzed by glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconolactonase (6PGL) and 6-phosphogluconate dehydrogenase (6PGDH) enzymes. The first and third steps (catalyzed by G6PDH and 6PGDH, respectively) are responsible for generating reduced nicotinamide adenine dinucleotide phosphate (NAPDH), a key cofactor for maintaining the reducing power of cells and detoxification of both endogenous and exogenous oxidants and electrophiles. Despite the importance of these enzymes, little attention has been paid to the fact that these proteins are targets of oxidants. In response to oxidative stimuli metabolic pathways are modulated, with the PPP often up-regulated in order to enhance or maintain the reductive capacity of cells. Under such circumstances, oxidation and inactivation of the PPP enzymes could be detrimental. Damage to the PPP enzymes may result in a downward spiral, as depending on the extent and sites of modification, these alterations may result in a loss of enzymatic activity and therefore increased oxidative damage due to NADPH depletion. In recent years, it has become evident that the three enzymes of the oxidative phase of the PPP have different susceptibilities to inactivation on exposure to different oxidants. In this review, we discuss existing knowledge on the role that these enzymes play in the metabolism of cells, and their susceptibility to oxidation and inactivation with special emphasis on NADPH production. Perspectives on achieving a better understanding of the molecular basis of the oxidation these enzymes within cellular environments are given., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
Published: 2023
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45. Mosquito control exposures and breast cancer risk: analysis of 1071 cases and 2096 controls from the Ghana Breast Health Study.

Author: Olivos N, Banta JE, Spencer-Hwang R, Ansong D, Beane Freeman LE, Clegg-Lamptey JN, Wiafe-Addai B, Edusei L, Adjei E, Titiloye N, Dedey F, Aitpillah F, Oppong J, Vanderpuye V, Osei-Bonsu E, Ahearn TU, Biritwum R, Yarney J, Awuah B, Nyarko K, Garcia-Closas M, Abubakar M, Brinton LA, Figueroa JD, and Wiafe S
Subjects: Animals, Humans, Female, Mosquito Control, Ghana epidemiology, Insecticides adverse effects, Breast Neoplasms epidemiology, Breast Neoplasms etiology, Breast Neoplasms prevention & control, Malaria prevention & control, Insect Repellents adverse effects
Abstract: Epidemiologic data on insecticide exposures and breast cancer risk are inconclusive and mostly from high-income countries. Using data from 1071 invasive pathologically confirmed breast cancer cases and 2096 controls from the Ghana Breast Health Study conducted from 2013 to 2015, we investigated associations with mosquito control products to reduce the spread of mosquito-borne diseases, such as malaria. These mosquito control products were insecticide-treated nets, mosquito coils, repellent room sprays, and skin creams for personal protection against mosquitos. Multivariable and polytomous logistic regression models were used to estimate odds ratios (OR adj ) and 95% confidence intervals (CI) with breast cancer risk-adjusted for potential confounders and known risk factors. Among controls, the reported use of mosquito control products were mosquito coils (65%), followed by insecticide-treated nets (56%), repellent room sprays (53%), and repellent skin creams (15%). Compared to a referent group of participants unexposed to mosquito control products, there was no significant association between breast cancer risk and mosquito coils. There was an association in breast cancer risk with reported use of insecticide-treated nets; however, that association was weak and not statistically significant. Participants who reported using repellent sprays were at elevated risks compared to women who did not use any mosquito control products, even after adjustment for all other mosquito control products (OR = 1.42, 95% CI=1.15-1.75). We had limited power to detect an association with repellent skin creams. Although only a few participants reported using repellent room sprays weekly/daily or < month-monthly, no trends were evident with increased frequency of use of repellent sprays, and there was no statistical evidence of heterogeneity by estrogen receptor (ER) status (p-het > 0.25). Our analysis was limited when determining if an association existed with repellent skin creams; therefore, we cannot conclude an association. We found limited evidence of risk associations with widely used mosquito coils and insecticide-treated nets, which are reassuring given their importance for malaria prevention. Our findings regarding specific breast cancer risk associations, specifically those observed between repellent sprays, require further study., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Published: 2023
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46. Antioxidant Capacity of Free and Peptide Tryptophan Residues Determined by the ORAC (Oxygen Radical Absorbance Capacity) Assay Is Modulated by Radical-Radical Reactions and Oxidation Products.

Author: Figueroa JD, Barroso-Torres N, Morales M, Herrera B, Aranda M, Dorta E, and López-Alarcón C
Abstract: The ORAC (Oxygen Radical Absorbance Capacity) assay is commonly employed for determining the antioxidant capacity of bioactive peptides. To gain insights into the meaning of this index for peptides containing a single Trp, we studied the consumption of this residue and fluorescein (FLH, the probe of ORAC method), induced by radicals generated by AAPH (2,2'-Azo-bis(2-amidinopropane) dihydrochloride) thermolysis. ORAC values were rationalized from kinetics and computational calculations of bond dissociation energies (BDE) of the N-H bond (indole ring of Trp). Free Trp, di- and tri- peptides, and three larger peptides were studied. Solutions containing 70 nM FLH, 1-5 μM free Trp or peptides, and 10 mM AAPH were incubated at 37 °C in phosphate buffer. Kinetic studies showed that FLH minimally affected Trp consumption. However, a clear protection of FLH, characterized by pseudo-lag times, was evidenced, reflecting radical-radical reactions and FLH repairing. Peptides showed similar ORAC values (~1.9-2.8 Trolox equivalents), while BDE varied between 91.9 and 103.5 kcal. These results, added to the protection of FLH observed after total consumption of Trp, indicate a lack of discrimination of the assay for the chemical structure of peptides and the contribution of oxidation products to the index.
Published: 2023
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47. Cardiovascular events and venous thromboembolism after primary malignant or non-malignant brain tumour diagnosis: a population matched cohort study in Wales (United Kingdom).

Author: Poon MTC, Brennan PM, Jin K, Sudlow CLM, and Figueroa JD
Subjects: Adult, Humans, Cohort Studies, Wales epidemiology, Risk Factors, United Kingdom epidemiology, Venous Thromboembolism diagnosis, Venous Thromboembolism epidemiology, Venous Thromboembolism etiology, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Cardiovascular Diseases etiology, Stroke complications, Brain Neoplasms diagnosis, Brain Neoplasms epidemiology
Abstract: Background: Elevated standardised mortality ratio of cardiovascular diseases (CVD) in patients with brain tumours may result from differences in the CVD incidences and cardiovascular risk factors. We compared the risk of CVD among patients with a primary malignant or non-malignant brain tumour to a matched general population cohort, accounting for other co-morbidities., Methods: Using data from the Secured Anonymised Information Linkage (SAIL) Databank in Wales (United Kingdom), we identified all adults aged ≥ 18 years in the primary care database with first diagnosis of malignant or non-malignant brain tumour identified in the cancer registry in 2000-2014 and a matched cohort (case-to-control ratio 1:5) by age, sex and primary care provider from the general population without any cancer diagnosis. Outcomes included fatal and non-fatal major vascular events (stroke, ischaemic heart disease, aortic and peripheral vascular diseases) and venous thromboembolism (VTE). We used multivariable Cox models adjusted for clinical risk factors to compare risks, stratified by tumour behaviour (malignant or non-malignant) and follow-up period., Results: There were 2869 and 3931 people diagnosed with malignant or non-malignant brain tumours, respectively, between 2000 and 2014 in Wales. They were matched to 33,785 controls. Within the first year of tumour diagnosis, malignant tumour was associated with a higher risk of VTE (hazard ratio [HR] 21.58, 95% confidence interval 16.12-28.88) and stroke (HR 3.32, 2.44-4.53). After the first year, the risks of VTE (HR 2.20, 1.52-3.18) and stroke (HR 1.45, 1.00-2.10) remained higher than controls. Patients with non-malignant tumours had higher risks of VTE (HR 3.72, 2.73-5.06), stroke (HR 4.06, 3.35-4.93) and aortic and peripheral arterial disease (HR 2.09, 1.26-3.48) within the first year of diagnosis compared with their controls., Conclusions: The elevated CVD and VTE risks suggested risk reduction may be a strategy to improve life quality and survival in people with a brain tumour., (© 2023. The Author(s).)
Published: 2023
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48. Population-specific Mutation Patterns in Breast Tumors from African American, European American, and Kenyan Patients.

Author: Tang W, Zhang F, Byun JS, Dorsey TH, Yfantis HG, Ajao A, Liu H, Pichardo MS, Pichardo CM, Harris AR, Yang XR, Figueroa JD, Sayed S, Makokha FW, and Ambs S
Subjects: Female, Humans, F-Box-WD Repeat-Containing Protein 7 genetics, Kenya, Mutation, United States, White genetics, Black People genetics, Asian genetics, Black or African American genetics, Breast Neoplasms genetics
Abstract: Women of African descent have the highest breast cancer mortality in the United States and are more likely than women from other population groups to develop an aggressive disease. It remains uncertain to what extent breast cancer in Africa is reminiscent of breast cancer in African American or European American patients. Here, we performed whole-exome sequencing of genomic DNA from 191 breast tumor and non-cancerous adjacent tissue pairs obtained from 97 African American, 69 European American, 2 Asian American, and 23 Kenyan patients. Our analysis of the sequencing data revealed an elevated tumor mutational burden in both Kenyan and African American patients, when compared with European American patients. TP53 mutations were most prevalent, particularly in African American patients, followed by PIK3CA mutations, which showed similar frequencies in European American, African American, and the Kenyan patients. Mutations targeting TBX3 were confined to European Americans and those targeting the FBXW7 tumor suppressor to African American patients whereas mutations in the ARID1A gene that are known to confer resistance to endocrine therapy were distinctively enriched among Kenyan patients. A Kyoto Encyclopedia of Genes and Genomes pathway analysis could link FBXW7 mutations to an increased mitochondrial oxidative phosphorylation capacity in tumors carrying these mutations. Finally, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures in tumors correlated with the occurrence of driver mutations, immune cell profiles, and neighborhood deprivation with associations ranging from being mostly modest to occasionally robust. To conclude, we found mutational profiles that were different between these patient groups. The differences concentrated among genes with low mutation frequencies in breast cancer., Significance: The study describes differences in tumor mutational profiles between African American, European American, and Kenyan breast cancer patients. It also investigates how these profiles may relate to the tumor immune environment and the neighborhood environment in which the patients had residence. Finally, it describes an overrepresentation of ARID1A gene mutations in breast tumors of the Kenyan patients., (© 2023 The Authors; Published by the American Association for Cancer Research.)
Published: 2023
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49. Evaluation of the association of area-level socioeconomic deprivation and breast cancer recurrence by oestrogen receptor subtypes in Scotland.

Author: Dunlop HM, Williams LJ, Hall PS, Barber M, Dodds C, and Figueroa JD
Subjects: Humans, Female, Receptors, Estrogen, Mastectomy, Breast pathology, Socioeconomic Factors, Breast Neoplasms pathology
Abstract: Background: Women from socioeconomically deprived areas have lower breast cancer (BC) incidence rates for screen-detected oestrogen receptor (ER) + tumours and higher mortality for select tumour subtypes. We aimed to determine if ipsilateral breast cancer recurrence (IBR) differs by Scottish Index of Multiple Deprivation (SIMD) quintile and tumour subtype in Scotland., Methods: Patient data for primary invasive BC diagnosed in 2007-2008 in Scotland was analysed. Manual case-note review for 3495 patients from 10 years post-diagnosis was used. To determine the probability of IBR while accounting for the competing risk of death from any cause, cumulative incidence functions stratified by ER subtype and surgery were plotted. Multivariable Cox Proportional Hazards models were used to estimate the association of SIMD accounting for other predictors of IBR., Results: Among 2819 ER + tumours, 423 patients had a recurrence and 438 died. SIMD was related to death (p = 0.018) with the most deprived more likely to have died in the 10-year period (17.7% vs. 12.9%). We found no significant differences by SIMD in prognostic tumour characteristics (grade, TNM stage, treatment, screen-detection) or risk of IBR. Among 676 patients diagnosed with ER- tumours, 105 died and 185 had a recurrence. We found no significant differences in prognostic tumour characteristics by SIMD except screen detection with the most deprived more likely than the least to have their tumours detected from screening (46.9% vs. 28%, p = 0.03). Among patients with ER- tumours, 50% had mastectomy and the most deprived had increased 5-year IBR risk compared to the least deprived (HR 3.03 [1.41-6.53])., Conclusions: IBR is not a major contributor to mortality differences by SIMD for the majority of BC patients in our study. The lack of inequities in IBR are likely due to standardised treatment protocols and access to healthcare. The association with socioeconomic deprivation and recurrence for ER- tumours requires further study., (© 2023. BioMed Central Ltd., part of Springer Nature.)
Published: 2023
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50. Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.

Author: Wichert K, Hoppe R, Ickstadt K, Behrens T, Winter S, Herold R, Terschüren C, Lo WY, Guénel P, Truong T, Bolla MK, Wang Q, Dennis J, Michailidou K, Lush M, Andrulis IL, Brenner H, Chang-Claude J, Cox A, Cross SS, Czene K, Eriksson M, Figueroa JD, García-Closas M, Goldberg MS, Hamann U, He W, Holleczek B, Hopper JL, Jakubowska A, Ko YD, Lubiński J, Mulligan AM, Obi N, Rhenius V, Shah M, Shu XO, Simard J, Southey MC, Zheng W, Dunning AM, Pharoah PDP, Hall P, Easton DF, Brüning T, Brauch H, Harth V, and Rabstein S
Subjects: Humans, Female, Bayes Theorem, Polymorphism, Single Nucleotide, Logistic Models, Case-Control Studies, Genetic Predisposition to Disease, Breast Neoplasms genetics, Breast Neoplasms epidemiology, Melatonin genetics, Melatonin metabolism
Abstract: Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483 R ∧ rs1473473 D ∧ rs3729931 D : OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation., (© 2023. The Author(s).)
Published: 2023
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