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Your search keyword '"Abu-Ful Z."' showing total 17 results
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17 results on '"Abu-Ful Z."'

1. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author

Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Bien, S, Diez-Obrero, V, Li, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Harris, S, Svinti, V, McDonnell, K, Farrington, S, Studd, J, Vaughan-Shaw, P, Shu, X-O, Long, J, Cai, Q, Guo, X, Lu, Y, Scacheri, P, Huyghe, J, Harrison, T, Shibata, D, Haiman, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obon-Santacana, M, Martin-Sanchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, S-S, Shin, M-H, Shin, A, Ahn, Y-O, Kim, D-H, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, Y-T, Jia, W-H, Potter, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Boehm, J, Mecklin, L-P, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hanninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Mannisto, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellvi-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, Y-R, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, H-J, White, E, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Joshi, A, Schafmayer, C, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Toland, A, Markowitz, S, Kim, A, Gruber, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bezieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Le Marchand, L, Wu, A, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R, Peters, U, Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Bien, S, Diez-Obrero, V, Li, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Harris, S, Svinti, V, McDonnell, K, Farrington, S, Studd, J, Vaughan-Shaw, P, Shu, X-O, Long, J, Cai, Q, Guo, X, Lu, Y, Scacheri, P, Huyghe, J, Harrison, T, Shibata, D, Haiman, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obon-Santacana, M, Martin-Sanchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, S-S, Shin, M-H, Shin, A, Ahn, Y-O, Kim, D-H, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, Y-T, Jia, W-H, Potter, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Boehm, J, Mecklin, L-P, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hanninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Mannisto, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellvi-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, Y-R, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, H-J, White, E, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Joshi, A, Schafmayer, C, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Toland, A, Markowitz, S, Kim, A, Gruber, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bezieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Le Marchand, L, Wu, A, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R, and Peters, U

Abstract

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Published
2023

2. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author

Mueller, SH, Lai, AG, Valkovskaya, M, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Abu-Ful, Z, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baert, T, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Brucker, SY, Buys, SS, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Chung, WK, Colonna, S, Cornelissen, S, Couch, FJ, Czene, K, Daly, MB, Devilee, P, Dork, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Gago-Dominguez, M, Gao, Y-T, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Gentry-Maharaj, A, Grassmann, F, Guenel, P, Gundert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Harkness, EF, Harrington, PA, Hartikainen, JM, Hartman, M, Hein, A, Ho, W-K, Hooning, MJ, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Huo, D, Investigators, A, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kang, D, Khusnutdinova, EK, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Mannermaa, A, Manoochehri, M, Margolin, S, Matsuo, K, Mavroudis, D, Menon, U, Muir, K, Murphy, RA, Nevanlinna, H, Newman, WG, Niederacher, D, O'Brien, KM, Obi, N, Offit, K, Olopade, O, Olshan, AF, Olsson, H, Park, SK, Patel, A, Perou, CM, Peto, J, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Ramachandran, D, Rashid, MU, Rennert, G, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneider, MO, Scott, C, Shah, M, Sharma, P, Shen, C-Y, Shu, X-O, Simard, J, Surowy, H, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Vachon, CM, Vijai, J, Weinberg, CR, Wendt, C, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Yang, XR, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Easton, DF, Hemingway, H, Hamann, U, Kuchenbaecker, KB, Mueller, SH, Lai, AG, Valkovskaya, M, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Abu-Ful, Z, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baert, T, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Brucker, SY, Buys, SS, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Chung, WK, Colonna, S, Cornelissen, S, Couch, FJ, Czene, K, Daly, MB, Devilee, P, Dork, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Gago-Dominguez, M, Gao, Y-T, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Gentry-Maharaj, A, Grassmann, F, Guenel, P, Gundert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Harkness, EF, Harrington, PA, Hartikainen, JM, Hartman, M, Hein, A, Ho, W-K, Hooning, MJ, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Huo, D, Investigators, A, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kang, D, Khusnutdinova, EK, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Mannermaa, A, Manoochehri, M, Margolin, S, Matsuo, K, Mavroudis, D, Menon, U, Muir, K, Murphy, RA, Nevanlinna, H, Newman, WG, Niederacher, D, O'Brien, KM, Obi, N, Offit, K, Olopade, O, Olshan, AF, Olsson, H, Park, SK, Patel, A, Perou, CM, Peto, J, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Ramachandran, D, Rashid, MU, Rennert, G, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneider, MO, Scott, C, Shah, M, Sharma, P, Shen, C-Y, Shu, X-O, Simard, J, Surowy, H, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Vachon, CM, Vijai, J, Weinberg, CR, Wendt, C, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Yang, XR, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Easton, DF, Hemingway, H, Hamann, U, and Kuchenbaecker, KB

Abstract

BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.

Published
2023

3. Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk

Author

Kramer, I., Hooning, M.J., Mavaddat, N., Hauptmann, M., Keeman, R., Steyerberg, E.W., Giardiello, D., Antoniou, A.C., Pharoah, P.D.P., Canisius, S., Abu-Ful, Z., Andrulis, I.L., Anton-Culver, H., Aronson, K.J., Augustinsson, A., Becher, H., Beckmann, M.W., Behrens, S., Benitez, J., Bermisheva, M., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Bonanni, B., Brauch, H., Bremer, M., Brucker, S.Y., Burwinkel, B., Castelao, J.E., Chan, T.L., Chang-Claude, J., Chanock, S.J., Chenevix-Trench, G., Choi, J.Y., Clarke, C.L., Collee, J.M., Couch, F.J., Cox, A., Cross, S.S., Czene, K., Daly, M.B., Devilee, P., Dork, T., dos-Santos-Silva, I., Dunning, A.M., Dwek, M., Eccles, D.M., Evans, D.G., Fasching, P.A., Flyger, H., Gago-Dominguez, M., Garcia-Closas, M., Garcia-Saenz, J.A., Giles, G.G., Goldgar, D.E., Gonzalez-Neira, A., Haiman, C.A., Hakansson, N., Hamann, U., Hartman, M., Heemskerk-Gerritsen, B.A.M., Hollestelle, A., Hopper, J.L., Hou, M.F., Howell, A., Ito, H., Jakimovska, M., Jakubowska, A., Janni, W., John, E.M., Jung, A., Kang, D., Kets, C.M., Khusnutdinova, E., Ko, Y.D., Kristensen, V.N., Kurian, A.W., Kwong, A., Lambrechts, D., Marchand, L. le, Li, J.M., Lindblom, A., Mannermaa, A., Manoochehri, M., Margolin, S., Matsuo, K., Mavroudis, D., Meindl, A., Milne, R.L., Mulligan, A.M., Muranen, T.A., Neuhausen, S.L., Nevanlinna, H., Newman, W.G., Olshan, A.F., Olson, J.E., Olsson, H., Park-Simon, T.W., Peto, J., Petridis, C., Plaseska-Karanfilska, D., Presneau, N., Pylkas, K., Radice, P., Rennert, G., Romero, A., Roylance, R., Saloustros, E., Sawyer, E.J., Schmutzler, R.K., Schwentner, L., Scott, C., See, M.H., Shah, M., Shen, C.Y., Shu, X.O., Siesling, S., Slager, S., Sohn, C., Southey, M.C., Spinelli, J.J., Stone, J., Tapper, W.J., Tengstrom, M., Teo, S.H., Terry, M.B., Tollenaar, R.A.E.M., Tomlinson, I., Troester, M.A., Vachon, C.M., Ongeval, C. van, Veen, E.M. van, Winqvist, R., Wolk, A., Zheng, W., Ziogas, A., Easton, D.F., Hall, P., Schmidt, M.K., NBCS Collaborators, ABCTB Investigators, and kConFab Investigators

Subjects
parasitic diseases
Abstract

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

Published
2020

4. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author

Zhan, H.Y., Ahearn, T.U., Lecarpentier, J., Barnes, D., Beesley, J., Qi, G.H., Jiang, X., O'Mara, T.A., Zhao, N., Bolla, M.K., Dunning, A.M., Dennis, J., Wang, Q., Abu Ful, Z., Aittomaki, K., Andrulis, I.L., Anton-Culver, H., Arndt, V., Aronson, K.J., Arun, B.K., Auer, P.L., Azzollini, J., Barrowdale, D., Becher, H., Beckmann, M.W., Behrens, S., Benitez, J., Bermisheva, M., Bialkowska, K., Blanco, A., Blomqvist, C., Bogdanova, N.V., Bojesen, S.E., Bonanni, B., Bondavalli, D., Borg, A., Brauch, H., Brenner, H., Briceno, I., Broeks, A., Brucker, S.Y., Bruning, T., Burwinkel, B., Buys, S.S., Byers, H., Caldes, T., Caligo, M.A., Calvello, M., Campa, D., Castelao, J.E., Chang-Claude, J., Chanock, S.J., Christiaens, M., Christiansen, H., Chung, W.K., Claes, K.B.M., Clarke, C.L., Cornelissen, S., Couch, F.J., Cox, A., Cross, S.S., Czene, K., Daly, M.B., Devilee, P., Diez, O., Domchek, S.M., Dork, T., Dwek, M., Eccles, D.M., Ekici, A.B., Evans, D.G., Fasching, P.A., Figueroa, J., Foretova, L., Fostira, F., Friedman, E., Frost, D., Gago-Dominguez, M., Gapstur, S.M., Garber, J., Garcia-Saenz, J.A., Gaudet, M.M., Gayther, S.A., Giles, G.G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., Gonzalez-Neira, A., Greene, M.H., Gronwald, J., Guenel, P., Haberle, L., Hahnen, E., Haiman, C.A., Hake, C.R., Hall, P., Hamann, U., Harkness, E.F., Heemskerk-Gerritsen, B.A.M., Hillemanns, P., Hogervorst, F.B.L., Holleczek, B., Hollestelle, A., Hooning, M.J., Hoover, R.N., Hopper, J.L., Howell, A., Huebner, H., Hulick, P.J., Imyanitov, E.N., Isaacs, C., Izatt, L., Jager, A., Jakimovska, M., Jakubowska, A., James, P., Janavicius, R., Janni, W., John, E.M., Jones, M.E., Jung, A., Kaaks, R., Kapoor, P.M., Karlan, B.Y., Keeman, R., Khan, S., Khusnutdinova, E., Kitahara, C.M., Ko, Y.D., Konstantopoulou, I., Koppert, L.B., Koutros, S., Kristensen, V.N., Laenkholm, A.V., Lambrechts, D., Larsson, S.C., Laurent-Puig, P., Lazaro, C., Lazarova, E., Lejbkowicz, F., Leslie, G., Lesueur, F., Lindblom, A., Lissowska, J., W.Y. lo, Loud, J.T., Lubinski, J., Lukomska, A., MacInnis, R.J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Matricardi, L., McGuffog, L., McLean, C., Mebirouk, N., Meindl, A., Menon, U., Miller, A., Mingazheva, E., Montagna, M., Mulligan, A.M., Mulot, C., Muranen, T.A., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Neven, P., Newman, W.G., Nielsens, F.C., Nikitina-Zake, L., Nodora, J., Offit, K., Olah, E., Olopade, O.I., Olsson, H., Orr, N., Papi, L., Papp, J., Park-Simon, T.W., Parsons, M.T., Peissel, B., Peixoto, A., Peshkin, B., Peterlongo, P., Peto, J., Phillips, K.A., Piedmonte, M., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Prokofyeva, D., Rack, B., Radice, P., Ramus, S.J., Rantala, J., Rashid, M.U., Rennert, G., Rennert, H.S., Risch, H.A., Romero, A., Rookus, M.A., Rubner, M., Rudiger, T., Saloustros, E., Sampson, S., Sandler, D.P., Sawyer, E.J., Scheuner, M.T., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schottker, B., Schurmann, P., Senter, L., Sharma, P., Sherman, M.E., Shu, X.O., Singer, C.F., Smichkoska, S., Soucy, P., Southey, M.C., Spinelli, J.J., Stone, J., Stoppa-Lyonnet, D., Swerdlow, A.J., Szabo, C.I., Tamimi, R.M., Tapper, W.J., Taylor, J.A., Teixeira, M.R., Terry, M., Thomassen, M., Thull, D.L., Tischkowitz, M., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Troester, M.A., Truong, T., Tung, N., Untch, M., Vachon, C.M., Ouweland, A.M.W. van den, Kolk, L.E. van der, Veen, E.M. van, vanRensburg, E.J., Vega, A., Wappenschmidt, B., Weinberg, C.R., Weitzel, J.N., Wildiers, H., Winqvist, R., Wolk, A., Yang, X.H.R., Yannoukakos, D., Zheng, W., Zorn, K.K., Milne, R.L., Kraft, P., Simard, J., Pharoah, P.D.P., Michailidou, K., Antoniou, A.C., Schmidt, M.K., Chenevix-Trench, G., Easton, D.F., Chatterjee, N., Garcia-Closas, M., kConFab Investigators, ABCTB Investigators, EMBRACE Study, and GEMO Study Collaborators

Abstract

Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade.Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Published
2020

5. Combined Associations of a Polygenic Risk Score and Classical Risk Factors with Breast Cancer Risk.

Author

Kapoor P.M., Mavaddat N., Choudhury P.P., Wilcox A.N., Lindstrom S., Behrens S., Michailidou K., Dennis J., Bolla M.K., Wang Q., Jung A., Abu-Ful Z., Ahearn T., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Auer P.L., Freeman L.E.B., Becher H., Beckmann M.W., Beeghly-Fadiel A., Benitez J., Bernstein L., Bojesen S.E., Brauch H., Brenner H., Bruning T., Cai Q., Campa D., Canzian F., Carracedo A., Carter B.D., Castelao J.E., Chanock S.J., Chatterjee N., Chenevix-Trench G., Clarke C.L., Couch F.J., Cox A., Cross S.S., Czene K., Dai J.Y., Earp H.S., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Figueroa J., Fritschi L., Gabrielson M., Gago-Dominguez M., Gao C., Gapstur S.M., Gaudet M.M., Giles G.G., Gonzalez-Neira A., Guenel P., Haeberle L., Haiman C.A., Hakansson N., Hall P., Hamann U., Hatse S., Heyworth J., Holleczek B., Hoover R.N., Hopper J.L., Howell A., Hunter D.J., John E.M., Jones M.E., Kaaks R., Keeman R., Kitahara C.M., Ko Y.-D., Koutros S., Kurian A.W., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Linet M., Lissowska J., Llaneza A., Macinnis R.J., Martinez M.E., Maurer T., Mclean C., Neuhausen S.L., Newman W.G., Norman A., O'brien K.M., Olshan A.F., Olson J.E., Olsson H., Orr N., Perou C.M., Pita G., Polley E.C., Prentice R.L., Rennert G., Rennert H.S., Ruddy K.J., Sandler D.P., Saunders C., Schoemaker M.J., Schottker B., Schumacher F., Scott C., Scott R.J., Shu X.-O., Smeets A., Southey M.C., Spinelli J.J., Stone J., Swerdlow A.J., Tamimi R.M., Taylor J.A., Troester M.A., Vachon C.M., Van Veen E.M., Wang X., Weinberg C.R., Weltens C., Willett W., Winham S.J., Wolk A., Yang X.R., Zheng W., Ziogas A., Dunning A.M., Pharoah P.D.P., Schmidt M.K., Kraft P., Easton D.F., Milne R.L., Garcia-Closas M., Chang-Claude J., Kapoor P.M., Mavaddat N., Choudhury P.P., Wilcox A.N., Lindstrom S., Behrens S., Michailidou K., Dennis J., Bolla M.K., Wang Q., Jung A., Abu-Ful Z., Ahearn T., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Auer P.L., Freeman L.E.B., Becher H., Beckmann M.W., Beeghly-Fadiel A., Benitez J., Bernstein L., Bojesen S.E., Brauch H., Brenner H., Bruning T., Cai Q., Campa D., Canzian F., Carracedo A., Carter B.D., Castelao J.E., Chanock S.J., Chatterjee N., Chenevix-Trench G., Clarke C.L., Couch F.J., Cox A., Cross S.S., Czene K., Dai J.Y., Earp H.S., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Figueroa J., Fritschi L., Gabrielson M., Gago-Dominguez M., Gao C., Gapstur S.M., Gaudet M.M., Giles G.G., Gonzalez-Neira A., Guenel P., Haeberle L., Haiman C.A., Hakansson N., Hall P., Hamann U., Hatse S., Heyworth J., Holleczek B., Hoover R.N., Hopper J.L., Howell A., Hunter D.J., John E.M., Jones M.E., Kaaks R., Keeman R., Kitahara C.M., Ko Y.-D., Koutros S., Kurian A.W., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Linet M., Lissowska J., Llaneza A., Macinnis R.J., Martinez M.E., Maurer T., Mclean C., Neuhausen S.L., Newman W.G., Norman A., O'brien K.M., Olshan A.F., Olson J.E., Olsson H., Orr N., Perou C.M., Pita G., Polley E.C., Prentice R.L., Rennert G., Rennert H.S., Ruddy K.J., Sandler D.P., Saunders C., Schoemaker M.J., Schottker B., Schumacher F., Scott C., Scott R.J., Shu X.-O., Smeets A., Southey M.C., Spinelli J.J., Stone J., Swerdlow A.J., Tamimi R.M., Taylor J.A., Troester M.A., Vachon C.M., Van Veen E.M., Wang X., Weinberg C.R., Weltens C., Willett W., Winham S.J., Wolk A., Yang X.R., Zheng W., Ziogas A., Dunning A.M., Pharoah P.D.P., Schmidt M.K., Kraft P., Easton D.F., Milne R.L., Garcia-Closas M., and Chang-Claude J.

Abstract

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer. Copyright © 2020 The Author(s).

Published
2021

6. Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk

Author

Kapoor, PM, Mavaddat, N, Choudhury, PP, Wilcox, AN, Lindstrom, S, Behrens, S, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Jung, A, Abu-Ful, Z, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Freeman, LEB, Becher, H, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bojesen, SE, Brauch, H, Brenner, H, Bruening, T, Cai, Q, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chanock, SJ, Chatterjee, N, Chenevix-Trench, G, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Earp, HS, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Gaudet, MM, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hatse, S, Heyworth, J, Holleczek, B, Hoover, RN, Hopper, JL, Howell, A, Hunter, DJ, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, MacInnis, RJ, Martinez, ME, Maurer, T, McLean, C, Neuhausen, SL, Newman, WG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pita, G, Polley, EC, Prentice, RL, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Saunders, C, Schoemaker, MJ, Schoettker, B, Schumacher, F, Scott, C, Scott, RJ, Shu, X-O, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Troester, MA, Vachon, CM, van Veen, EM, Wang, X, Weinberg, CR, Weltens, C, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, Easton, DF, Milne, RL, Garcia-Closas, M, Chang-Claude, J, Kapoor, PM, Mavaddat, N, Choudhury, PP, Wilcox, AN, Lindstrom, S, Behrens, S, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Jung, A, Abu-Ful, Z, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Freeman, LEB, Becher, H, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bojesen, SE, Brauch, H, Brenner, H, Bruening, T, Cai, Q, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chanock, SJ, Chatterjee, N, Chenevix-Trench, G, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Earp, HS, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Gaudet, MM, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hatse, S, Heyworth, J, Holleczek, B, Hoover, RN, Hopper, JL, Howell, A, Hunter, DJ, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, MacInnis, RJ, Martinez, ME, Maurer, T, McLean, C, Neuhausen, SL, Newman, WG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pita, G, Polley, EC, Prentice, RL, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Saunders, C, Schoemaker, MJ, Schoettker, B, Schumacher, F, Scott, C, Scott, RJ, Shu, X-O, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Troester, MA, Vachon, CM, van Veen, EM, Wang, X, Weinberg, CR, Weltens, C, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, Easton, DF, Milne, RL, Garcia-Closas, M, and Chang-Claude, J

Abstract

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Published
2021

7. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author

Zhang, H. (Haoyu), Ahearn, T. U. (Thomas U.), Lecarpentier, J. (Julie), Barnes, D. (Daniel), Beesley, J. (Jonathan), Qi, G. (Guanghao), Hang, X. (Xia), O'Mara, T. A. (Tracy A.), Zhao, N. (Ni), Bolla, M. K. (Manjeet K.), Dunning, A. M. (Alison M.), Dennis, J. (Joe), Wang, Q. (Qin), Abu Ful, Z. (Zumuruda), Aittomaki, K. (Kristiina), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Auer, P. L. (Paul L.), Azzollini, J. (Jacopo), Barrowdale, D. (Daniel), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bialkowska, K. (Katarzyna), Blanco, A. (Ana), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Bondavalli, D. (Davide), Borg, A. (Ake), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Briceno, I. (Ignacio), Broeks, A. (Annegien), Brucker, S. Y. (Sara Y.), Bruening, T. (Thomas), Burwinkel, B. (Barbara), Buys, S. S. (Saundra S.), Byers, H. (Helen), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Calvello, M. (Mariarosaria), Campa, D. (Daniele), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Christiaens, M. (Melissa), Christiansen, H. (Hans), Chung, W. K. (Wendy K.), Claes, K. B. (Kathleen B. M.), Clarke, C. L. (Christine L.), Cornelissen, S. (Sten), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Diez, O. (Orland), Domchek, S. M. (Susan M.), Doerk, T. (Thilo), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Foretova, L. (Lenka), Fostira, F. (Florentia), Friedman, E. (Eitan), Frost, D. (Debra), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garber, J. (Judy), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Gayther, S. A. (Simon A.), Giles, G. G. (Graham G.), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Greene, M. H. (Mark H.), Gronwald, J. (Jacek), Guenel, P. (Pascal), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hake, C. R. (Christopher R.), Hall, P. (Per), Hamann, U. (Ute), Harkness, E. F. (Elaine F.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Hillemanns, P. (Peter), Hogervorst, F. B. (Frans B. L.), Holleczek, B. (Bernd), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Huebner, H. (Hanna), Hulick, P. J. (Peter J.), Imyanitov, E. N. (Evgeny N.), Isaacs, C. (Claudine), Izatt, L. (Louise), Jager, A. (Agnes), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, P. (Paul), Janavicius, R. (Ramunas), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kapoor, P. M. (Pooja Middha), Karlan, B. Y. (Beth Y.), Keeman, R. (Renske), Khan, S. (Sofia), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Ko, Y.-D. (Yon-Dschun), Konstantopoulou, I. (Irene), Koppert, L. B. (Linetta B.), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Laenkholm, A.-V. (Anne-Vibeke), Lambrechts, D. (Diether), Larsson, S. C. (Susanna C.), Laurent-Puig, P. (Pierre), Lazaro, C. (Conxi), Lazarova, E. (Emilija), Lejbkowicz, F. (Flavio), Leslie, G. (Goska), Lesueur, F. (Fabienne), Lindblom, A. (Annika), Lissowska, J. (Jolanta), Lo, W.-Y. (Wing-Yee), Loud, J. T. (Jennifer T.), Lubinski, J. (Jan), Lukomska, A. (Alicja), Maclnnis, R. J. (Robert J.), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martinez, M. E. (Maria Elena), Matricardi, L. (Laura), McGuffog, L. (Lesley), McLean, C. (Catriona), Mebirouk, N. (Noura), Meindl, A. (Alfons), Menon, U. (Usha), Miller, A. (Austin), Mingazheva, E. (Elvira), Montagna, M. (Marco), Mulligan, A. M. (Anna Marie), Mulot, C. (Claire), Muranen, T. A. (Taru A.), Nathanson, K. L. (Katherine L.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Neven, P. (Patrick), Newman, W. G. (William G.), Nielsens, F. C. (Finn C.), Nikitina-Zake, L. (Liene), Nodora, J. (Jesse), Offit, K. (Kenneth), Olah, E. (Edith), Olopade, O. I. (Olufunmilayo, I), Olsson, H. (Hakan), Orr, N. (Nick), Papi, L. (Laura), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. T. (Michael T.), Peissel, B. (Bernard), Peixoto, A. (Ana), Peshkin, B. (Beth), Peterlongo, P. (Paolo), Peto, J. (Julian), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Plaseska-Karanfilska, D. (Dijana), Prajzendanc, K. (Karolina), Prentice, R. (Ross), Prokofyeva, D. (Darya), Rack, B. (Brigitte), Radice, P. (Paolo), Ramus, S. J. (Susan J.), Rantala, J. (Johanna), Rashid, M. U. (Muhammad U.), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Risch, H. A. (Harvey A.), Romero, A. (Atocha), Rookus, M. A. (Matti A.), Ruebner, M. (Matthias), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sampson, S. (Sarah), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Scheuner, M. T. (Maren T.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Schoettker, B. (Ben), Schuermann, P. (Peter), Senter, L. (Leigha), Sharma, P. (Priyanka), Sherman, M. E. (Mark E.), Shu, X.-O. (Xiao-Ou), Singer, C. F. (Christian F.), Smichkoska, S. (Snezhana), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Stone, J. (Jennifer), Stoppa-Lyonnet, D. (Dominique), Swerdlow, A. J. (Anthony J.), Szabo, C. I. (Csilla, I), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teixeira, M. R. (Manuel R.), Terry, M. (MaryBeth), Thomassen, M. (Mads), Thull, D. L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Torres, D. (Diana), Troester, M. A. (Melissa A.), Truong, T. (Therese), Tung, N. (Nadine), Untch, M. (Michael), Vachon, C. M. (Celine M.), van den Ouweland, A. M. (Ans M. W.), van der Kolk, L. E. (Lizet E.), van Veen, E. M. (Elke M.), vanRensburg, E. J. (Elizabeth J.), Vega, A. (Ana), Wappenschmidt, B. (Barbara), Weinberg, C. R. (Clarice R.), Weitzel, J. N. (Jeffrey N.), Wildiers, H. (Hans), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Zheng, W. (Wei), Zorn, K. K. (Kristin K.), Milne, R. L. (Roger L.), Kraft, P. (Peter), Simard, J. (Jacques), Pharoah, P. D. (Paul D. P.), Michailidou, K. (Kyriaki), Antoniou, A. C. (Antonis C.), Schmidt, M. K. (Marjanka K.), Chenevix-Trench, G. (Georgia), Easton, D. F. (Douglas F.), Chatterjee, N. (Nilanjan), and Garcia-Closas, M. (Montserrat)

Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P

Published
2020

8. Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Author

Heemskerk-Gerritsen B.A.M., Ito H., Jakimovska M., Jakubowska A., Janni W., John E.M., Jung A., Kang D., Kets C.M., Khusnutdinova E., Ko Y.-D., Kristensen V.N., Kurian A.W., Kwong A., Lambrechts D., Le Marchand L., Li J., Lindblom A., Lubinski J., Mannermaa A., Manoochehri M., Margolin S., Matsuo K., Mavroudis D., Meindl A., Milne R.L., Mulligan A.M., Muranen T.A., Neuhausen S.L., Nevanlinna H., Newman W.G., Olshan A.F., Olson J.E., Olsson H., Park-Simon T.-W., Peto J., Petridis C., Plaseska-Karanfilska D., Presneau N., Pylkas K., Radice P., Rennert G., Romero A., Roylance R., Saloustros E., Sawyer E.J., Schmutzler R.K., Schwentner L., Scott C., See M.-H., Shah M., Shen C.-Y., Shu X.-O., Siesling S., Slager S., Sohn C., Spinelli J.J., Stone J., Tapper W.J., Tengstrom M., Teo S.H., Terry M.B., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Vachon C.M., van Ongeval C., van Veen E.M., Winqvist R., Wolk A., Zheng W., Ziogas A., Easton D.F., Hall P., Schmidt M.K., Kramer I., Hooning M.J., Mavaddat N., Hauptmann M., Keeman R., Steyerberg E.W., Giardiello D., Antoniou A.C., Pharoah P.D.P., Canisius S., Abu-Ful Z., Andrulis I.L., Anton-Culver H., Aronson K.J., Augustinsson A., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Brauch H., Bremer M., Brucker S.Y., Burwinkel B., Castelao J.E., Chan T.L., Chang-Claude J., Chanock S.J., Chenevix-Trench G., Choi J.-Y., Clarke C.L., Borresen-Dale A.-L., Sahlberg K., Ottestad L., Karesen R., Schlichting E., Holmen M.M., Sauer T., Haakensen V., Engebraten O., Naume B., Fossa A., Kiserud C., Reinertsen K., Helland A., Riis M., Geisler J., Alnaes G.G., Collee J.M., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Evans D.G., Fasching P.A., Flyger H., Gago-Dominguez M., Garcia-Closas M., Garcia-Saenz J.A., Giles G.G., Goldgar D.E., Gonzalez-Neira A., Haiman C.A., Hakansson N., Hamann U., Hartman M., Hollestelle A., Hopper J.L., Hou M.-F., Howell A., Clarke C., Marsh D., Scott R., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Simpson P., Graham J.D., Sachchithananthan M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Bennett I., Bogwitz M., Botes L., Brennan M., Brown M., Buckley M., Burke J., Butow P., Caldon L., Campbell I., Chauhan D., Chauhan M., Christian A., Cohen P., Colley A., Crook A., Cui J., Cummings M., Dawson S.-J., deFazio A., Delatycki M., Dickson R., Dixon J., Edkins T., Edwards S., Farshid G., Fellows A., Fenton G., Field M., Flanagan J., Fong P., Forrest L., Fox S., French J., Friedlander M., Gaff C., Gattas M., George P., Greening S., Harris M., Hart S., Hayward N., Hopper J., Hoskins C., Hunt C., James P., Jenkins M., Kidd A., Kirk J., Koehler J., Kollias J., Lakhani S., Lawrence M., Lindeman G., Lipton L., Lobb L., Mann G., McLachlan S.A., Meiser B., Nightingale S., O'Connell S., O'Sullivan S., Ortega D.G., Pachter N., Patterson B., Pearn A., Phillips K., Pieper E., Rickard E., Robinson B., Saleh M., Salisbury E., Saunders C., Saunus J., Sexton A., Shelling A., Southey M.C., Spurdle A., Taylor J., Taylor R., Thorne H., Trainer A., Tucker K., Visvader J., Walker L., Williams R., Winship I., Young M.A., Heemskerk-Gerritsen B.A.M., Ito H., Jakimovska M., Jakubowska A., Janni W., John E.M., Jung A., Kang D., Kets C.M., Khusnutdinova E., Ko Y.-D., Kristensen V.N., Kurian A.W., Kwong A., Lambrechts D., Le Marchand L., Li J., Lindblom A., Lubinski J., Mannermaa A., Manoochehri M., Margolin S., Matsuo K., Mavroudis D., Meindl A., Milne R.L., Mulligan A.M., Muranen T.A., Neuhausen S.L., Nevanlinna H., Newman W.G., Olshan A.F., Olson J.E., Olsson H., Park-Simon T.-W., Peto J., Petridis C., Plaseska-Karanfilska D., Presneau N., Pylkas K., Radice P., Rennert G., Romero A., Roylance R., Saloustros E., Sawyer E.J., Schmutzler R.K., Schwentner L., Scott C., See M.-H., Shah M., Shen C.-Y., Shu X.-O., Siesling S., Slager S., Sohn C., Spinelli J.J., Stone J., Tapper W.J., Tengstrom M., Teo S.H., Terry M.B., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Vachon C.M., van Ongeval C., van Veen E.M., Winqvist R., Wolk A., Zheng W., Ziogas A., Easton D.F., Hall P., Schmidt M.K., Kramer I., Hooning M.J., Mavaddat N., Hauptmann M., Keeman R., Steyerberg E.W., Giardiello D., Antoniou A.C., Pharoah P.D.P., Canisius S., Abu-Ful Z., Andrulis I.L., Anton-Culver H., Aronson K.J., Augustinsson A., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Brauch H., Bremer M., Brucker S.Y., Burwinkel B., Castelao J.E., Chan T.L., Chang-Claude J., Chanock S.J., Chenevix-Trench G., Choi J.-Y., Clarke C.L., Borresen-Dale A.-L., Sahlberg K., Ottestad L., Karesen R., Schlichting E., Holmen M.M., Sauer T., Haakensen V., Engebraten O., Naume B., Fossa A., Kiserud C., Reinertsen K., Helland A., Riis M., Geisler J., Alnaes G.G., Collee J.M., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Evans D.G., Fasching P.A., Flyger H., Gago-Dominguez M., Garcia-Closas M., Garcia-Saenz J.A., Giles G.G., Goldgar D.E., Gonzalez-Neira A., Haiman C.A., Hakansson N., Hamann U., Hartman M., Hollestelle A., Hopper J.L., Hou M.-F., Howell A., Clarke C., Marsh D., Scott R., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Simpson P., Graham J.D., Sachchithananthan M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Bennett I., Bogwitz M., Botes L., Brennan M., Brown M., Buckley M., Burke J., Butow P., Caldon L., Campbell I., Chauhan D., Chauhan M., Christian A., Cohen P., Colley A., Crook A., Cui J., Cummings M., Dawson S.-J., deFazio A., Delatycki M., Dickson R., Dixon J., Edkins T., Edwards S., Farshid G., Fellows A., Fenton G., Field M., Flanagan J., Fong P., Forrest L., Fox S., French J., Friedlander M., Gaff C., Gattas M., George P., Greening S., Harris M., Hart S., Hayward N., Hopper J., Hoskins C., Hunt C., James P., Jenkins M., Kidd A., Kirk J., Koehler J., Kollias J., Lakhani S., Lawrence M., Lindeman G., Lipton L., Lobb L., Mann G., McLachlan S.A., Meiser B., Nightingale S., O'Connell S., O'Sullivan S., Ortega D.G., Pachter N., Patterson B., Pearn A., Phillips K., Pieper E., Rickard E., Robinson B., Saleh M., Salisbury E., Saunders C., Saunus J., Sexton A., Shelling A., Southey M.C., Spurdle A., Taylor J., Taylor R., Thorne H., Trainer A., Tucker K., Visvader J., Walker L., Williams R., Winship I., and Young M.A.

Abstract

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.Copyright © 2020 American Society of Human Genetics

Published
2020

9. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author

Zhan, H, Ahearn, TU, Lecarpentier, J, Barnes, D, Beesley, J, Qi, G, Jiang, X, O'Mara, TA, Zhao, N, Bolla, MK, Dunning, AM, Dennis, J, Wang, Q, Abu Ful, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Arun, BK, Auer, PL, Azzollini, J, Barrowdale, D, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Bruening, T, Burwinkel, B, Buys, SS, Byers, H, Caldes, T, Caligo, MA, Calvello, M, Campa, D, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiaens, M, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Diez, O, Domchek, SM, Doerk, T, Dwek, M, Eccles, DM, Ekici, AB, Evans, DG, Fasching, PA, Figueroa, J, Foretova, L, Fostira, F, Friedman, E, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hake, CR, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Hillemanns, P, Hogervorst, FBL, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huebner, H, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jager, A, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khan, S, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, Loud, JT, Lubinski, J, Lukomska, A, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Matricardi, L, McGuffog, L, McLean, C, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Mingazheva, E, Montagna, M, Mulligan, AM, Mulot, C, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsens, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, O, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, Piedmonte, M, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Prokofyeva, D, Rack, B, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Risch, HA, Romero, A, Rookus, MA, Ruebner, M, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schoettker, B, Schuermann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, C, Tamimi, RM, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, M, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van den Ouweland, AMW, van der Kolk, LE, van Veen, EM, vanRensburg, EJ, Vega, A, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wildiers, H, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zheng, W, Zorn, KK, Milne, RL, Kraft, P, Simard, J, Pharoah, PDP, Michailidou, K, Antoniou, AC, Schmidt, MK, Chenevix-Trench, G, Easton, DF, Chatterjee, N, Garcia-Closas, M, Zhan, H, Ahearn, TU, Lecarpentier, J, Barnes, D, Beesley, J, Qi, G, Jiang, X, O'Mara, TA, Zhao, N, Bolla, MK, Dunning, AM, Dennis, J, Wang, Q, Abu Ful, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Arun, BK, Auer, PL, Azzollini, J, Barrowdale, D, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Bruening, T, Burwinkel, B, Buys, SS, Byers, H, Caldes, T, Caligo, MA, Calvello, M, Campa, D, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiaens, M, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Diez, O, Domchek, SM, Doerk, T, Dwek, M, Eccles, DM, Ekici, AB, Evans, DG, Fasching, PA, Figueroa, J, Foretova, L, Fostira, F, Friedman, E, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hake, CR, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Hillemanns, P, Hogervorst, FBL, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huebner, H, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jager, A, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khan, S, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, Loud, JT, Lubinski, J, Lukomska, A, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Matricardi, L, McGuffog, L, McLean, C, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Mingazheva, E, Montagna, M, Mulligan, AM, Mulot, C, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsens, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, O, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, Piedmonte, M, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Prokofyeva, D, Rack, B, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Risch, HA, Romero, A, Rookus, MA, Ruebner, M, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schoettker, B, Schuermann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, C, Tamimi, RM, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, M, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van den Ouweland, AMW, van der Kolk, LE, van Veen, EM, vanRensburg, EJ, Vega, A, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wildiers, H, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zheng, W, Zorn, KK, Milne, RL, Kraft, P, Simard, J, Pharoah, PDP, Michailidou, K, Antoniou, AC, Schmidt, MK, Chenevix-Trench, G, Easton, DF, Chatterjee, N, and Garcia-Closas, M

Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Published
2020

10. Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Author

Kramer I, Hooning MJ, Mavaddat N, Hauptmann M, Keeman R, Steyerberg EW, Giardiello D, Antoniou AC, Pharoah PDP, Canisius S, Abu-Ful Z, Andrulis IL, Anton-Culver H, Aronson KJ, Augustinsson A, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Brauch H, Bremer M, Brucker SY, Burwinkel B, Castelao JE, Chan TL, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Choi J-Y, Clarke CL, NBCS Collaborators, Collée JM, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Evans DG, Fasching PA, Flyger H, Gago-Dominguez M, García-Closas M, García-Sáenz JA, Giles GG, Goldgar DE, González-Neira A, Haiman CA, Håkansson N, Hamann U, Hartman M, Heemskerk-Gerritsen BAM, Hollestelle A, Hopper JL, Hou M-F, Howell A, ABCTB Investigators, kConFab Investigators, Ito H, Jakimovska M, Jakubowska A, Janni W, John EM, Jung A, Kang D, Kets CM, Khusnutdinova E, Ko Y-D, Kristensen VN, Kurian AW, Kwong A, Lambrechts D, Le Marchand L, Li J, Lindblom A, Lubiński J, Mannermaa A, Manoochehri M, Margolin S, Matsuo K, Mavroudis D, Meindl A, Milne RL, Mulligan AM, Muranen TA, Neuhausen SL, Nevanlinna H, Newman WG, Olshan AF, Olson JE, Olsson H, Park-Simon T-W, Peto J, Petridis C, Plaseska-Karanfilska D, Presneau N, Pylkäs K, Radice P, Rennert G, Romero A, Roylance R, Saloustros E, Sawyer EJ, Schmutzler RK, Schwentner L, Scott C, See M-H, Shah M, Shen C-Y, Shu X-O, Siesling S, Slager S, Sohn C, Southey MC, Spinelli JJ, Stone J, Tapper WJ, Tengström M, Teo SH, Terry MB, Tollenaar RAEM, Tomlinson I, Troester MA, Vachon CM, van Ongeval C, van Veen EM, Winqvist R, Wolk A, Zheng W, Ziogas A, Easton DF, Hall P, Schmidt MK, Kramer I, Hooning MJ, Mavaddat N, Hauptmann M, Keeman R, Steyerberg EW, Giardiello D, Antoniou AC, Pharoah PDP, Canisius S, Abu-Ful Z, Andrulis IL, Anton-Culver H, Aronson KJ, Augustinsson A, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Brauch H, Bremer M, Brucker SY, Burwinkel B, Castelao JE, Chan TL, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Choi J-Y, Clarke CL, NBCS Collaborators, Collée JM, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Evans DG, Fasching PA, Flyger H, Gago-Dominguez M, García-Closas M, García-Sáenz JA, Giles GG, Goldgar DE, González-Neira A, Haiman CA, Håkansson N, Hamann U, Hartman M, Heemskerk-Gerritsen BAM, Hollestelle A, Hopper JL, Hou M-F, Howell A, ABCTB Investigators, kConFab Investigators, Ito H, Jakimovska M, Jakubowska A, Janni W, John EM, Jung A, Kang D, Kets CM, Khusnutdinova E, Ko Y-D, Kristensen VN, Kurian AW, Kwong A, Lambrechts D, Le Marchand L, Li J, Lindblom A, Lubiński J, Mannermaa A, Manoochehri M, Margolin S, Matsuo K, Mavroudis D, Meindl A, Milne RL, Mulligan AM, Muranen TA, Neuhausen SL, Nevanlinna H, Newman WG, Olshan AF, Olson JE, Olsson H, Park-Simon T-W, Peto J, Petridis C, Plaseska-Karanfilska D, Presneau N, Pylkäs K, Radice P, Rennert G, Romero A, Roylance R, Saloustros E, Sawyer EJ, Schmutzler RK, Schwentner L, Scott C, See M-H, Shah M, Shen C-Y, Shu X-O, Siesling S, Slager S, Sohn C, Southey MC, Spinelli JJ, Stone J, Tapper WJ, Tengström M, Teo SH, Terry MB, Tollenaar RAEM, Tomlinson I, Troester MA, Vachon CM, van Ongeval C, van Veen EM, Winqvist R, Wolk A, Zheng W, Ziogas A, Easton DF, Hall P, and Schmidt MK

Abstract

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

Published
2020

11. Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.

Author

Chen Z, Guo X, Tao R, Huyghe JR, Law PJ, Fernandez-Rozadilla C, Ping J, Jia G, Long J, Li C, Shen Q, Xie Y, Timofeeva MN, Thomas M, Schmit SL, Díez-Obrero V, Devall M, Moratalla-Navarro F, Fernandez-Tajes J, Palles C, Sherwood K, Briggs SEW, Svinti V, Donnelly K, Farrington SM, Blackmur J, Vaughan-Shaw PG, Shu XO, Lu Y, Broderick P, Studd J, Harrison TA, Conti DV, Schumacher FR, Melas M, Rennert G, Obón-Santacana M, Martín-Sánchez V, Oh JH, Kim J, Jee SH, Jung KJ, Kweon SS, Shin MH, Shin A, Ahn YO, Kim DH, Oze I, Wen W, Matsuo K, Matsuda K, Tanikawa C, Ren Z, Gao YT, Jia WH, Hopper JL, Jenkins MA, Win AK, Pai RK, Figueiredo JC, Haile RW, Gallinger S, Woods MO, Newcomb PA, Duggan D, Cheadle JP, Kaplan R, Kerr R, Kerr D, Kirac I, Böhm J, Mecklin JP, Jousilahti P, Knekt P, Aaltonen LA, Rissanen H, Pukkala E, Eriksson JG, Cajuso T, Hänninen U, Kondelin J, Palin K, Tanskanen T, Renkonen-Sinisalo L, Männistö S, Albanes D, Weinstein SJ, Ruiz-Narvaez E, Palmer JR, Buchanan DD, Platz EA, Visvanathan K, Ulrich CM, Siegel E, Brezina S, Gsur A, Campbell PT, Chang-Claude J, Hoffmeister M, Brenner H, Slattery ML, Potter JD, Tsilidis KK, Schulze MB, Gunter MJ, Murphy N, Castells A, Castellví-Bel S, Moreira L, Arndt V, Shcherbina A, Bishop DT, Giles GG, Southey MC, Idos GE, McDonnell KJ, Abu-Ful Z, Greenson JK, Shulman K, Lejbkowicz F, Offit K, Su YR, Steinfelder R, Keku TO, van Guelpen B, Hudson TJ, Hampel H, Pearlman R, Berndt SI, Hayes RB, Martinez ME, Thomas SS, Pharoah PDP, Larsson SC, Yen Y, Lenz HJ, White E, Li L, Doheny KF, Pugh E, Shelford T, Chan AT, Cruz-Correa M, Lindblom A, Hunter DJ, Joshi AD, Schafmayer C, Scacheri PC, Kundaje A, Schoen RE, Hampe J, Stadler ZK, Vodicka P, Vodickova L, Vymetalkova V, Edlund CK, Gauderman WJ, Shibata D, Toland A, Markowitz S, Kim A, Chanock SJ, van Duijnhoven F, Feskens EJM, Sakoda LC, Gago-Dominguez M, Wolk A, Pardini B, FitzGerald LM, Lee SC, Ogino S, Bien SA, Kooperberg C, Li CI, Lin Y, Prentice R, Qu C, Bézieau S, Yamaji T, Sawada N, Iwasaki M, Le Marchand L, Wu AH, Qu C, McNeil CE, Coetzee G, Hayward C, Deary IJ, Harris SE, Theodoratou E, Reid S, Walker M, Ooi LY, Lau KS, Zhao H, Hsu L, Cai Q, Dunlop MG, Gruber SB, Houlston RS, Moreno V, Casey G, Peters U, Tomlinson I, and Zheng W

Subjects
Female, Humans, Male, Case-Control Studies, Chromosome Mapping, Exome Sequencing, Transcriptome, Colorectal Neoplasms genetics, East Asian People genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Quantitative Trait Loci, White People genetics
Abstract

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development., (© 2024. The Author(s).)

Published
2024
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12. Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.

Author

Fernandez-Rozadilla C, Timofeeva M, Chen Z, Law P, Thomas M, Schmit S, Díez-Obrero V, Hsu L, Fernandez-Tajes J, Palles C, Sherwood K, Briggs S, Svinti V, Donnelly K, Farrington S, Blackmur J, Vaughan-Shaw P, Shu XO, Long J, Cai Q, Guo X, Lu Y, Broderick P, Studd J, Huyghe J, Harrison T, Conti D, Dampier C, Devall M, Schumacher F, Melas M, Rennert G, Obón-Santacana M, Martín-Sánchez V, Moratalla-Navarro F, Oh JH, Kim J, Jee SH, Jung KJ, Kweon SS, Shin MH, Shin A, Ahn YO, Kim DH, Oze I, Wen W, Matsuo K, Matsuda K, Tanikawa C, Ren Z, Gao YT, Jia WH, Hopper J, Jenkins M, Win AK, Pai R, Figueiredo J, Haile R, Gallinger S, Woods M, Newcomb P, Duggan D, Cheadle J, Kaplan R, Maughan T, Kerr R, Kerr D, Kirac I, Böhm J, Mecklin LP, Jousilahti P, Knekt P, Aaltonen L, Rissanen H, Pukkala E, Eriksson J, Cajuso T, Hänninen U, Kondelin J, Palin K, Tanskanen T, Renkonen-Sinisalo L, Zanke B, Männistö S, Albanes D, Weinstein S, Ruiz-Narvaez E, Palmer J, Buchanan D, Platz E, Visvanathan K, Ulrich C, Siegel E, Brezina S, Gsur A, Campbell P, Chang-Claude J, Hoffmeister M, Brenner H, Slattery M, Potter J, Tsilidis K, Schulze M, Gunter M, Murphy N, Castells A, Castellví-Bel S, Moreira L, Arndt V, Shcherbina A, Stern M, Pardamean B, Bishop T, Giles G, Southey M, Idos G, McDonnell K, Abu-Ful Z, Greenson J, Shulman K, Lejbkowicz F, Offit K, Su YR, Steinfelder R, Keku T, van Guelpen B, Hudson T, Hampel H, Pearlman R, Berndt S, Hayes R, Martinez ME, Thomas S, Corley D, Pharoah P, Larsson S, Yen Y, Lenz HJ, White E, Li L, Doheny K, Pugh E, Shelford T, Chan A, Cruz-Correa M, Lindblom A, Hunter D, Joshi A, Schafmayer C, Scacheri P, Kundaje A, Nickerson D, Schoen R, Hampe J, Stadler Z, Vodicka P, Vodickova L, Vymetalkova V, Papadopoulos N, Edlund C, Gauderman W, Thomas D, Shibata D, Toland A, Markowitz S, Kim A, Chanock S, van Duijnhoven F, Feskens E, Sakoda L, Gago-Dominguez M, Wolk A, Naccarati A, Pardini B, FitzGerald L, Lee SC, Ogino S, Bien S, Kooperberg C, Li C, Lin Y, Prentice R, Qu C, Bézieau S, Tangen C, Mardis E, Yamaji T, Sawada N, Iwasaki M, Haiman C, Le Marchand L, Wu A, Qu C, McNeil C, Coetzee G, Hayward C, Deary I, Harris S, Theodoratou E, Reid S, Walker M, Ooi LY, Moreno V, Casey G, Gruber S, Tomlinson I, Zheng W, Dunlop M, Houlston R, and Peters U

Published
2023
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13. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.

Author

Mueller SH, Lai AG, Valkovskaya M, Michailidou K, Bolla MK, Wang Q, Dennis J, Lush M, Abu-Ful Z, Ahearn TU, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Augustinsson A, Baert T, Freeman LEB, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Brenner H, Brucker SY, Buys SS, Castelao JE, Chan TL, Chang-Claude J, Chanock SJ, Choi JY, Chung WK, Colonna SV, Cornelissen S, Couch FJ, Czene K, Daly MB, Devilee P, Dörk T, Dossus L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Engel C, Evans DG, Fasching PA, Fletcher O, Flyger H, Gago-Dominguez M, Gao YT, García-Closas M, García-Sáenz JA, Genkinger J, Gentry-Maharaj A, Grassmann F, Guénel P, Gündert M, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hall P, Harkness EF, Harrington PA, Hartikainen JM, Hartman M, Hein A, Ho WK, Hooning MJ, Hoppe R, Hopper JL, Houlston RS, Howell A, Hunter DJ, Huo D, Ito H, Iwasaki M, Jakubowska A, Janni W, John EM, Jones ME, Jung A, Kaaks R, Kang D, Khusnutdinova EK, Kim SW, Kitahara CM, Koutros S, Kraft P, Kristensen VN, Kubelka-Sabit K, Kurian AW, Kwong A, Lacey JV, Lambrechts D, Le Marchand L, Li J, Linet M, Lo WY, Long J, Lophatananon A, Mannermaa A, Manoochehri M, Margolin S, Matsuo K, Mavroudis D, Menon U, Muir K, Murphy RA, Nevanlinna H, Newman WG, Niederacher D, O'Brien KM, Obi N, Offit K, Olopade OI, Olshan AF, Olsson H, Park SK, Patel AV, Patel A, Perou CM, Peto J, Pharoah PDP, Plaseska-Karanfilska D, Presneau N, Rack B, Radice P, Ramachandran D, Rashid MU, Rennert G, Romero A, Ruddy KJ, Ruebner M, Saloustros E, Sandler DP, Sawyer EJ, Schmidt MK, Schmutzler RK, Schneider MO, Scott C, Shah M, Sharma P, Shen CY, Shu XO, Simard J, Surowy H, Tamimi RM, Tapper WJ, Taylor JA, Teo SH, Teras LR, Toland AE, Tollenaar RAEM, Torres D, Torres-Mejía G, Troester MA, Truong T, Vachon CM, Vijai J, Weinberg CR, Wendt C, Winqvist R, Wolk A, Wu AH, Yamaji T, Yang XR, Yu JC, Zheng W, Ziogas A, Ziv E, Dunning AM, Easton DF, Hemingway H, Hamann U, and Kuchenbaecker KB

Subjects
Humans, Female, Genetic Predisposition to Disease, Black People, Genetic Testing, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide, Formins genetics, Breast Neoplasms genetics
Abstract

Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes., Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry., Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10 -6 ) and AC058822.1 (P = 1.47 × 10 -4 ), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C., Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10 -5 ), demonstrating the importance of diversifying study cohorts., (© 2023. The Author(s).)

Published
2023
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14. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.

Author

Fernandez-Rozadilla C, Timofeeva M, Chen Z, Law P, Thomas M, Schmit S, Díez-Obrero V, Hsu L, Fernandez-Tajes J, Palles C, Sherwood K, Briggs S, Svinti V, Donnelly K, Farrington S, Blackmur J, Vaughan-Shaw P, Shu XO, Long J, Cai Q, Guo X, Lu Y, Broderick P, Studd J, Huyghe J, Harrison T, Conti D, Dampier C, Devall M, Schumacher F, Melas M, Rennert G, Obón-Santacana M, Martín-Sánchez V, Moratalla-Navarro F, Oh JH, Kim J, Jee SH, Jung KJ, Kweon SS, Shin MH, Shin A, Ahn YO, Kim DH, Oze I, Wen W, Matsuo K, Matsuda K, Tanikawa C, Ren Z, Gao YT, Jia WH, Hopper J, Jenkins M, Win AK, Pai R, Figueiredo J, Haile R, Gallinger S, Woods M, Newcomb P, Duggan D, Cheadle J, Kaplan R, Maughan T, Kerr R, Kerr D, Kirac I, Böhm J, Mecklin LP, Jousilahti P, Knekt P, Aaltonen L, Rissanen H, Pukkala E, Eriksson J, Cajuso T, Hänninen U, Kondelin J, Palin K, Tanskanen T, Renkonen-Sinisalo L, Zanke B, Männistö S, Albanes D, Weinstein S, Ruiz-Narvaez E, Palmer J, Buchanan D, Platz E, Visvanathan K, Ulrich C, Siegel E, Brezina S, Gsur A, Campbell P, Chang-Claude J, Hoffmeister M, Brenner H, Slattery M, Potter J, Tsilidis K, Schulze M, Gunter M, Murphy N, Castells A, Castellví-Bel S, Moreira L, Arndt V, Shcherbina A, Stern M, Pardamean B, Bishop T, Giles G, Southey M, Idos G, McDonnell K, Abu-Ful Z, Greenson J, Shulman K, Lejbkowicz F, Offit K, Su YR, Steinfelder R, Keku T, van Guelpen B, Hudson T, Hampel H, Pearlman R, Berndt S, Hayes R, Martinez ME, Thomas S, Corley D, Pharoah P, Larsson S, Yen Y, Lenz HJ, White E, Li L, Doheny K, Pugh E, Shelford T, Chan A, Cruz-Correa M, Lindblom A, Hunter D, Joshi A, Schafmayer C, Scacheri P, Kundaje A, Nickerson D, Schoen R, Hampe J, Stadler Z, Vodicka P, Vodickova L, Vymetalkova V, Papadopoulos N, Edlund C, Gauderman W, Thomas D, Shibata D, Toland A, Markowitz S, Kim A, Chanock S, van Duijnhoven F, Feskens E, Sakoda L, Gago-Dominguez M, Wolk A, Naccarati A, Pardini B, FitzGerald L, Lee SC, Ogino S, Bien S, Kooperberg C, Li C, Lin Y, Prentice R, Qu C, Bézieau S, Tangen C, Mardis E, Yamaji T, Sawada N, Iwasaki M, Haiman C, Le Marchand L, Wu A, Qu C, McNeil C, Coetzee G, Hayward C, Deary I, Harris S, Theodoratou E, Reid S, Walker M, Ooi LY, Moreno V, Casey G, Gruber S, Tomlinson I, Zheng W, Dunlop M, Houlston R, and Peters U

Subjects
Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, Multiomics, Polymorphism, Single Nucleotide genetics, Colorectal Neoplasms genetics, East Asian People genetics, European People genetics
Abstract

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2023
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15. Implementation of oral anticoagulation treatment guidelines in patients with newly diagnosed atrial fibrillation.

Author

Arbel A, Abu-Ful Z, Preis M, Cohen S, and Saliba W

Subjects
Administration, Oral, Anticoagulants, Female, Health Services, Humans, Retrospective Studies, Risk Factors, Atrial Fibrillation complications, Atrial Fibrillation diagnosis, Atrial Fibrillation drug therapy, Stroke epidemiology, Stroke etiology, Stroke prevention & control
Abstract

Aims: Oral anticoagulants (OACs) are considered the mainstay in preventing stroke in atrial fibrillation (AF). OAC treatment remains suboptimal among AF patients, even after the introduction of direct oral anticoagulants (DOACs). We aimed to assess trends overtime and current implementation of OAC treatment guidelines in AF, using a large dataset of real world data from Israel., Methods: This is a retrospective cohort study that includes all adult members of Clalit Health Services, the largest healthcare provider in Israel, with newly diagnosed nonvalvular AF between January 2014 and December 2019 with CHA 2 DS 2 -VASc score ≥2. OAC treatment rates were calculated and multivariate regression models were used to identify predictors of OACs initiation., Results: Overall, 46 531 patients were included in the study. The 3-months cumulative OAC treatment rates increased consistently over the years: 46.9% (95% confidence interval, 46.1-47.7%), 54.9% (54.1-55.6%) and 61.7% (60.9-62.4%) during 2014-2015, 2016-2017 and 2018-2019, respectively. DOACs constituted 51.3% of prescribed OACs in 2014-2015 and increased to 95.1% during 2018-2019. On multivariate analyses, the likelihood of OACs initiation among AF patients increased across the years and across higher socioeconomic classes, and was more likely among females, Jews, statins users and patients previously screened for colorectal cancer, but less likely among smokers and patients with impaired renal function. The likelihood of treatment increased with higher CHA 2 DS 2 -VASc score and decreased with higher HAS-BLED score., Conclusion: Despite the increasing OAC treatment rates among high-risk AF patients, mainly attributed to the expanding DOAC use, OAC treatment scope is still far from optimal., (© 2021 British Pharmacological Society.)

Published
2021
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16. Adherence with direct oral anticoagulants in patients with atrial fibrillation: Trends, risk factors, and outcomes.

Author

Arbel A, Abu-Ful Z, Preis M, Cohen S, and Saliba W

Abstract

Background: Adherence to direct oral anticoagulants (DOACs) remains a concern among non-valvular atrial fibrillation (AF) patients. We aimed to assess patterns of adherence with DOACs and examine their association with ischemic stroke and systemic embolism (SE)., Methods: This retrospective cohort study includes all adult members of Clalit Health Services, the largest healthcare provider in Israel, with newly diagnosed non-valvular AF between January 2014 and March 2019, who initiated DOACs within 90 days of AF diagnosis and used DOACs exclusively. Adherence was assessed using the proportion of days covered (PDC) over the first year of treatment, and high adherence was defined as PDC ≥80%. Regression models were used to identify predictors of high adherence to DOACs and to examine the association between adherence and stroke or SE., Results: Overall 15,255 patients were included in this study. The proportion of highly adherent (PDC ≥80%) DOACs users was around 75% and decreased slightly over the years. On multivariable analyses, the likelihood of high adherence to DOACs increased with age and across higher socioeconomic classes, and was more likely among females, Jews, statins users, and patients with CHA 2 DS 2 -VASc score ≥2. Risk of stroke and SE was lower among highly adherent DOACs users; adjusted HR 0.56 (95% CI, 0.45-0.71), compared to users with PDC <80%., Conclusions: Adherence with DOACs is still sub-optimal among non-valvular AF patients, resulting in a higher risk of stroke and SE., Competing Interests: The authors declare no conflicts of interest for this article., (© 2021 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Published
2021
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17. Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

Author

Kapoor PM, Mavaddat N, Choudhury PP, Wilcox AN, Lindström S, Behrens S, Michailidou K, Dennis J, Bolla MK, Wang Q, Jung A, Abu-Ful Z, Ahearn T, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Auer PL, Freeman LEB, Becher H, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bernstein L, Bojesen SE, Brauch H, Brenner H, Brüning T, Cai Q, Campa D, Canzian F, Carracedo A, Carter BD, Castelao JE, Chanock SJ, Chatterjee N, Chenevix-Trench G, Clarke CL, Couch FJ, Cox A, Cross SS, Czene K, Dai JY, Earp HS, Ekici AB, Eliassen AH, Eriksson M, Evans DG, Fasching PA, Figueroa J, Fritschi L, Gabrielson M, Gago-Dominguez M, Gao C, Gapstur SM, Gaudet MM, Giles GG, González-Neira A, Guénel P, Haeberle L, Haiman CA, Håkansson N, Hall P, Hamann U, Hatse S, Heyworth J, Holleczek B, Hoover RN, Hopper JL, Howell A, Hunter DJ, John EM, Jones ME, Kaaks R, Keeman R, Kitahara CM, Ko YD, Koutros S, Kurian AW, Lambrechts D, Le Marchand L, Lee E, Lejbkowicz F, Linet M, Lissowska J, Llaneza A, MacInnis RJ, Martinez ME, Maurer T, McLean C, Neuhausen SL, Newman WG, Norman A, O'Brien KM, Olshan AF, Olson JE, Olsson H, Orr N, Perou CM, Pita G, Polley EC, Prentice RL, Rennert G, Rennert HS, Ruddy KJ, Sandler DP, Saunders C, Schoemaker MJ, Schöttker B, Schumacher F, Scott C, Scott RJ, Shu XO, Smeets A, Southey MC, Spinelli JJ, Stone J, Swerdlow AJ, Tamimi RM, Taylor JA, Troester MA, Vachon CM, van Veen EM, Wang X, Weinberg CR, Weltens C, Willett W, Winham SJ, Wolk A, Yang XR, Zheng W, Ziogas A, Dunning AM, Pharoah PDP, Schmidt MK, Kraft P, Easton DF, Milne RL, García-Closas M, and Chang-Claude J

Subjects
Aged, Aged, 80 and over, Body Mass Index, Breast Neoplasms metabolism, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Logistic Models, Medical History Taking, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Estrogen metabolism, Risk Factors, White People, Breast Neoplasms genetics
Abstract

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer., (© The Author(s) 2020. Published by Oxford University Press.)

Published
2021
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