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1. Artificial intelligence for detection of microsatellite instability in colorectal cancer—a multicentric analysis of a pre-screening tool for clinical application

Author: Echle, A., Ghaffari Laleh, N., Quirke, P., Grabsch, H.I., Muti, H.S., Saldanha, O.L., Brockmoeller, S.F., van den Brandt, P.A., Hutchins, G.G.A., Richman, S.D., Horisberger, K., Galata, C., Ebert, M.P., Eckardt, M., Boutros, M., Horst, D., Reissfelder, C., Alwers, E., Brinker, T.J., Langer, R., Jenniskens, J.C.A., Offermans, K., Mueller, W., Gray, R., Gruber, S.B., Greenson, J.K., Rennert, G., Bonner, J.D., Schmolze, D., Chang-Claude, J., Brenner, H., Trautwein, C., Boor, P., Jaeger, D., Gaisa, N.T., Hoffmeister, M., West, N.P., and Kather, J.N.
Published: 2022
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2. Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk

Author: Tian, Y, Lin, Y, Qu, C, Arndt, V, Baurley, JW, Berndt, SI, Bien, SA, Bishop, DT, Brenner, H, Buchanan, DD, Budiarto, A, Campbell, PT, Carreras-Torres, R, Casey, G, Chan, AT, Chen, R, Chen, X, Conti, DV, Diez-Obrero, V, Dimou, N, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gunter, MJ, Harlid, S, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Joshi, AD, Keku, TO, Kawaguchi, E, Kim, AE, Kundaje, A, Larsson, SC, Marchand, LL, Lewinger, JP, Li, L, Moreno, V, Morrison, J, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pardamean, B, Pellatt, AJ, Peoples, AR, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Ruiz-Narvaez, EA, Sakoda, LC, Schoen, RE, Shcherbina, A, Stern, MC, Su, Y-R, Thibodeau, SN, Thomas, DC, Tsilidis, KK, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Peters, U, Gauderman, WJ, Hsu, L, Chang-Claude, J, Tian, Y, Lin, Y, Qu, C, Arndt, V, Baurley, JW, Berndt, SI, Bien, SA, Bishop, DT, Brenner, H, Buchanan, DD, Budiarto, A, Campbell, PT, Carreras-Torres, R, Casey, G, Chan, AT, Chen, R, Chen, X, Conti, DV, Diez-Obrero, V, Dimou, N, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gunter, MJ, Harlid, S, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Joshi, AD, Keku, TO, Kawaguchi, E, Kim, AE, Kundaje, A, Larsson, SC, Marchand, LL, Lewinger, JP, Li, L, Moreno, V, Morrison, J, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pardamean, B, Pellatt, AJ, Peoples, AR, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Ruiz-Narvaez, EA, Sakoda, LC, Schoen, RE, Shcherbina, A, Stern, MC, Su, Y-R, Thibodeau, SN, Thomas, DC, Tsilidis, KK, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Peters, U, Gauderman, WJ, Hsu, L, and Chang-Claude, J
Abstract: BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
Published: 2024

3. Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Author: Kentistou, KA, Kaisinger, LR, Stankovic, S, Vaudel, M, Mendes de Oliveira, E, Messina, A, Walters, RG, Liu, X, Busch, AS, Helgason, H, Thompson, DJ, Santoni, F, Petricek, KM, Zouaghi, Y, Huang-Doran, I, Gudbjartsson, DF, Bratland, E, Lin, K, Gardner, EJ, Zhao, Y, Jia, RY, Terao, C, Riggan, MJ, Bolla, MK, Yazdanpanah, M, Yazdanpanah, N, Bradfield, JP, Broer, L, Campbell, A, Chasman, DI, Cousminer, DL, Franceschini, N, Franke, LH, Girotto, G, He, C, Järvelin, M-R, Joshi, PK, Kamatani, Y, Karlsson, R, Luan, J, Lunetta, KL, Mägi, R, Mangino, M, Medland, SE, Meisinger, C, Noordam, R, Nutile, T, Concas, MP, Polašek, O, Porcu, E, Ring, SM, Sala, C, Smith, AV, Tanaka, T, van der Most, PJ, Vitart, V, Wang, CA, Willemsen, G, Zygmunt, M, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Auer, PL, Barnes, CLK, Beckmann, MW, Berrington de Gonzalez, A, Bogdanova, NV, Bojesen, SE, Brenner, H, Buring, JE, Canzian, F, Chang-Claude, J, Couch, FJ, Cox, A, Crisponi, L, Czene, K, Daly, MB, Demerath, EW, Dennis, J, Devilee, P, De Vivo, I, Dörk, T, Dunning, AM, Dwek, M, Eriksson, JG, Fasching, PA, Fernandez-Rhodes, L, Ferreli, L, Fletcher, O, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, González-Neira, A, Grallert, H, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Hakonarson, H, Hart, RJ, Hickey, M, Hooning, MJ, Hoppe, R, Hopper, JL, Hottenga, J-J, Hu, FB, Huebner, H, Hunter, DJ, ABCTB Investigators, Jernström, H, John, EM, Karasik, D, Khusnutdinova, EK, Kristensen, VN, Lacey, JV, Lambrechts, D, Launer, LJ, Lind, PA, Lindblom, A, Magnusson, PKE, Mannermaa, A, McCarthy, MI, Meitinger, T, Menni, C, Michailidou, K, Millwood, IY, Milne, RL, Montgomery, GW, Nevanlinna, H, Nolte, IM, Nyholt, DR, Obi, N, O'Brien, KM, Offit, K, Oldehinkel, AJ, Ostrowski, SR, Palotie, A, Pedersen, OB, Peters, A, Pianigiani, G, Plaseska-Karanfilska, D, Pouta, A, Pozarickij, A, Radice, P, Rennert, G, Rosendaal, FR, Ruggiero, D, Saloustros, E, Sandler, DP, Schipf, S, Schmidt, CO, Schmidt, MK, Small, K, Spedicati, B, Stampfer, M, Stone, J, Tamimi, RM, Teras, LR, Tikkanen, E, Turman, C, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Zemel, BS, Zheng, W, van Dijk, KW, Alizadeh, BZ, Bandinelli, S, Boerwinkle, E, Boomsma, DI, Ciullo, M, Chenevix-Trench, G, Cucca, F, Esko, T, Gieger, C, Grant, SFA, Gudnason, V, Hayward, C, Kolčić, I, Kraft, P, Lawlor, DA, Martin, NG, Nøhr, EA, Pedersen, NL, Pennell, CE, Ridker, PM, Robino, A, Snieder, H, Sovio, U, Spector, TD, Stöckl, D, Sudlow, C, Timpson, NJ, Toniolo, D, Uitterlinden, A, Ulivi, S, Völzke, H, Wareham, NJ, Widen, E, Wilson, JF, Lifelines Cohort Study, Danish Blood Donor Study, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, Pharoah, PDP, Li, L, Easton, DF, Njølstad, PR, Sulem, P, Murabito, JM, Murray, A, Manousaki, D, Juul, A, Erikstrup, C, Stefansson, K, Horikoshi, M, Chen, Z, Farooqi, IS, Pitteloud, N, Johansson, S, Day, FR, Perry, JRB, Ong, KK, Kentistou, KA, Kaisinger, LR, Stankovic, S, Vaudel, M, Mendes de Oliveira, E, Messina, A, Walters, RG, Liu, X, Busch, AS, Helgason, H, Thompson, DJ, Santoni, F, Petricek, KM, Zouaghi, Y, Huang-Doran, I, Gudbjartsson, DF, Bratland, E, Lin, K, Gardner, EJ, Zhao, Y, Jia, RY, Terao, C, Riggan, MJ, Bolla, MK, Yazdanpanah, M, Yazdanpanah, N, Bradfield, JP, Broer, L, Campbell, A, Chasman, DI, Cousminer, DL, Franceschini, N, Franke, LH, Girotto, G, He, C, Järvelin, M-R, Joshi, PK, Kamatani, Y, Karlsson, R, Luan, J, Lunetta, KL, Mägi, R, Mangino, M, Medland, SE, Meisinger, C, Noordam, R, Nutile, T, Concas, MP, Polašek, O, Porcu, E, Ring, SM, Sala, C, Smith, AV, Tanaka, T, van der Most, PJ, Vitart, V, Wang, CA, Willemsen, G, Zygmunt, M, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Auer, PL, Barnes, CLK, Beckmann, MW, Berrington de Gonzalez, A, Bogdanova, NV, Bojesen, SE, Brenner, H, Buring, JE, Canzian, F, Chang-Claude, J, Couch, FJ, Cox, A, Crisponi, L, Czene, K, Daly, MB, Demerath, EW, Dennis, J, Devilee, P, De Vivo, I, Dörk, T, Dunning, AM, Dwek, M, Eriksson, JG, Fasching, PA, Fernandez-Rhodes, L, Ferreli, L, Fletcher, O, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, González-Neira, A, Grallert, H, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Hakonarson, H, Hart, RJ, Hickey, M, Hooning, MJ, Hoppe, R, Hopper, JL, Hottenga, J-J, Hu, FB, Huebner, H, Hunter, DJ, ABCTB Investigators, Jernström, H, John, EM, Karasik, D, Khusnutdinova, EK, Kristensen, VN, Lacey, JV, Lambrechts, D, Launer, LJ, Lind, PA, Lindblom, A, Magnusson, PKE, Mannermaa, A, McCarthy, MI, Meitinger, T, Menni, C, Michailidou, K, Millwood, IY, Milne, RL, Montgomery, GW, Nevanlinna, H, Nolte, IM, Nyholt, DR, Obi, N, O'Brien, KM, Offit, K, Oldehinkel, AJ, Ostrowski, SR, Palotie, A, Pedersen, OB, Peters, A, Pianigiani, G, Plaseska-Karanfilska, D, Pouta, A, Pozarickij, A, Radice, P, Rennert, G, Rosendaal, FR, Ruggiero, D, Saloustros, E, Sandler, DP, Schipf, S, Schmidt, CO, Schmidt, MK, Small, K, Spedicati, B, Stampfer, M, Stone, J, Tamimi, RM, Teras, LR, Tikkanen, E, Turman, C, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Zemel, BS, Zheng, W, van Dijk, KW, Alizadeh, BZ, Bandinelli, S, Boerwinkle, E, Boomsma, DI, Ciullo, M, Chenevix-Trench, G, Cucca, F, Esko, T, Gieger, C, Grant, SFA, Gudnason, V, Hayward, C, Kolčić, I, Kraft, P, Lawlor, DA, Martin, NG, Nøhr, EA, Pedersen, NL, Pennell, CE, Ridker, PM, Robino, A, Snieder, H, Sovio, U, Spector, TD, Stöckl, D, Sudlow, C, Timpson, NJ, Toniolo, D, Uitterlinden, A, Ulivi, S, Völzke, H, Wareham, NJ, Widen, E, Wilson, JF, Lifelines Cohort Study, Danish Blood Donor Study, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, Pharoah, PDP, Li, L, Easton, DF, Njølstad, PR, Sulem, P, Murabito, JM, Murray, A, Manousaki, D, Juul, A, Erikstrup, C, Stefansson, K, Horikoshi, M, Chen, Z, Farooqi, IS, Pitteloud, N, Johansson, S, Day, FR, Perry, JRB, and Ong, KK
Abstract: Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.
Published: 2024

4. Very High Mutation Rate in Offspring of Chernobyl Accident Liquidators

Author: Korol, A. B., Kirzhner, V. M., Avivi, A., Fahima, T., Nevo, Eviatar, Shapiro, S., Rennert, G., Piatak, O., Stepanova, E. I., and Skvarskaja, E.
Published: 2001

5. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Author: Aglago, EK, Kim, A, Lin, Y, Qu, C, Evangelou, M, Ren, Y, Morrison, J, Albanes, D, Arndt, V, Barry, EL, Baurley, JW, Berndt, S, Bien, SA, Bishop, DT, Bouras, E, Brenner, H, Buchanan, DD, Budiarto, A, Carreras-Torres, R, Casey, G, Cenggoro, TW, Chen, AT, Chang-Claude, J, Chen, X, Conti, D, Devall, M, Diez-Obrero, V, Dimou, N, Drew, D, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Hampel, H, Harlid, S, Hidaka, A, Harrison, TA, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, K, Joshi, AD, Kawaguchi, ES, Keku, TO, Kundaje, A, Larsson, SC, Le Marchand, L, Lewinger, JP, Li, L, Lynch, BM, Mahesworo, B, Mandic, M, Obon-Santacana, M, Morento, V, Murphy, N, Men, H, Nassir, R, Newcomb, PA, Ogino, S, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Scacheri, PC, Schmit, SL, Schoen, RE, Shcherbina, A, Slattery, ML, Stern, MC, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Tian, Y, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Wang, J, White, E, Wolk, A, Woods, MO, Wu, AH, Zemlianskaia, N, Hsu, L, Gauderman, WJ, Peters, U, Tsilidis, KK, Campbell, PT, Aglago, EK, Kim, A, Lin, Y, Qu, C, Evangelou, M, Ren, Y, Morrison, J, Albanes, D, Arndt, V, Barry, EL, Baurley, JW, Berndt, S, Bien, SA, Bishop, DT, Bouras, E, Brenner, H, Buchanan, DD, Budiarto, A, Carreras-Torres, R, Casey, G, Cenggoro, TW, Chen, AT, Chang-Claude, J, Chen, X, Conti, D, Devall, M, Diez-Obrero, V, Dimou, N, Drew, D, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Hampel, H, Harlid, S, Hidaka, A, Harrison, TA, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, K, Joshi, AD, Kawaguchi, ES, Keku, TO, Kundaje, A, Larsson, SC, Le Marchand, L, Lewinger, JP, Li, L, Lynch, BM, Mahesworo, B, Mandic, M, Obon-Santacana, M, Morento, V, Murphy, N, Men, H, Nassir, R, Newcomb, PA, Ogino, S, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Scacheri, PC, Schmit, SL, Schoen, RE, Shcherbina, A, Slattery, ML, Stern, MC, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Tian, Y, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Wang, J, White, E, Wolk, A, Woods, MO, Wu, AH, Zemlianskaia, N, Hsu, L, Gauderman, WJ, Peters, U, Tsilidis, KK, and Campbell, PT
Abstract: UNLABELLED: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
Published: 2023

6. Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

Author: Levi, H, Carmi, S, Rosset, S, Yerushalmi, R, Zick, A, Yablonski-Peretz, T, Wang, Q, Bolla, MK, Dennis, J, Michailidou, K, Lush, M, Ahearn, T, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Augustinsson, A, Auvinen, P, Freeman, LB, Beckmann, M, Behrens, S, Bermisheva, M, Bodelon, C, Bogdanova, NV, Bojesen, SE, Brenner, H, Byers, H, Camp, N, Castelao, J, Chang-Claude, J, Chirlaque, M-D, Chung, W, Clarke, C, Collee, MJ, Colonna, S, Couch, F, Cox, A, Cross, SS, Czene, K, Daly, M, Devilee, P, Dork, T, Dossus, L, Eccles, DM, Eliassen, AH, Eriksson, M, Evans, G, Fasching, P, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Giles, GG, Goldberg, M, Guenel, P, Hall, P, Hamann, U, He, W, Hillemanns, P, Hollestelle, A, Hoppe, R, Hopper, J, Jakovchevska, S, Jakubowska, A, Jernstrom, H, John, E, Johnson, N, Jones, M, Vijai, J, Kaaks, R, Khusnutdinova, E, Kitahara, C, Koutros, S, Kristensen, V, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Loibl, S, Lori, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Mavroudis, D, Menon, U, Mulligan, A, Murphy, R, Nevelsteen, I, Newman, WG, Obi, N, O'Brien, K, Offit, K, Olshan, A, Plaseska-Karanfilska, D, Olson, J, Panico, S, Park-Simon, T-W, Patel, A, Peterlongo, P, Rack, B, Radice, P, Rennert, G, Rhenius, V, Romero, A, Saloustros, E, Sandler, D, Schmidt, MK, Schwentner, L, Shah, M, Sharma, P, Simard, J, Southey, M, Stone, J, Tapper, WJ, Taylor, J, Teras, L, Toland, AE, Troester, M, Truong, T, van der Kolk, LE, Weinberg, C, Wendt, C, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, P, Easton, DF, Ben-Sachar, S, Elefant, N, Shamir, R, Elkon, R, Levi, H, Carmi, S, Rosset, S, Yerushalmi, R, Zick, A, Yablonski-Peretz, T, Wang, Q, Bolla, MK, Dennis, J, Michailidou, K, Lush, M, Ahearn, T, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Augustinsson, A, Auvinen, P, Freeman, LB, Beckmann, M, Behrens, S, Bermisheva, M, Bodelon, C, Bogdanova, NV, Bojesen, SE, Brenner, H, Byers, H, Camp, N, Castelao, J, Chang-Claude, J, Chirlaque, M-D, Chung, W, Clarke, C, Collee, MJ, Colonna, S, Couch, F, Cox, A, Cross, SS, Czene, K, Daly, M, Devilee, P, Dork, T, Dossus, L, Eccles, DM, Eliassen, AH, Eriksson, M, Evans, G, Fasching, P, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Giles, GG, Goldberg, M, Guenel, P, Hall, P, Hamann, U, He, W, Hillemanns, P, Hollestelle, A, Hoppe, R, Hopper, J, Jakovchevska, S, Jakubowska, A, Jernstrom, H, John, E, Johnson, N, Jones, M, Vijai, J, Kaaks, R, Khusnutdinova, E, Kitahara, C, Koutros, S, Kristensen, V, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Loibl, S, Lori, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Mavroudis, D, Menon, U, Mulligan, A, Murphy, R, Nevelsteen, I, Newman, WG, Obi, N, O'Brien, K, Offit, K, Olshan, A, Plaseska-Karanfilska, D, Olson, J, Panico, S, Park-Simon, T-W, Patel, A, Peterlongo, P, Rack, B, Radice, P, Rennert, G, Rhenius, V, Romero, A, Saloustros, E, Sandler, D, Schmidt, MK, Schwentner, L, Shah, M, Sharma, P, Simard, J, Southey, M, Stone, J, Tapper, WJ, Taylor, J, Teras, L, Toland, AE, Troester, M, Truong, T, van der Kolk, LE, Weinberg, C, Wendt, C, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, P, Easton, DF, Ben-Sachar, S, Elefant, N, Shamir, R, and Elkon, R
Abstract: BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
Published: 2023

7. Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Author: Carreras-Torres, R, Kim, AE, Lin, Y, Diez-Obrero, V, Bien, SA, Qu, C, Wang, J, Dimou, N, Aglago, EK, Albanes, D, Arndt, V, Baurley, JW, Berndt, SI, Bezieau, S, Bishop, DT, Bouras, E, Brenner, H, Budiarto, A, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chen, X, Conti, D, Dampier, CH, Devall, MAM, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Kawaguchi, E, Keku, TO, Kundaje, A, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, JL, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Scacheri, PC, Schmit, SL, Schoen, RE, Shcherbina, A, Slattery, ML, Stern, MC, Su, Y-R, Tangen, CM, Thomas, DC, Tian, Y, Tsilidis, KK, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Cenggoro, TW, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Hsu, L, Peters, U, Moreno, V, Gauderman, WJ, Carreras-Torres, R, Kim, AE, Lin, Y, Diez-Obrero, V, Bien, SA, Qu, C, Wang, J, Dimou, N, Aglago, EK, Albanes, D, Arndt, V, Baurley, JW, Berndt, SI, Bezieau, S, Bishop, DT, Bouras, E, Brenner, H, Budiarto, A, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chen, X, Conti, D, Dampier, CH, Devall, MAM, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Kawaguchi, E, Keku, TO, Kundaje, A, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, JL, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Scacheri, PC, Schmit, SL, Schoen, RE, Shcherbina, A, Slattery, ML, Stern, MC, Su, Y-R, Tangen, CM, Thomas, DC, Tian, Y, Tsilidis, KK, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Cenggoro, TW, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Hsu, L, Peters, U, Moreno, V, and Gauderman, WJ
Abstract: BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. IMPACT: These findings can guide potential prevention treatments.
Published: 2023

8. A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2

Author: Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, Michailidou, K, Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, and Michailidou, K
Abstract: A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.
Published: 2023

9. Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort.

Author: Su, Y-R, Sakoda, LC, Jeon, J, Thomas, M, Lin, Y, Schneider, JL, Udaltsova, N, Lee, JK, Lansdorp-Vogelaar, I, Peterse, EFP, Zauber, AG, Zheng, J, Zheng, Y, Hauser, E, Baron, JA, Barry, EL, Bishop, DT, Brenner, H, Buchanan, DD, Burnett-Hartman, A, Campbell, PT, Casey, G, Castellví-Bel, S, Chan, AT, Chang-Claude, J, Figueiredo, JC, Gallinger, SJ, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hua, X, Huyghe, JR, Jenkins, MA, Keku, TO, Marchand, LL, Li, L, Lindblom, A, Moreno, V, Newcomb, PA, Pharoah, PDP, Platz, EA, Potter, JD, Qu, C, Rennert, G, Schoen, RE, Slattery, ML, Song, M, van Duijnhoven, FJB, Van Guelpen, B, Vodicka, P, Wolk, A, Woods, MO, Wu, AH, Hayes, RB, Peters, U, Corley, DA, Hsu, L, Su, Y-R, Sakoda, LC, Jeon, J, Thomas, M, Lin, Y, Schneider, JL, Udaltsova, N, Lee, JK, Lansdorp-Vogelaar, I, Peterse, EFP, Zauber, AG, Zheng, J, Zheng, Y, Hauser, E, Baron, JA, Barry, EL, Bishop, DT, Brenner, H, Buchanan, DD, Burnett-Hartman, A, Campbell, PT, Casey, G, Castellví-Bel, S, Chan, AT, Chang-Claude, J, Figueiredo, JC, Gallinger, SJ, Giles, GG, Gruber, SB, Gsur, A, Gunter, MJ, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hua, X, Huyghe, JR, Jenkins, MA, Keku, TO, Marchand, LL, Li, L, Lindblom, A, Moreno, V, Newcomb, PA, Pharoah, PDP, Platz, EA, Potter, JD, Qu, C, Rennert, G, Schoen, RE, Slattery, ML, Song, M, van Duijnhoven, FJB, Van Guelpen, B, Vodicka, P, Wolk, A, Woods, MO, Wu, AH, Hayes, RB, Peters, U, Corley, DA, and Hsu, L
Abstract: BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.
Published: 2023

10. 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

11. Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses

Author: Dimou, N, Kim, AE, Flanagan, O, Murphy, N, Diez-Obrero, V, Shcherbina, A, Aglago, EK, Bouras, E, Campbell, PT, Casey, G, Gallinger, S, Gruber, SB, Jenkins, MA, Lin, Y, Moreno, V, Ruiz-Narvaez, E, Stern, MC, Tian, Y, Tsilidis, KK, Arndt, V, Barry, EL, Baurley, JW, Berndt, SI, Bezieau, S, Bien, SA, Bishop, DT, Brenner, H, Budiarto, A, Carreras-Torres, R, Cenggoro, TW, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, X, Conti, DV, Dampier, CH, Devall, M, Drew, DA, Figueiredo, JC, Giles, GG, Gsur, A, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jordahl, K, Kawaguchi, E, Keku, TO, Larsson, SC, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, J, Newcomb, PA, Newton, CC, Obon-Santacana, M, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Scacheri, PC, Schoen, RE, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Ulrich, CM, Um, CY, van Duijnhoven, FJB, Visvanathan, K, Vodicka, P, Vodickova, L, White, E, Wolk, A, Woods, MO, Qu, C, Kundaje, A, Hsu, L, Gauderman, WJ, Gunter, MJ, Peters, U, Dimou, N, Kim, AE, Flanagan, O, Murphy, N, Diez-Obrero, V, Shcherbina, A, Aglago, EK, Bouras, E, Campbell, PT, Casey, G, Gallinger, S, Gruber, SB, Jenkins, MA, Lin, Y, Moreno, V, Ruiz-Narvaez, E, Stern, MC, Tian, Y, Tsilidis, KK, Arndt, V, Barry, EL, Baurley, JW, Berndt, SI, Bezieau, S, Bien, SA, Bishop, DT, Brenner, H, Budiarto, A, Carreras-Torres, R, Cenggoro, TW, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, X, Conti, DV, Dampier, CH, Devall, M, Drew, DA, Figueiredo, JC, Giles, GG, Gsur, A, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jordahl, K, Kawaguchi, E, Keku, TO, Larsson, SC, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, J, Newcomb, PA, Newton, CC, Obon-Santacana, M, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Scacheri, PC, Schoen, RE, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Ulrich, CM, Um, CY, van Duijnhoven, FJB, Visvanathan, K, Vodicka, P, Vodickova, L, White, E, Wolk, A, Woods, MO, Qu, C, Kundaje, A, Hsu, L, Gauderman, WJ, Gunter, MJ, and Peters, U
Abstract: BACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10-11) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10-09). DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.
Published: 2023

12. 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

13. Genome-wide interaction analysis of folate for colorectal cancer risk

Author: Bouras, E, Kim, AE, Lin, Y, Morrison, J, Du, M, Albanes, D, Barry, EL, Baurley, JW, Berndt, SI, Bien, SA, Bishop, TD, Brenner, H, Budiarto, A, Burnett-Hartman, A, Campbell, PT, Carreras-Torres, R, Casey, G, Cenggoro, TW, Chan, AT, Chang-Claude, J, Conti, DV, Cotterchio, M, Devall, M, Diez-Obrero, V, Dimou, N, Drew, DA, Figueiredo, JC, Giles, GG, Gruber, SB, Gunter, MJ, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Joshi, AD, Kawaguchi, ES, Keku, TO, Kundaje, A, Le Marchand, L, Lewinger, JP, Li, L, Lynch, BM, Mahesworo, B, Mannisto, S, Moreno, V, Murphy, N, Newcomb, PA, Obon-Santacana, M, Ose, J, Palmer, JR, Papadimitriou, N, Pardamean, B, Pellatt, AJ, Peoples, AR, Platz, EA, Potter, JD, Qi, L, Qu, C, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Schmit, SL, Shcherbina, A, Stern, MC, Su, Y-R, Tangen, CM, Thomas, DC, Tian, Y, Um, CY, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Wang, J, White, E, Wolk, A, Woods, MO, Ulrich, CM, Hsu, L, Gauderman, WJ, Peters, U, Tsilidis, KK, Bouras, E, Kim, AE, Lin, Y, Morrison, J, Du, M, Albanes, D, Barry, EL, Baurley, JW, Berndt, SI, Bien, SA, Bishop, TD, Brenner, H, Budiarto, A, Burnett-Hartman, A, Campbell, PT, Carreras-Torres, R, Casey, G, Cenggoro, TW, Chan, AT, Chang-Claude, J, Conti, DV, Cotterchio, M, Devall, M, Diez-Obrero, V, Dimou, N, Drew, DA, Figueiredo, JC, Giles, GG, Gruber, SB, Gunter, MJ, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Joshi, AD, Kawaguchi, ES, Keku, TO, Kundaje, A, Le Marchand, L, Lewinger, JP, Li, L, Lynch, BM, Mahesworo, B, Mannisto, S, Moreno, V, Murphy, N, Newcomb, PA, Obon-Santacana, M, Ose, J, Palmer, JR, Papadimitriou, N, Pardamean, B, Pellatt, AJ, Peoples, AR, Platz, EA, Potter, JD, Qi, L, Qu, C, Rennert, G, Ruiz-Narvaez, E, Sakoda, LC, Schmit, SL, Shcherbina, A, Stern, MC, Su, Y-R, Tangen, CM, Thomas, DC, Tian, Y, Um, CY, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Wang, J, White, E, Wolk, A, Woods, MO, Ulrich, CM, Hsu, L, Gauderman, WJ, Peters, U, and Tsilidis, KK
Abstract: BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the assoc
Published: 2023

14. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Author: Middha, PK, Wang, X, Behrens, S, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baert, T, Freeman, LEB, Becher, H, Beckmann, MW, Benitez, J, Bojesen, SE, Brauch, H, Brenner, H, Brooks-Wilson, A, Campa, D, Canzian, F, Carracedo, A, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Cordina-Duverger, E, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dossus, L, Dugue, P-A, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Giles, GG, Gonzalez-Neira, A, Grassmann, F, Grundy, A, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, SE, Harkness, EF, Holleczek, B, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Ingvar, C, Isaksson, K, Jernstroem, H, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lacey, JV, Lambrechts, D, Larson, NL, Larsson, S, Le Marchand, L, Lejbkowicz, F, Li, S, Linet, M, Lissowska, J, Martinez, ME, Maurer, T, Mulligan, AM, Mulot, C, Murphy, RA, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, O'Brien, KM, Olson, JE, Patel, AV, Prentice, R, Rees-Punia, E, Rennert, G, Rhenius, V, Ruddy, KJ, Sandler, DP, Scott, CG, Shah, MT, Shu, X-O, Smeets, A, Southey, MC, Stone, J, Tamimi, RM, Taylor, JA, Teras, LR, Tomczyk, K, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Weinberg, CR, Wildiers, H, Willett, W, Winham, SJ, Wolk, A, Yang, X, Zamora, MP, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Garcia-Closas, M, Schmidt, MK, Kraft, P, Milne, RL, Lindstroem, S, Easton, DF, Chang-Claude, J, Middha, PK, Wang, X, Behrens, S, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baert, T, Freeman, LEB, Becher, H, Beckmann, MW, Benitez, J, Bojesen, SE, Brauch, H, Brenner, H, Brooks-Wilson, A, Campa, D, Canzian, F, Carracedo, A, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Cordina-Duverger, E, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dossus, L, Dugue, P-A, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Giles, GG, Gonzalez-Neira, A, Grassmann, F, Grundy, A, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, SE, Harkness, EF, Holleczek, B, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Ingvar, C, Isaksson, K, Jernstroem, H, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lacey, JV, Lambrechts, D, Larson, NL, Larsson, S, Le Marchand, L, Lejbkowicz, F, Li, S, Linet, M, Lissowska, J, Martinez, ME, Maurer, T, Mulligan, AM, Mulot, C, Murphy, RA, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, O'Brien, KM, Olson, JE, Patel, AV, Prentice, R, Rees-Punia, E, Rennert, G, Rhenius, V, Ruddy, KJ, Sandler, DP, Scott, CG, Shah, MT, Shu, X-O, Smeets, A, Southey, MC, Stone, J, Tamimi, RM, Taylor, JA, Teras, LR, Tomczyk, K, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Weinberg, CR, Wildiers, H, Willett, W, Winham, SJ, Wolk, A, Yang, X, Zamora, MP, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Garcia-Closas, M, Schmidt, MK, Kraft, P, Milne, RL, Lindstroem, S, Easton, DF, and Chang-Claude, J
Abstract: BACKGROUND: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. METHODS: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. RESULTS: Assuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). CONCLUSIONS: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.
Published: 2023

15. The role of CHADS2 and CHA2DS2‐VASc scores in the prediction of stroke in individuals without atrial fibrillation: a population‐based study

Author: Saliba, W., Gronich, N., Barnett‐Griness, O., and Rennert, G.
Published: 2016
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16. Neutrophil to lymphocyte ratio and risk of a first episode of stroke in patients with atrial fibrillation: a cohort study

Author: Saliba, W., Barnett‐Griness, O., Elias, M., and Rennert, G.
Published: 2015
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17. Statins use and risk of mortality in patient with Clostridium difficile infection

Author: Saliba, W., Barnett-Griness, O., Elias, M., and Rennert, G.
Published: 2014
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18. SO-35 T-cell abundance measured by immunoSEQ predicts overall survival in colorectal cancer

Author: Gruber, S., primary, Idos, G., additional, Bonner, J., additional, Lindsey, S., additional, Rennert, H., additional, and Rennert, G., additional
Published: 2022
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19. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Author: Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon Y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Offman J., Kote-Jarai Z., Eeles R.A., Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon Y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Offman J., Kote-Jarai Z., and Eeles R.A.
Abstract: BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHOD(S): The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3.0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This
Published: 2022

20. A Genome-Wide Gene-Based Gene-Environment Interaction Study of Breast Cancer in More than 90,000 Women

Author: Wang, X, Chen, H, Kapoor, PM, Su, Y-R, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Michailidou, K, Pharoah, PDP, Hopper, JL, Southey, MC, Koutros, S, Freeman, LEB, Stone, J, Rennert, G, Shibli, R, Murphy, RA, Aronson, K, Guenel, P, Truong, T, Teras, LR, Hodge, JM, Canzian, F, Kaaks, R, Brenner, H, Arndt, V, Hoppe, R, Lo, W-Y, Behrens, S, Mannermaa, A, Kosma, V-M, Jung, A, Becher, H, Glies, GG, Haiman, CA, Maskarinec, G, Scott, C, Winham, S, Simard, J, Goldberg, MS, Zheng, W, Long, J, Troester, MA, Love, MI, Peng, C, Tamimi, R, Eliassen, H, Garcia-Closas, M, Figueroa, J, Ahearn, T, Yang, R, Evans, DG, Howell, A, Hall, P, Czene, K, Wolk, A, Sandler, DP, Taylor, JA, Swerdlow, AJ, Orr, N, Lacey, JV, Wang, S, Olsson, H, Easton, DF, Milne, RL, Hsu, L, Kraft, P, Chang-Claude, J, Lindstroem, S, Wang, X, Chen, H, Kapoor, PM, Su, Y-R, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Michailidou, K, Pharoah, PDP, Hopper, JL, Southey, MC, Koutros, S, Freeman, LEB, Stone, J, Rennert, G, Shibli, R, Murphy, RA, Aronson, K, Guenel, P, Truong, T, Teras, LR, Hodge, JM, Canzian, F, Kaaks, R, Brenner, H, Arndt, V, Hoppe, R, Lo, W-Y, Behrens, S, Mannermaa, A, Kosma, V-M, Jung, A, Becher, H, Glies, GG, Haiman, CA, Maskarinec, G, Scott, C, Winham, S, Simard, J, Goldberg, MS, Zheng, W, Long, J, Troester, MA, Love, MI, Peng, C, Tamimi, R, Eliassen, H, Garcia-Closas, M, Figueroa, J, Ahearn, T, Yang, R, Evans, DG, Howell, A, Hall, P, Czene, K, Wolk, A, Sandler, DP, Taylor, JA, Swerdlow, AJ, Orr, N, Lacey, JV, Wang, S, Olsson, H, Easton, DF, Milne, RL, Hsu, L, Kraft, P, Chang-Claude, J, and Lindstroem, S
Abstract: BACKGROUND: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. METHODS: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. RESULTS: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE=4.44×10-6). CONCLUSION: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. IMPACT: Our study suggests a limited role of gene-environment interactions in breast cancer risk.
Published: 2022

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

Author: Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, Chatterjee, N, Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, and Chatterjee, N
Abstract: BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Published: 2022

22. Rare germline copy number variants (CNVs) and breast cancer risk

Author: Dennis, J, Tyrer, JP, Walker, LC, Michailidou, K, Dorling, L, Bolla, MK, Wang, Q, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, Collee, JM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, Jager, A, Jakubowska, A, John, EM, Johnson, N, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Larson, NL, Linet, M, Ogrodniczak, A, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Milne, RL, Muranen, TA, Murphy, RA, Nevanlinna, H, Olson, JE, Olsson, H, Park-Simon, T-W, Perou, CM, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shibli, R, Smeets, A, Soucy, P, Southey, MC, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Teras, LR, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wendt, C, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Simard, J, Dunning, AM, Pharoah, PDP, Easton, DF, Dennis, J, Tyrer, JP, Walker, LC, Michailidou, K, Dorling, L, Bolla, MK, Wang, Q, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, Collee, JM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, Jager, A, Jakubowska, A, John, EM, Johnson, N, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Larson, NL, Linet, M, Ogrodniczak, A, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Milne, RL, Muranen, TA, Murphy, RA, Nevanlinna, H, Olson, JE, Olsson, H, Park-Simon, T-W, Perou, CM, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shibli, R, Smeets, A, Soucy, P, Southey, MC, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Teras, LR, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wendt, C, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Simard, J, Dunning, AM, Pharoah, PDP, and Easton, DF
Abstract: Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
Published: 2022

23. 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

24. Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk

Author: Haas, CB, Su, Y-R, Petersen, P, Wang, X, Bien, SA, Lin, Y, Albanes, D, Weinstein, SJ, Jenkins, MA, Figueiredo, JC, Newcomb, PA, Casey, G, Le Marchand, L, Campbell, PT, Moreno, V, Potter, JD, Sakoda, LC, Slattery, ML, Chan, AT, Li, L, Giles, GG, Milne, RL, Gruber, SB, Rennert, G, Woods, MO, Gallinger, SJ, Berndt, S, Hayes, RB, Huang, W-Y, Wolk, A, White, E, Nan, H, Nassir, R, Lindor, NM, Lewinger, JP, Kim, AE, Conti, D, Gauderman, WJ, Buchanan, DD, Peters, U, Hsu, L, Haas, CB, Su, Y-R, Petersen, P, Wang, X, Bien, SA, Lin, Y, Albanes, D, Weinstein, SJ, Jenkins, MA, Figueiredo, JC, Newcomb, PA, Casey, G, Le Marchand, L, Campbell, PT, Moreno, V, Potter, JD, Sakoda, LC, Slattery, ML, Chan, AT, Li, L, Giles, GG, Milne, RL, Gruber, SB, Rennert, G, Woods, MO, Gallinger, SJ, Berndt, S, Hayes, RB, Huang, W-Y, Wolk, A, White, E, Nan, H, Nassir, R, Lindor, NM, Lewinger, JP, Kim, AE, Conti, D, Gauderman, WJ, Buchanan, DD, Peters, U, and Hsu, L
Abstract: Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.
Published: 2022

25. 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

26. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author: Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Lynch, BM, Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, and Lynch, BM
Abstract: OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer r
Published: 2022

27. Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk

Author: Tian, Y, Kim, AE, Bien, SA, Lin, Y, Qu, C, Harrison, TA, Carreras-Torres, R, Diez-Obrero, V, Dimou, N, Drew, DA, Hidaka, A, Huyghe, JR, Jordahl, KM, Morrison, J, Murphy, N, Obon-Santacana, M, Ulrich, CM, Ose, J, Peoples, AR, Ruiz-Narvaez, EA, Shcherbina, A, Stern, MC, Su, Y-R, van Duijnhoven, FJB, Arndt, V, Baurley, JW, Berndt, S, Bishop, DT, Brenner, H, Buchanan, DD, Chan, AT, Figueiredo, JC, Gallinger, S, Gruber, SB, Harlid, S, Hoffmeister, M, Jenkins, MA, Joshi, AD, Keku, TO, Larsson, SC, Le Marchand, L, Li, L, Giles, GG, Milne, RL, Nan, H, Nassir, R, Ogino, S, Budiarto, A, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Sakoda, LC, Schoen, RE, Slattery, ML, Thibodeau, SN, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Casey, G, Conti, D, Gunter, MJ, Kundaje, A, Lewinger, JP, Moreno, V, Newcomb, PA, Pardamean, B, Thomas, DC, Tsilidis, KK, Peters, U, Gauderman, WJ, Hsu, L, Chang-Claude, J, Tian, Y, Kim, AE, Bien, SA, Lin, Y, Qu, C, Harrison, TA, Carreras-Torres, R, Diez-Obrero, V, Dimou, N, Drew, DA, Hidaka, A, Huyghe, JR, Jordahl, KM, Morrison, J, Murphy, N, Obon-Santacana, M, Ulrich, CM, Ose, J, Peoples, AR, Ruiz-Narvaez, EA, Shcherbina, A, Stern, MC, Su, Y-R, van Duijnhoven, FJB, Arndt, V, Baurley, JW, Berndt, S, Bishop, DT, Brenner, H, Buchanan, DD, Chan, AT, Figueiredo, JC, Gallinger, S, Gruber, SB, Harlid, S, Hoffmeister, M, Jenkins, MA, Joshi, AD, Keku, TO, Larsson, SC, Le Marchand, L, Li, L, Giles, GG, Milne, RL, Nan, H, Nassir, R, Ogino, S, Budiarto, A, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Sakoda, LC, Schoen, RE, Slattery, ML, Thibodeau, SN, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Casey, G, Conti, D, Gunter, MJ, Kundaje, A, Lewinger, JP, Moreno, V, Newcomb, PA, Pardamean, B, Thomas, DC, Tsilidis, KK, Peters, U, Gauderman, WJ, Hsu, L, and Chang-Claude, J
Abstract: BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
Published: 2022

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

Author: Ahearn, T. U. (Thomas U.), Zhang, H. (Haoyu), Michailidou, K. (Kyriaki), Milne, R. L. (Roger L.), Bolla, M. K. (Manjeet K.), Dennis, J. (Joe), Dunning, A. M. (Alison M.), Lush, M. (Michael), Wang, Q. (Qin), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Auer, P. L. (Paul L.), Augustinsson, A. (Annelie), Baten, A. (Adinda), Becher, H. (Heiko), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Blomqvist, C. (Carl), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brooks-Wilson, A. (Angela), Bruening, T. (Thomas), Burwinkel, B. (Barbara), Buys, S. S. (Saundra S.), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Clarke, C. L. (Christine L.), Collee, J. M. (J. Margriet), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Dork, T. (Thilo), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Floris, G. (Giuseppe), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Gonzalez-Neira, A. (Anna), Alnaes, G. I. (Grethe I. Grenaker), Grip, M. (Mervi), Guenel, P. (Pascal), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), Harkness, E. F. (Elaine F.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Holleczek, B. (Bernd), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Jakimovska, M. (Milena), Jakubowska, A. (Anna), John, E. M. (Esther M.), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kauppila, S. (Saila), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Ko, Y.-D. (Yon-Dschun), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Kruger, U. (Ute), Kubelka-Sabit, K. (Katerina), Kurian, A. W. (Allison W.), Kyriacou, K. (Kyriacos), Lambrechts, D. (Diether), Lee, D. G. (Derrick G.), Lindblom, A. (Annika), Linet, M. (Martha), Lissowska, J. (Jolanta), Llaneza, A. (Ana), Lo, W.-Y. (Wing-Yee), MacInnis, R. J. (Robert J.), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Martinez, M. E. (Maria Elena), McLean, C. (Catriona), Meindl, A. (Alfons), Menon, U. (Usha), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nodora, J. (Jesse), Offit, K. (Kenneth), Olsson, H. (Hakan), Orr, N. (Nick), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peto, J. (Julian), Pita, G. (Guillermo), Plaseska-Karanfilska, D. (Dijana), Prentice, R. (Ross), Punie, K. (Kevin), Pylkas, K. (Katri), Radice, P. (Paolo), Rennert, G. (Gad), Romero, A. (Atocha), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sampson, S. (Sarah), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schoemaker, M. J. (Minouk J.), Schottker, B. (Ben), Sherman, M. E. (Mark E.), Shu, X.-O. (Xiao-Ou), Smichkoska, S. (Snezhana), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Torres, D. (Diana), Troester, M. A. (Melissa A.), Vachon, C. M. (Celine M.), van Deurzen, C. H. (Carolien H. M.), van Veen, E. M. (Elke M.), Wagner, P. (Philippe), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Wesseling, J. (Jelle), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Zheng, W. (Wei), Couch, F. J. (Fergus J.), Simard, J. (Jacques), Kraft, P. (Peter), Easton, D. F. (Douglas F.), Pharoah, P. D. (Paul D. P.), Schmidt, M. K. (Marjanka K.), Garcia-Closas, M. (Montserrat), Chatterjee, N. (Nilanjan), Ahearn, T. U. (Thomas U.), Zhang, H. (Haoyu), Michailidou, K. (Kyriaki), Milne, R. L. (Roger L.), Bolla, M. K. (Manjeet K.), Dennis, J. (Joe), Dunning, A. M. (Alison M.), Lush, M. (Michael), Wang, Q. (Qin), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Auer, P. L. (Paul L.), Augustinsson, A. (Annelie), Baten, A. (Adinda), Becher, H. (Heiko), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Blomqvist, C. (Carl), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brooks-Wilson, A. (Angela), Bruening, T. (Thomas), Burwinkel, B. (Barbara), Buys, S. S. (Saundra S.), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Clarke, C. L. (Christine L.), Collee, J. M. (J. Margriet), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Dork, T. (Thilo), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Floris, G. (Giuseppe), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Gonzalez-Neira, A. (Anna), Alnaes, G. I. (Grethe I. Grenaker), Grip, M. (Mervi), Guenel, P. (Pascal), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), Harkness, E. F. (Elaine F.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Holleczek, B. (Bernd), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Jakimovska, M. (Milena), Jakubowska, A. (Anna), John, E. M. (Esther M.), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kauppila, S. (Saila), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Ko, Y.-D. (Yon-Dschun), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Kruger, U. (Ute), Kubelka-Sabit, K. (Katerina), Kurian, A. W. (Allison W.), Kyriacou, K. (Kyriacos), Lambrechts, D. (Diether), Lee, D. G. (Derrick G.), Lindblom, A. (Annika), Linet, M. (Martha), Lissowska, J. (Jolanta), Llaneza, A. (Ana), Lo, W.-Y. (Wing-Yee), MacInnis, R. J. (Robert J.), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Martinez, M. E. (Maria Elena), McLean, C. (Catriona), Meindl, A. (Alfons), Menon, U. (Usha), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nodora, J. (Jesse), Offit, K. (Kenneth), Olsson, H. (Hakan), Orr, N. (Nick), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peto, J. (Julian), Pita, G. (Guillermo), Plaseska-Karanfilska, D. (Dijana), Prentice, R. (Ross), Punie, K. (Kevin), Pylkas, K. (Katri), Radice, P. (Paolo), Rennert, G. (Gad), Romero, A. (Atocha), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sampson, S. (Sarah), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schoemaker, M. J. (Minouk J.), Schottker, B. (Ben), Sherman, M. E. (Mark E.), Shu, X.-O. (Xiao-Ou), Smichkoska, S. (Snezhana), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Torres, D. (Diana), Troester, M. A. (Melissa A.), Vachon, C. M. (Celine M.), van Deurzen, C. H. (Carolien H. M.), van Veen, E. M. (Elke M.), Wagner, P. (Philippe), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Wesseling, J. (Jelle), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Zheng, W. (Wei), Couch, F. J. (Fergus J.), Simard, J. (Jacques), Kraft, P. (Peter), Easton, D. F. (Douglas F.), Pharoah, P. D. (Paul D. P.), Schmidt, M. K. (Marjanka K.), Garcia-Closas, M. (Montserrat), and Chatterjee, N. (Nilanjan)
Abstract: Background: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Published: 2022

29. Rare germline copy number variants (CNVs) and breast cancer risk

Author: Dennis, J. (Joe), Tyrer, J. P. (Jonathan P.), Walker, L. C. (Logan C.), Michailidou, K. (Kyriaki), Dorling, L. (Leila), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antonenkova, N. N. (Natalia N.), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Freeman, L. E. (Laura E. Beane), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Brenner, H. (Hermann), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chenevix-Trench, G. (Georgia), Clarke, C. L. (Christine L.), N. C. (NBCS Collaborators), Collee, J. M. (J. Margriet), C. C. (CTS Consortium), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Devilee, P. (Peter), Dörk, T. (Thilo), Dossus, L. (Laure), Eliassen, A. H. (A. Heather), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fritschi, L. (Lin), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Garcia-Closas, M. (Montserrat), Giles, G. G. (Graham G.), Gonzalez-Neira, A. (Anna), Guenel, P. (Pascal), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hollestelle, A. (Antoinette), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Howell, A. (Anthony), A. I. (ABCTB Investigators), k. I. (kConFab/AOCS Investigators), Jager, A. (Agnes), Jakubowska, A. (Anna), John, E. M. (Esther M.), Johnson, N. (Nichola), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Ko, Y.-D. (Yon-Dschun), Kosma, V.-M. (Veli-Matti), Koutros, S. (Stella), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kubelka-Sabit, K. (Katerina), Kurian, A. W. (Allison W.), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Larson, N. L. (Nicole L.), Linet, M. (Martha), Ogrodniczak, A. (Alicja), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Mavroudis, D. (Dimitrios), Milne, R. L. (Roger L.), Muranen, T. A. (Taru A.), Murphy, R. A. (Rachel A.), Nevanlinna, H. (Heli), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Park-Simon, T.-W. (Tjoung-Won), Perou, C. M. (Charles M.), Peterlongo, P. (Paolo), Plaseska-Karanfilska, D. (Dijana), Pylkas, K. (Katri), Rennert, G. (Gad), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Shibli, R. (Rana), Smeets, A. (Ann), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Taylor, J. A. (Jack A.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), Wendt, C. (Camilla), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Zheng, W. (Wei), Ziogas, A. (Argyrios), Simard, J. (Jacques), Dunning, A. M. (Alison M.), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Dennis, J. (Joe), Tyrer, J. P. (Jonathan P.), Walker, L. C. (Logan C.), Michailidou, K. (Kyriaki), Dorling, L. (Leila), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antonenkova, N. N. (Natalia N.), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Freeman, L. E. (Laura E. Beane), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Brenner, H. (Hermann), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chenevix-Trench, G. (Georgia), Clarke, C. L. (Christine L.), N. C. (NBCS Collaborators), Collee, J. M. (J. Margriet), C. C. (CTS Consortium), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Devilee, P. (Peter), Dörk, T. (Thilo), Dossus, L. (Laure), Eliassen, A. H. (A. Heather), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fritschi, L. (Lin), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Garcia-Closas, M. (Montserrat), Giles, G. G. (Graham G.), Gonzalez-Neira, A. (Anna), Guenel, P. (Pascal), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hollestelle, A. (Antoinette), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Howell, A. (Anthony), A. I. (ABCTB Investigators), k. I. (kConFab/AOCS Investigators), Jager, A. (Agnes), Jakubowska, A. (Anna), John, E. M. (Esther M.), Johnson, N. (Nichola), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Ko, Y.-D. (Yon-Dschun), Kosma, V.-M. (Veli-Matti), Koutros, S. (Stella), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kubelka-Sabit, K. (Katerina), Kurian, A. W. (Allison W.), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Larson, N. L. (Nicole L.), Linet, M. (Martha), Ogrodniczak, A. (Alicja), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Mavroudis, D. (Dimitrios), Milne, R. L. (Roger L.), Muranen, T. A. (Taru A.), Murphy, R. A. (Rachel A.), Nevanlinna, H. (Heli), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Park-Simon, T.-W. (Tjoung-Won), Perou, C. M. (Charles M.), Peterlongo, P. (Paolo), Plaseska-Karanfilska, D. (Dijana), Pylkas, K. (Katri), Rennert, G. (Gad), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Shibli, R. (Rana), Smeets, A. (Ann), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Taylor, J. A. (Jack A.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), Wendt, C. (Camilla), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Zheng, W. (Wei), Ziogas, A. (Argyrios), Simard, J. (Jacques), Dunning, A. M. (Alison M.), Pharoah, P. D. (Paul D. P.), and Easton, D. F. (Douglas F.)
Abstract: Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
Published: 2022

30. Iam hiQ—a novel pair of accuracy indices for imputed genotypes

Author: Rosenberger, A., Tozzi, V., Bickeböller, H., Hung, R.J., Christiani, D.C., Caporaso, N.E., Liu, G., Bojesen, S.E., Le Marchand, L., Albanes, D., Aldrich, M.C., Tardon, A., Fernández-Tardón, G., Rennert, G., Field, J.K., Davies, M., Liloglou, T., Kiemeney, L.A., Lazarus, P., Haugen, A., Zienolddiny, S., Lam, S., Schabath, M.B., Andrew, A.S., Duell, E.J., Arnold, S.M., Brunnström, H., Melander, O., Goodman, G.E., Chen, C., Doherty, J.A., Teare, M.D., Cox, A., Woll, P.J., Risch, A., Muley, T.R., Johansson, M., Brennan, P., Landi, M.T., Shete, S.S., and Amos, C.I.
Abstract: Background\ud \ud Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand.\ud \ud \ud \ud Results\ud \ud Applying both measures to a large case–control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2).\ud \ud \ud \ud Conclusion\ud \ud We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data.
Published: 2022

31. Smoking Attenuates the Negative Association between Carotenoids Consumption and Colorectal Cancer Risk

Author: Chaiter, Y., Gruber, S. B., Ben-Amotz, A., Almog, R., Rennert, H. S., Fischler, R., Rozen, G., and Rennert, G.
Published: 2009
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32. Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population

Author: Lavie, O., Narod, S., Lejbkowicz, F., Dishon, S., Goldberg, Y., Gemer, O., and Rennert, G.
Published: 2011
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33. Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel

Author: Rennert, G, Dishon, S, Rennert, H S, and Fares, F
Published: 2005

34. Cancer Genetics Service Provision : A Comparison of Seven European Centres

Author: Hopwood, P., van Asperen, C.J., Borreani, G., Bourret, P., Decruyenaere, M., Dishon, S., Eisinger, F., Evans, D.G.R., Evers-Kiebooms, G., Gangeri, L., Hagoel, L., Legius, E., Nippert, I., Rennert, G., Schlegelberger, B., Sevilla, C., Sobol, H., Tibben, A., Welkenhuysen, M., and Julian-Reynier, C.
Published: 2003

35. Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application

Author: Echle, A, Ghaffari Laleh, N, Quirke, P, Grabsch, H I, Muti, H S, Saldanha, O L, Brockmoeller, S F, van den Brandt, P A, Hutchins, G G A, Richman, S D, Horisberger, K, Galata, C, Ebert, M P, Eckardt, M, Boutros, M, Horst, D, Reissfelder, C, Alwers, E, Brinker, T J, Langer, R, Jenniskens, J C A, Offermans, K, Mueller, W, Gray, R, Gruber, S B, Greenson, J K, Rennert, G, Bonner, J D, Schmolze, D, Chang-Claude, J, Brenner, H, Trautwein, C, Boor, P, Jaeger, D, Gaisa, N T, Hoffmeister, M, West, N P, Kather, J N, Pathologie, RS: GROW - R2 - Basic and Translational Cancer Biology, Epidemiologie, RS: GROW - R1 - Prevention, and RS: CAPHRI - R5 - Optimising Patient Care
Subjects: RISK, Cancer Research, PREDICTION, deep learning, colorectal cancer, 610 Medicine & health, DNA Mismatch Repair, digestive system diseases, MODEL, Lynch syndrome, Oncology, Artificial Intelligence, biomarker, 570 Life sciences, biology, Humans, Microsatellite Instability, Colorectal Neoplasms, Early Detection of Cancer
Abstract: ESMO open 7(2), 100400 (2022). doi:10.1016/j.esmoop.2022.100400, Published by BMJ, London
Published: 2021

36. Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Author: Baxter, J.S., Johnson, N., Tomczyk, K., Gillespie, A., Maguire, S., Brough, R., Fachal, L., Michailidou, K., Bolla, M.K., Wang, Q., Dennis, J., Ahearn, T.U., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arndt, V., Aronson, K.J., Augustinsson, A., Becher, H., Beckmann, M.W., Behrens, S., Benitez, J., Bermisheva, M., Bogdanova, N.V., Bojesen, S.E., Brenner, H., Brucker, S.Y., Cai, Q.Y., Campa, D., Canzian, F., Castelao, J.E., Chan, T.L., Chang-Claude, J., Chanock, S.J., Chenevix-Trench, G., Choi, J.Y., Clarke, C.L., Collaborators, N., Colonna, S., Conroy, D.M., Couch, F.J., Cox, A., Cross, S.S., Czene, K., Daly, M.B., Devilee, P., Dork, T., Dossus, L., Dwek, M., Eccles, D.M., Ekici, A.B., Eliassen, A.H., Engel, C., Fasching, P.A., Figueroa, J., Flyger, H., Gago-Dominguez, M., Gao, C., Garcia-Closas, M., Garcia-Saenz, J.A., Ghoussaini, M., Giles, G.G., Goldberg, M.S., Gonzalez-Neira, A., Guenel, P., Gundert, M., Haeberle, L., Hahnen, E., Haiman, C.A., Hall, P., Hamann, U., Hartman, M., Hatse, S., Hauke, J., Hollestelle, A., Hoppe, R., Hopper, J.L., Hou, M.F., Ito, H., Iwasaki, M., Jager, A., Jakubowska, A., Janni, W., John, E.M., Joseph, V., Jung, A., Kaaks, R., Kang, D., Keeman, R., Khusnutdinova, E., Kim, S.W., Kosma, V.M., Kraft, P., Kristensen, V.N., Kubelka-Sabit, K., Kurian, A.W., Kwong, A., Lacey, J.V., Lambrechts, D., Larson, N.L., Larsson, S.C., Marchand, L. le, Lejbkowicz, F., Li, J.M., Long, J.R., Lophatananon, A., LubiNski, J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Matsuo, K., Mavroudis, D., Mayes, R., Menon, U., Milne, R.L., Taib, N.A.M., Muir, K., Muranen, T.A., Murphy, R.A., Nevanlinna, H., O'Brien, K.M., Offit, K., Olson, J.E., Olsson, H., Park, S.K., Park-Simon, T.W., Patel, A.V., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Presneau, N., Pylkas, K., Rack, B., Rennert, G., Romero, A., Ruebner, M., Rudiger, T., Saloustros, E., Sandler, D.P., Sawyer, E.J., Schmidt, M.K., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Shah, M., Shen, C.Y., Shu, X.O., Simard, J., Southey, M.C., Stone, J., Surowy, H., Swerdlow, A.J., Tamimi, R.M., Tapper, W.J., Taylor, J.A., Teo, S.H., Teras, L.R., Terry, M.B., Toland, A.E., Tomlinson, I., Truong, T., Tseng, C.C., Untch, M., Vachon, C.M., Ouweland, A.M.W. van den, Wang, S.S., Weinberg, C.R., Wendt, C., Winham, S.J., Winqvist, R., Wolk, A., Wu, A.H., Yamaji, T., Zheng, W., Ziogas, A., Pharoah, P.D.P., Dunning, A.M., Easton, D.F., Pettitt, S.J., Lord, C.J., Haider, S., Orr, N., Fletcher, O., kConFab Investigators, ABCTB Investigators, Medical Oncology, Clinical Genetics, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Biosciences, Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Basic medicine, breast cancer risk, 0302 clinical medicine, Transcription (biology), Risk Factors, WIDE ASSOCIATION, TRANSCRIPTION, Promoter Regions, Genetic, Genetics (clinical), Sequence Deletion, Genetics, Genetics & Heredity, 0303 health sciences, Chromosome Mapping, 3. Good health, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 2, Pair 2, Female, Medical Genetics, Life Sciences & Biomedicine, Human, Tumor suppressor gene, SUSCEPTIBILITY LOCI, In silico, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Chromosomes, Article, Cell Line, RNAS, Promoter Regions, 03 medical and health sciences, functional annotation, risk locus, CRISPR-Cas Systems, Genetic Association Studies, Genetic Variation, Humans, Insulin-Like Growth Factor Binding Protein 5, Molecular Sequence Annotation, 11Q13, Genetic, SDG 3 - Good Health and Well-being, Enhancer, Transcription factor, 030304 developmental biology, Medicinsk genetik, Reporter gene, Science & Technology, IDENTIFICATION, Clinical medicine, Estrogen receptor alpha
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31). ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:108 issue:7 pages:1190-1203 ispartof: location:United States status: published
Published: 2021

37. Dietary intervention studies and cancer prevention

Author: Rennert, G
Published: 2002

38. Screening with faecal occult blood test (FOBT) for colorectal cancer: assessment of two methods that attempt to improve compliance

Author: Ore, L, Hagoel, L, Lavi, I, and Rennert, G
Published: 2001

39. Breast cancer screening in 21 countries: delivery of services, notification of results and outcomes ascertainment

Author: Ballard-Barbash, R, Klabunde, C, Paci, E, Broeders, M, Coleman, E A, Fracheboud, J, Bouchard, F, Rennert, G, and Shapiro, S
Published: 1999

40. Lung Cancer in Israel, 1962-1982: II. Ethnic Differences among Jews

Author: Rennert, G., Rennert, H. S., Katz, L., and Epstein, L.
Published: 1990

41. Lung Cancer Histology in Major Ethnic Groups among the Jews. Israel, 1962-1982

Author: Rennert, G., Rennert, H. S., and Epstein, L.
Published: 1991

42. Establishing an International Computer Network for Research and Teaching in Public Health and Epidemiology

Author: Østbye, T., Bojan, F., Rennert, G., Hurlen, P., and Garner, B.
Published: 1991

43. Lung Cancer in Israel, 1962-1982: I. Jews and Arabs

Author: Rennert, G., Tamir, A., Katz, L., Steinitz, R., and Epstein, L.
Published: 1988

44. O-023 Observational data outcomes of chemotherapy backbone for MSI – high metastatic colorectal cancer in molecular epidemiology of colorectal cancer in Israel

Author: Shulman, K., Barnett-Griness, O., Friedman, V., Gruber Stephen, B., Lejbkowicz, F., and Rennert, G.
Published: 2016
Full Text: View/download PDF

45. The relationship between obesity and the increase in serum 25(OH)D levels in response to vitamin D supplementation

Author: Saliba, W., Barnett-Griness, O., and Rennert, G.
Published: 2013
Full Text: View/download PDF

46. CYP3A7*1C allele:linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author: Johnson, N. (Nichola), Maguire, S. (Sarah), Morra, A. (Anna), Kapoor, P. M. (Pooja Middha), Tomczyk, K. (Katarzyna), Jones, M. E. (Michael E.), Schoemaker, M. J. (Minouk J.), Gilham, C. (Clare), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Dennis, J. (Joe), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antonenkova, N. N. (Natalia N.), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Augustinsson, A. (Annelie), Baynes, C. (Caroline), Freeman, L. E. (Laura E. Beane), Beckmann, M. W. (Matthias W.), Benitez, J. (Javier), Bermisheva, M. (Marina), Blomqvist, C. (Carl), Boeckx, B. (Bram), Bogdanova, N. V. (Natalia V.), Bojesen, S. E. (Stig E.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Burwinkel, B. (Barbara), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Clarke, C. L. (Christine L.), Conroy, D. M. (Don M.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Doerk, T. (Thilo), Eliassen, A. H. (A. Heather), Engel, C. (Christoph), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Floris, G. (Giuseppe), Flyger, H. (Henrik), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garcia-Closas, M. (Montserrat), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Gonzalez-Neira, A. (Anna), Guenel, P. (Pascal), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Harrington, P. A. (Patricia A.), Hart, S. N. (Steven N.), Hooning, M. J. (Maartje J.), Hopper, J. L. (John L.), Howell, A. (Anthony), Hunter, D. J. (David J.), Jager, A. (Agnes), Jakubowska, A. (Anna), John, E. M. (Esther M.), Kaaks, R. (Rudolf), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Kosma, V.-M. (Veli-Matti), Koutros, S. (Stella), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Linet, M. (Martha), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J. W. (John W. M.), Mavroudis, D. (Dimitrios), Mayes, R. (Rebecca), Meindl, A. (Alfons), Milne, R. L. (Roger L.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Obi, N. (Nadia), Olshan, A. F. (Andrew F.), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Orban, E. (Ester), Park-Simon, T.-W. (Tjoung-Won), Peterlongo, P. (Paolo), Plaseska-Karanfilska, D. (Dijana), Pylkäs, K. (Katri), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Ruddy, K. J. (Kathryn J.), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Scott, C. (Christopher), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Smichkoska, S. (Snezhana), Sohn, C. (Christof), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Stone, J. (Jennifer), Tamimi, R. M. (Rulla M.), Taylor, J. A. (Jack A.), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), van Veen, E. M. (Elke M.), Wang, S. S. (Sophia S.), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Wildiers, H. (Hans), Winqvist, R. (Robert), Wolk, A. (Alicja), Zheng, W. (Wei), Ziogas, A. (Argyrios), Dunning, A. M. (Alison M.), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Howie, A. F. (A. Forbes), Peto, J. (Julian), dos-Santos-Silva, I. (Isabel), Swerdlow, A. J. (Anthony J.), Chang-Claude, J. (Jenny), Schmidt, M. K. (Marjanka K.), Orr, N. (Nick), and Fletcher, O. (Olivia)
Abstract: Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10⁻¹⁸); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10⁻¹⁸). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
Published: 2021

47. Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Author: Park, HA, Neumeyer, S, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baten, A, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Brucker, SY, Burwinkel, B, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Børresen-Dale, A-L, Grenaker Alnæs, GI, Sahlberg, KK, Ottestad, L, Kåresen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebråten, O, Naume, B, Fosså, A, Kiserud, CE, Reinertsen, KV, Helland, Å, Riis, M, Geisler, J, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dörk, T, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grip, M, Guénel, P, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Han, S, Harkness, EF, Hart, SN, He, W, Heemskerk-Gerritsen, BAM, Hopper, JL, Hunter, DJ, Clarke, C, Marsh, D, Scott, R, Baxter, R, Yip, D, Carpenter, J, Davis, A, Pathmanathan, N, Simpson, P, Graham, 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, SA, Meiser, B, Milne, R, Nightingale, S, O’Connell, S, O’Sullivan, S, Ortega, DG, Pachter, N, Patterson, B, Pearn, A, Phillips, K, Pieper, E, Rickard, E, Robinson, B, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Sexton, A, Shelling, A, Southey, M, Spurdle, A, Taylor, J, Taylor, R, Thorne, H, Trainer, A, Tucker, K, Visvader, J, Walker, L, Williams, R, Winship, I, Young, MA, Jager, A, Jakubowska, A, John, EM, Jung, A, Kaaks, R, Kapoor, PM, Keeman, R, Khusnutdinova, E, Kitahara, CM, Koppert, LB, Koutros, S, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lo, W-Y, Lubiński, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Muranen, TA, Nevanlinna, H, Newman, WG, Nordestgaard, BG, Offit, K, Olshan, AF, Olsson, H, Park-Simon, T-W, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Radice, P, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schoemaker, MJ, Schwentner, L, Shah, M, Shu, X-O, Simard, J, Smeets, A, Southey, MC, Spinelli, JJ, Stevens, V, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, van Veen, EM, Vijai, J, Wang, S, Wendt, C, Winqvist, R, Wolk, A, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Zheng, W, Kraft, P, Chang-Claude, J, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Park, Hanla A. [0000-0001-8055-3729], Dennis, Joe [0000-0003-4591-1214], Augustinsson, Annelie [0000-0003-3415-0536], Brenner, Hermann [0000-0002-6129-1572], Canzian, Federico [0000-0002-4261-4583], Cox, Angela [0000-0002-5138-1099], Devilee, Peter [0000-0002-8023-2009], Fasching, Peter A. [0000-0003-4885-8471], Harkness, Elaine F. [0000-0001-6625-7739], Hart, Steven N. [0000-0001-7714-2734], Heemskerk-Gerritsen, Bernadette A. M. [0000-0002-9724-6693], Jakubowska, Anna [0000-0002-5650-0501], Kapoor, Pooja Middha [0000-0001-5503-8215], Kurian, Allison W. [0000-0002-6175-9470], Newman, William G. [0000-0002-6382-4678], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Sawyer, Elinor J. [0000-0001-8285-4111], Scott, Christopher [0000-0003-1340-0647], Smeets, Ann [0000-0002-5091-6602], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Pharoah, Paul D. P. [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Medicin och hälsovetenskap, Cancer Research, Genotyping Techniques, Breast Neoplasms, Case-Control Studies, Cigarette Smoking, Female, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, ALCOHOL, Medical and Health Sciences, 0302 clinical medicine, Breast cancer, Pleiotropy, Epidemiology, Medicine, TOBACCO, Breast Neoplasms/epidemiology, Cigarette Smoking/adverse effects, WOMEN, ASSOCIATION, Single Nucleotide, 3. Good health, Substance abuse, 692/699/67/1347, 030220 oncology & carcinogenesis, Life Sciences & Biomedicine, 692/499, medicine.medical_specialty, 3122 Cancers, Single-nucleotide polymorphism, Article, 03 medical and health sciences, Internal medicine, ddc:610, Polymorphism, Genetic association, Science & Technology, business.industry, Cancer, medicine.disease, 030104 developmental biology, Clinical research, Risk factors, TISSUE, INFERENCE, CIGARETTE-SMOKING, business
Abstract: Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10–2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
Published: 2021

48. The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Author: Lakeman, I.M.M., Broek, A.J. van den, Vos, Janet R., Barnes, D.R., Adlard, J., Andrulis, I.L., Arason, A., Arnold, N., Arun, B.K., Balmaña, J., Barrowdale, D., Benitez, J., Borg, A., Caldés, T., Caligo, M.A., Chung, W.K., Claes, K.B.M., Collée, J.M., Couch, F.J., Daly, M.B., Dennis, J., Dhawan, M., Domchek, S.M., Eeles, R., Engel, C., Evans, D.G., Feliubadaló, L., Foretova, L., Friedman, E., Frost, D., Ganz, P.A., Garber, J., Gayther, S.A., Gerdes, A.M., Godwin, A.K., Goldgar, D.E., Hahnen, E., Hake, C.R., Hamann, U., Hogervorst, F.B., Hooning, M.J., Hopper, J.L., Hulick, P.J., Imyanitov, E.N., Isaacs, C., Izatt, L., Jakubowska, A., James, P.A., Janavicius, R., Jensen, U.B., Jiao, Y., John, E.M., Joseph, V., Karlan, B.Y., Kets, C.M., Konstantopoulou, I., Kwong, A., Legrand, C., Leslie, G., Lesueur, F., Loud, J.T., Lubiński, J., Manoukian, S., McGuffog, L., Miller, A., Gomes, D.M., Montagna, M., Mouret-Fourme, E., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Yie, J.N.Y., Olah, E., Olopade, O.I., Park, S.K., Parsons, M.T., Peterlongo, P., Piedmonte, M., Radice, P., Rantala, J., Rennert, G., Risch, H.A., Schmutzler, R.K., Sharma, P., Simard, J., Singer, C.F., Stadler, Z., Stoppa-Lyonnet, D., Sutter, C., Tan, Y.Y., Teixeira, M.R., Teo, S.H., Teulé, A., Thomassen, M., Thull, D.L., Tischkowitz, M., Toland, A.E., Tung, N., Rensburg, E.J. van, Vega, A., Robson, M., Schmidt, M.K., Lakeman, I.M.M., Broek, A.J. van den, Vos, Janet R., Barnes, D.R., Adlard, J., Andrulis, I.L., Arason, A., Arnold, N., Arun, B.K., Balmaña, J., Barrowdale, D., Benitez, J., Borg, A., Caldés, T., Caligo, M.A., Chung, W.K., Claes, K.B.M., Collée, J.M., Couch, F.J., Daly, M.B., Dennis, J., Dhawan, M., Domchek, S.M., Eeles, R., Engel, C., Evans, D.G., Feliubadaló, L., Foretova, L., Friedman, E., Frost, D., Ganz, P.A., Garber, J., Gayther, S.A., Gerdes, A.M., Godwin, A.K., Goldgar, D.E., Hahnen, E., Hake, C.R., Hamann, U., Hogervorst, F.B., Hooning, M.J., Hopper, J.L., Hulick, P.J., Imyanitov, E.N., Isaacs, C., Izatt, L., Jakubowska, A., James, P.A., Janavicius, R., Jensen, U.B., Jiao, Y., John, E.M., Joseph, V., Karlan, B.Y., Kets, C.M., Konstantopoulou, I., Kwong, A., Legrand, C., Leslie, G., Lesueur, F., Loud, J.T., Lubiński, J., Manoukian, S., McGuffog, L., Miller, A., Gomes, D.M., Montagna, M., Mouret-Fourme, E., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Yie, J.N.Y., Olah, E., Olopade, O.I., Park, S.K., Parsons, M.T., Peterlongo, P., Piedmonte, M., Radice, P., Rantala, J., Rennert, G., Risch, H.A., Schmutzler, R.K., Sharma, P., Simard, J., Singer, C.F., Stadler, Z., Stoppa-Lyonnet, D., Sutter, C., Tan, Y.Y., Teixeira, M.R., Teo, S.H., Teulé, A., Thomassen, M., Thull, D.L., Tischkowitz, M., Toland, A.E., Tung, N., Rensburg, E.J. van, Vega, A., Robson, M., and Schmidt, M.K.
Abstract: Contains fulltext : 244113.pdf (Publisher’s version ) (Open Access), PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS(313)) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS(313) and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS(313) showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS(313), HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS(313) 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS(313) can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS(313) needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
Published: 2021

49. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author: Coignard, J. (Juliette), Lush, M. (Michael), Beesley, J. (Jonathan), O’Mara, T.A. (Tracy A.), Dennis, J. (Joe), Tyrer, J.P. (Jonathan P.), Barnes, D. (Daniel), McGuffog, L. (Lesley), Leslie, G. (Goska), Bolla, M.K. (Manjeet K.), Adank, M.A. (Muriel), Agata, S. (Simona), Ahearn, T. (Thomas), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Arnold, N. (Norbert), Aronson, K.J. (Kristan J.), Arun, B.K. (Banu), Augustinsson, A. (Annelie), Azzollini, J., Barrowdale, D. (Daniel), Baynes, C. (Caroline), Becher, H. (Heko), Bermisheva, M. (Marina), Bernstein, L. (Leslie), Białkowska, K. (Katarzyna), Blomqvist, C. (Carl), Bojesen, S.E. (Stig), Bonnani, B. (Bernardo), Borg, Å. (Åke), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Burwinkel, B. (Barbara), Buys, S.S. (Saundra S.), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campa, D. (Daniele), Carter, B.D. (Brian D.), Castelao, J.E. (Jose ), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen J.), Chung, W.K. (Wendy K.), Claes, K.B.M. (Kathleen B. M.), Clarke, C.L. (Christine L.), Bertrand, O. (Ophélie), Caputo, S. (Sandrine), Dupré, A. (Anaïs), Le Mentec, M. (Marine), Belotti, M. (Muriel), Birot, A.-M. (Anne-Marie), Buecher, B. (Bruno), Fourme, E. (Emmanuelle), Gauthier-Villars, M. (Marion), Golmard, L. (Lisa), Houdayer, C. (Claude), Moncoutier, V. (Virginie), de Pauw, A. (Antoine), Saule, C. (Claire), Sinilnikova, O. (Olga), Mazoyer, S. (Sylvie), Damiola, F. (Francesca), Barjhoux, L. (Laure), Verny-Pierre, C. (Carole), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Calender, A. (Alain), Giraud, S. (Sophie), Caron, O. (Olivier), Guillaud-Bataille, M. (Marine), Bressac-de Paillerets, B. (Brigitte), Bignon, Y.-J. (Yves-Jean), Uhrhammer, N. (Nancy), Lasset, C. (Christine), Bonadona, V. (Valérie), Berthet, P. (Pascaline), Vaur, D. (Dominique), Castera, L. (Laurent), Noguchi, T. (Tetsuro), Popovici, C. (Cornel), Sobol, H. (Hagay), Bourdon, V. (Violaine), Remenieras, A. (Audrey), Nogues, C. (Catherine), Coupier, I. (Isabelle), Pujol, P. (Pascal), Dumont, A. (Aurélie), Révillion, F. (Françoise), Adenis, C. (Claude), Muller, D.W. (Danièle), Barouk-Simonet, E. (Emmanuelle), Bonnet, F. (Françoise), Bubien, V. (Virginie), Sevenet, N. (Nicolas), Longy, M. (Michel), Toulas, C. (Christine), Guimbaud, R. (Rosine), Gladieff, L. (Laurence), Feillel, V. (Viviane), Leroux, D. (Dominique), Dreyfus, H. (Hélène), Rebischung, C. (Christine), Peysselon, M. (Magalie), Coron, F. (Fanny), Faivre, L. (Laurence), Baurand, A. (Amandine), Jacquot, C. (Caroline), Bertolone, G. (Geoffrey), Lizard, S. (Sarab), Prieur, F. (Fabienne), Lebrun, M. (Marine), Kientz, C. (Caroline), Ferrer, S.F., Mari, V. (Véronique), Vénat-Bouvet, L. (Laurence), Delnatte, C. (Capucine), Bézieau, S. (Stéphane), Mortemousque, I. (Isabelle), Coulet, F. (Florence), Colas, C. (Chrystelle), Soubrier, F. (Florent), Warcoin, M. (Mathilde), Sokolowska, J. (Johanna), Bronner, M. (Myriam), Collonge-Rame, M.-A., Damette, A. (Alexandre), Gesta, P. (Paul), Lallaoui, H. (Hakima), Chiesa, J. (Jean), Molina-Gomes, D. (Denise), Ingster, O. (Olivier), Gregory, H. (Helen), Miedzybrodzka, Z. (Zosia), Morrison, P.J. (Patrick J.), Ong, K.-R. (Kai-ren), Donaldson, A. (Alan), Rogers, M.T. (Mark), Kennedy, M.J. (M. John), Porteous, M.E. (Mary), Brewer, C. (Carole), Davidson, R. (Rosemarie), Izatt, L. (Louise), Brady, A. (A.), Barwell, J. (Julian), Adlard, J.W. (Julian), Foo, C. (Claire), Lalloo, F. (Fiona), Side, L.E. (Lucy E.), Eason, J. (Jacqueline), Henderson, A. (Alex), Walker, L. (Lisa), Eeles, R. (Rosalind), Cook, J. (Jackie), Snape, K. (Katie), Eccles, D. (Diana), Murray, A. (Alexandra), McCann, E. (Emma), Collée, J.M. (J. Margriet), Conroy, D.M. (Don M.), Czene, K. (Kamila), Daly, M.B. (Mary B.), Devilee, P. (Peter), Diez, O. (Orland), Ding, Y.C. (Yuan Chun), Domchek, S.M. (Susan), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Dunning, A.M. (Alison M.), Dwek, M. (Miriam), Eccles, D.M. (Diana M.), Eliassen, A.H. (A. Heather), Engel, C. (Christoph), Eriksson, M. (Mikael), Evans, D.G. (D. Gareth), Fasching, P.A. (Peter), Flyger, H. (Henrik), Fostira, F. (Florentia), Friedman, E. (Eitan), Fritschi, L. (Lin), Frost, D. (Debra), Gago-Dominguez, M. (Manuela), Gapstur, S.M. (Susan M.), Garber, J. (Judy), Garcia-Barberan, V. (Vanesa), García-Closas, M. (Montserrat), García-Sáenz, J.A. (José A.), Gaudet, M.M. (Mia M.), Gayther, S.A. (Simon), Gehrig, A. (Andrea), Georgoulias, V. (Vassilios), Giles, G.G. (Graham G.), Godwin, A.K. (Andrew K.), Goldberg, M.S. (Mark), Radice, P. (Paolo), González-Neira, A. (Anna), Greene, M.H. (Mark H.), Guénel, P. (Pascal), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C.A. (Christopher), Håkansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Harrington, P.A. (Patricia A.), Hart, S.N. (Steven N.), He, W. (Wei), Hogervorst, F.B.L. (Frans B. L.), Hollestelle, A. (Antoinette), Hopper, J.L. (John), Horcasitas, D.J. (Darling J.), Hulick, P.J. (Peter J.), Hunter, D.J. (David J.), Imyanitov, E.N. (Evgeny), Fox, S.B. (Stephen), Campbell, I. (Ian), Spurdle, A. (Amanda), Webb, P. (Penny), De Fazio, A. (Anna), Tassell, M. (Margaret), Kirk, J. (Judy), Lindeman, G.J. (Geoffrey), Price, M. (Melanie), Southey, M.C. (Melissa), Milne, R.L. (Roger), Deb, S. (Sid), Bowtell, D. (David), Hout, A.H. (Annemarie) van der, Ouweland, A.M.W. (Ans) van den, Mensenkamp, A.R. (Arjen R.), Deurzen, C.H.M. (Carolien) van, Kets, C.M. (Marleen), Seynaeve, C.M. (Caroline), van Asperen, C.J. (Christi J.), Aalfs, C.M. (Cora), Gómez Garcia, E.B. (Encarna B.), Leeuwen, F.E. (Flora) van, Bock, G.H. (Geertruida) de, Meijers-Heijboer, E.J. (Hanne), Obdeijn, A.I.M. (Inge-Marie), Gille, J.J.P. (J. J.P.), Oosterwijk, J.C. (Jan), Wijnen, J.T. (Juul), Kolk, L.E. (Lizet) van der, Hooning, M.J. (Maartje), Ausems, M.G.E.M. (Margreet), Mourits, M.J. (Marjan), Blok, M.J. (Marinus J.), Rookus, M.A. (Matti), van der Luijt, R.B. (Rob B.), Cronenburg, T.C.T.E.F. van, Pol, C. (Carmen) van der, Russell, N.S. (Nicola), Siesling, S. (Sabine), Overbeek, L.I.H. (Lucy), Wijnands, R. (R.), Lange, J.L. (J.) de, Clarke, C. (Christine), Graham, D. (Dinny), Sachchithananthan, M. (Mythily), Marsh, D. (Deborah), Scott, R.J. (Rodney), Baxter, R. (Robert), Yip, D. (Desmond), Carpenter, T.A. (Adrian), Davis, A. (Alison), Pathmanathan, N. (Nirmala), Simpson, P. (Peter), Jager, A. (Agnes), Jakubowska, A. (Anna), James, M. (Margaret), Jensen, U.B. (Uffe Birk), John, E.M. (Esther), Jones, M.E. (Michael E.), Kaaks, R. (Rudolf), Kapoor, P.M. (Pooja Middha), Karlan, B.Y. (Beth), Keeman, R. (Renske), Khusnutdinova, E.K. (Elza), Kiiski, J.I. (Johanna I.), Ko, Y.-D. (Yon-Dschun), Kosma, V.-M. (Veli-Matti), Kraft, P. (Peter), Kurian, A.W. (Allison W.), Laitman, Y. (Yael), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindstrom, T. (Tricia), Lopez-Fernández, A. (Adria), Loud, J.T. (Jennifer T.), Luccarini, C. (Craig), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J.W.M. (John), Mebirouk, N. (Noura), Meindl, A. (Alfons), Miller, A. (Austin), Milne, R.L. (Roger L.), Montagna, M. (Marco), Nathanson, K.L. (Katherine), Floris, O.A.M., Nevanlinna, H. (Heli), Nielsen, F.C. (Finn C.), O’Brien, K.M. (Katie M.), Olopade, O.I. (Olofunmilayo), Olson, J.E. (Janet), Olsson, H. (Håkan), Osorio, A. (Ana), Ottini, L. (Laura), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. (Marilyn), Pedersen, I.S. (Inge Sokilde), Peshkin, B. (Beth), Peterlongo, P. (Paolo), Peto, J. (Julian), Pharoah, P.D.P. (Paul), Phillips, K.-A. (Kelly-Anne), Polley, E.C. (Eric C.), Poppe, B. (Bruce), Presneau, N. (Nadege), Pujana, M.A. (Miquel Angel), Punie, K. (Kevin), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Rennert, H.S. (Hedy S.), Robson, M. (Mark), Romero, A. (Atocha), Rossing, M. (Maria), Saloustros, E. (Emmanouil), Sandler, D.P. (Dale P.), Santella, R.M. (Regina), Scheuner, M.T. (Maren T.), Schmidt, M.K. (Marjanka K.), Schmidt, G. (Gunnar), Scott, C. (Christopher), Sharma, P. (Priyanka), Soucy, P. (Penny), Southey, M.C. (Melissa C.), Spinelli, J.J. (John J.), Steinsnyder, Z. (Zoe), Stone, J. (Jennifer), Stoppa-Lyonnet, D. (Dominique), Swerdlow, A.J. (Anthony ), Tamimi, R. (Rulla), Tapper, W.J. (William J.), Taylor, J.A. (Jack A.), Terry, M.B. (Mary Beth), Teulé, A. (Alex), Thull, D.L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Torres, D. (Diana), Trainer, A.H. (Alison H.), Truong, T. (Thérèse), Tung, N. (Nadine), Vachon, C. (Celine), Vega, A. (Ana), Joseph, V. (Vijai), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wendt, C. (Camilla), Wolk, K. (Kerstin), Yadav, S. (Siddhartha), Yang, X.R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Zheng, W. (Wei), Ziogas, A. (Argyrios), Zorn, K.K. (Kristin K.), Park, S.K. (Sue K.), Thomassen, M. (Mads), Offit, K. (Kenneth), Schmutzler, R.K. (Rita), Couch, F.J. (Fergus), Simard, J. (Jacques), Chenevix-Trench, G. (Georgia), Adamo, P. (Pio) d', Andrieu, N. (Nadine), Antoniou, A.C. (Antonis C.), Coignard, J. (Juliette), Lush, M. (Michael), Beesley, J. (Jonathan), O’Mara, T.A. (Tracy A.), Dennis, J. (Joe), Tyrer, J.P. (Jonathan P.), Barnes, D. (Daniel), McGuffog, L. (Lesley), Leslie, G. (Goska), Bolla, M.K. (Manjeet K.), Adank, M.A. (Muriel), Agata, S. (Simona), Ahearn, T. (Thomas), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Arnold, N. (Norbert), Aronson, K.J. (Kristan J.), Arun, B.K. (Banu), Augustinsson, A. (Annelie), Azzollini, J., Barrowdale, D. (Daniel), Baynes, C. (Caroline), Becher, H. (Heko), Bermisheva, M. (Marina), Bernstein, L. (Leslie), Białkowska, K. (Katarzyna), Blomqvist, C. (Carl), Bojesen, S.E. (Stig), Bonnani, B. (Bernardo), Borg, Å. (Åke), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Burwinkel, B. (Barbara), Buys, S.S. (Saundra S.), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campa, D. (Daniele), Carter, B.D. (Brian D.), Castelao, J.E. (Jose ), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen J.), Chung, W.K. (Wendy K.), Claes, K.B.M. (Kathleen B. M.), Clarke, C.L. (Christine L.), Bertrand, O. (Ophélie), Caputo, S. (Sandrine), Dupré, A. (Anaïs), Le Mentec, M. (Marine), Belotti, M. (Muriel), Birot, A.-M. (Anne-Marie), Buecher, B. (Bruno), Fourme, E. (Emmanuelle), Gauthier-Villars, M. (Marion), Golmard, L. (Lisa), Houdayer, C. (Claude), Moncoutier, V. (Virginie), de Pauw, A. (Antoine), Saule, C. (Claire), Sinilnikova, O. (Olga), Mazoyer, S. (Sylvie), Damiola, F. (Francesca), Barjhoux, L. (Laure), Verny-Pierre, C. (Carole), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Calender, A. (Alain), Giraud, S. (Sophie), Caron, O. (Olivier), Guillaud-Bataille, M. (Marine), Bressac-de Paillerets, B. (Brigitte), Bignon, Y.-J. (Yves-Jean), Uhrhammer, N. (Nancy), Lasset, C. (Christine), Bonadona, V. (Valérie), Berthet, P. (Pascaline), Vaur, D. (Dominique), Castera, L. (Laurent), Noguchi, T. (Tetsuro), Popovici, C. (Cornel), Sobol, H. (Hagay), Bourdon, V. (Violaine), Remenieras, A. (Audrey), Nogues, C. (Catherine), Coupier, I. (Isabelle), Pujol, P. (Pascal), Dumont, A. (Aurélie), Révillion, F. (Françoise), Adenis, C. (Claude), Muller, D.W. (Danièle), Barouk-Simonet, E. (Emmanuelle), Bonnet, F. (Françoise), Bubien, V. (Virginie), Sevenet, N. (Nicolas), Longy, M. (Michel), Toulas, C. (Christine), Guimbaud, R. (Rosine), Gladieff, L. (Laurence), Feillel, V. (Viviane), Leroux, D. (Dominique), Dreyfus, H. (Hélène), Rebischung, C. (Christine), Peysselon, M. (Magalie), Coron, F. (Fanny), Faivre, L. (Laurence), Baurand, A. (Amandine), Jacquot, C. (Caroline), Bertolone, G. (Geoffrey), Lizard, S. (Sarab), Prieur, F. (Fabienne), Lebrun, M. (Marine), Kientz, C. (Caroline), Ferrer, S.F., Mari, V. (Véronique), Vénat-Bouvet, L. (Laurence), Delnatte, C. (Capucine), Bézieau, S. (Stéphane), Mortemousque, I. (Isabelle), Coulet, F. (Florence), Colas, C. (Chrystelle), Soubrier, F. (Florent), Warcoin, M. (Mathilde), Sokolowska, J. (Johanna), Bronner, M. (Myriam), Collonge-Rame, M.-A., Damette, A. (Alexandre), Gesta, P. (Paul), Lallaoui, H. (Hakima), Chiesa, J. (Jean), Molina-Gomes, D. (Denise), Ingster, O. (Olivier), Gregory, H. (Helen), Miedzybrodzka, Z. (Zosia), Morrison, P.J. (Patrick J.), Ong, K.-R. (Kai-ren), Donaldson, A. (Alan), Rogers, M.T. (Mark), Kennedy, M.J. (M. John), Porteous, M.E. (Mary), Brewer, C. (Carole), Davidson, R. (Rosemarie), Izatt, L. (Louise), Brady, A. (A.), Barwell, J. (Julian), Adlard, J.W. (Julian), Foo, C. (Claire), Lalloo, F. (Fiona), Side, L.E. (Lucy E.), Eason, J. (Jacqueline), Henderson, A. (Alex), Walker, L. (Lisa), Eeles, R. (Rosalind), Cook, J. (Jackie), Snape, K. (Katie), Eccles, D. (Diana), Murray, A. (Alexandra), McCann, E. (Emma), Collée, J.M. (J. Margriet), Conroy, D.M. (Don M.), Czene, K. (Kamila), Daly, M.B. (Mary B.), Devilee, P. (Peter), Diez, O. (Orland), Ding, Y.C. (Yuan Chun), Domchek, S.M. (Susan), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Dunning, A.M. (Alison M.), Dwek, M. (Miriam), Eccles, D.M. (Diana M.), Eliassen, A.H. (A. Heather), Engel, C. (Christoph), Eriksson, M. (Mikael), Evans, D.G. (D. Gareth), Fasching, P.A. (Peter), Flyger, H. (Henrik), Fostira, F. (Florentia), Friedman, E. (Eitan), Fritschi, L. (Lin), Frost, D. (Debra), Gago-Dominguez, M. (Manuela), Gapstur, S.M. (Susan M.), Garber, J. (Judy), Garcia-Barberan, V. (Vanesa), García-Closas, M. (Montserrat), García-Sáenz, J.A. (José A.), Gaudet, M.M. (Mia M.), Gayther, S.A. (Simon), Gehrig, A. (Andrea), Georgoulias, V. (Vassilios), Giles, G.G. (Graham G.), Godwin, A.K. (Andrew K.), Goldberg, M.S. (Mark), Radice, P. (Paolo), González-Neira, A. (Anna), Greene, M.H. (Mark H.), Guénel, P. (Pascal), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C.A. (Christopher), Håkansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Harrington, P.A. (Patricia A.), Hart, S.N. (Steven N.), He, W. (Wei), Hogervorst, F.B.L. (Frans B. L.), Hollestelle, A. (Antoinette), Hopper, J.L. (John), Horcasitas, D.J. (Darling J.), Hulick, P.J. (Peter J.), Hunter, D.J. (David J.), Imyanitov, E.N. (Evgeny), Fox, S.B. (Stephen), Campbell, I. (Ian), Spurdle, A. (Amanda), Webb, P. (Penny), De Fazio, A. (Anna), Tassell, M. (Margaret), Kirk, J. (Judy), Lindeman, G.J. (Geoffrey), Price, M. (Melanie), Southey, M.C. (Melissa), Milne, R.L. (Roger), Deb, S. (Sid), Bowtell, D. (David), Hout, A.H. (Annemarie) van der, Ouweland, A.M.W. (Ans) van den, Mensenkamp, A.R. (Arjen R.), Deurzen, C.H.M. (Carolien) van, Kets, C.M. (Marleen), Seynaeve, C.M. (Caroline), van Asperen, C.J. (Christi J.), Aalfs, C.M. (Cora), Gómez Garcia, E.B. (Encarna B.), Leeuwen, F.E. (Flora) van, Bock, G.H. (Geertruida) de, Meijers-Heijboer, E.J. (Hanne), Obdeijn, A.I.M. (Inge-Marie), Gille, J.J.P. (J. J.P.), Oosterwijk, J.C. (Jan), Wijnen, J.T. (Juul), Kolk, L.E. (Lizet) van der, Hooning, M.J. (Maartje), Ausems, M.G.E.M. (Margreet), Mourits, M.J. (Marjan), Blok, M.J. (Marinus J.), Rookus, M.A. (Matti), van der Luijt, R.B. (Rob B.), Cronenburg, T.C.T.E.F. van, Pol, C. (Carmen) van der, Russell, N.S. (Nicola), Siesling, S. (Sabine), Overbeek, L.I.H. (Lucy), Wijnands, R. (R.), Lange, J.L. (J.) de, Clarke, C. (Christine), Graham, D. (Dinny), Sachchithananthan, M. (Mythily), Marsh, D. (Deborah), Scott, R.J. (Rodney), Baxter, R. (Robert), Yip, D. (Desmond), Carpenter, T.A. (Adrian), Davis, A. (Alison), Pathmanathan, N. (Nirmala), Simpson, P. (Peter), Jager, A. (Agnes), Jakubowska, A. (Anna), James, M. (Margaret), Jensen, U.B. (Uffe Birk), John, E.M. (Esther), Jones, M.E. (Michael E.), Kaaks, R. (Rudolf), Kapoor, P.M. (Pooja Middha), Karlan, B.Y. (Beth), Keeman, R. (Renske), Khusnutdinova, E.K. (Elza), Kiiski, J.I. (Johanna I.), Ko, Y.-D. (Yon-Dschun), Kosma, V.-M. (Veli-Matti), Kraft, P. (Peter), Kurian, A.W. (Allison W.), Laitman, Y. (Yael), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindstrom, T. (Tricia), Lopez-Fernández, A. (Adria), Loud, J.T. (Jennifer T.), Luccarini, C. (Craig), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J.W.M. (John), Mebirouk, N. (Noura), Meindl, A. (Alfons), Miller, A. (Austin), Milne, R.L. (Roger L.), Montagna, M. (Marco), Nathanson, K.L. (Katherine), Floris, O.A.M., Nevanlinna, H. (Heli), Nielsen, F.C. (Finn C.), O’Brien, K.M. (Katie M.), Olopade, O.I. (Olofunmilayo), Olson, J.E. (Janet), Olsson, H. (Håkan), Osorio, A. (Ana), Ottini, L. (Laura), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. (Marilyn), Pedersen, I.S. (Inge Sokilde), Peshkin, B. (Beth), Peterlongo, P. (Paolo), Peto, J. (Julian), Pharoah, P.D.P. (Paul), Phillips, K.-A. (Kelly-Anne), Polley, E.C. (Eric C.), Poppe, B. (Bruce), Presneau, N. (Nadege), Pujana, M.A. (Miquel Angel), Punie, K. (Kevin), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Rennert, H.S. (Hedy S.), Robson, M. (Mark), Romero, A. (Atocha), Rossing, M. (Maria), Saloustros, E. (Emmanouil), Sandler, D.P. (Dale P.), Santella, R.M. (Regina), Scheuner, M.T. (Maren T.), Schmidt, M.K. (Marjanka K.), Schmidt, G. (Gunnar), Scott, C. (Christopher), Sharma, P. (Priyanka), Soucy, P. (Penny), Southey, M.C. (Melissa C.), Spinelli, J.J. (John J.), Steinsnyder, Z. (Zoe), Stone, J. (Jennifer), Stoppa-Lyonnet, D. (Dominique), Swerdlow, A.J. (Anthony ), Tamimi, R. (Rulla), Tapper, W.J. (William J.), Taylor, J.A. (Jack A.), Terry, M.B. (Mary Beth), Teulé, A. (Alex), Thull, D.L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Torres, D. (Diana), Trainer, A.H. (Alison H.), Truong, T. (Thérèse), Tung, N. (Nadine), Vachon, C. (Celine), Vega, A. (Ana), Joseph, V. (Vijai), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wendt, C. (Camilla), Wolk, K. (Kerstin), Yadav, S. (Siddhartha), Yang, X.R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Zheng, W. (Wei), Ziogas, A. (Argyrios), Zorn, K.K. (Kristin K.), Park, S.K. (Sue K.), Thomassen, M. (Mads), Offit, K. (Kenneth), Schmutzler, R.K. (Rita), Couch, F.J. (Fergus), Simard, J. (Jacques), Chenevix-Trench, G. (Georgia), Adamo, P. (Pio) d', Andrieu, N. (Nadine), and Antoniou, A.C. (Antonis C.)
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021
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50. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (Nature Communications, (2021), 12, 1, (1078), 10.1038/s41467-020-20496-3).

Author: Coignard J., Lush M., Beesley J., O'Mara T.A., Dennis J., Tyrer J.P., Barnes D.R., McGuffog L., Leslie G., Bolla M.K., Agata S., Ahearn T., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Arnold N., Aronson K.J., Arun B.K., Augustinsson A., Azzollini J., Barrowdale D., Baynes C., Becher H., Bermisheva M., Bernstein L., Bialkowska K., Blomqvist C., Bojesen S.E., Bonanni B., Borg A., Brauch H., Brenner H., Burwinkel B., Buys S.S., Caldes T., Caligo M.A., Campa D., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chung W.K., Claes K.B.M., Clarke C.L., Bertrand O., Caputo S., Dupre A., Le Mentec M., Belotti M., Birot A.-M., Buecher B., Fourme E., Gauthier-Villars M., Golmard L., Houdayer C., Moncoutier V., de Pauw A., Saule C., Sinilnikova O., Mazoyer S., Damiola F., Barjhoux L., Verny-Pierre C., Leone M., Boutry-Kryza N., Calender A., Giraud S., Caron O., Guillaud-Bataille M., Bressac-de-Paillerets B., Bignon Y.-J., Uhrhammer N., Lasset C., Bonadona V., Berthet P., Vaur D., Castera L., Popovici C., Sobol H., Bourdon V., Noguchi T., Remenieras A., Nogues C., Coupier I., Pujol P., Dumont A., Revillion F., Adenis C., Muller D., Barouk-Simonet E., Bonnet F., Bubien V., Sevenet N., Longy M., Toulas C., Guimbaud R., Gladieff L., Feillel V., Leroux D., Dreyfus H., Rebischung C., Peysselon M., Coron F., Faivre L., Baurand A., Jacquot C., Bertolone G., Lizard S., Prieur F., Lebrun M., Kientz C., Ferrer S.F., Mari V., Venat-Bouvet L., Delnatte C., Bezieau S., Mortemousque I., Coulet F., Colas C., Soubrier F., Warcoin M., Sokolowska J., Bronner M., Collonge-Rame M.-A., Damette A., Gesta P., Lallaoui H., Chiesa J., Molina-Gomes D., Ingster O., Gregory H., Miedzybrodzka Z., Morrison P.J., Ong K.-R., Donaldson A., Rogers M.T., Kennedy M.J., Porteous M.E., Brewer C., Davidson R., Izatt L., Brady A., Barwell J., Adlard J., Foo C., Lalloo F., Side L.E., Eason J., Henderson A., Walker L., Eeles R.A., Cook J., Snape K., Eccles D., Murray A., McCann E., Conroy D.M., Czene K., Daly M.B., Devilee P., Diez O., Ding Y.C., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Eliassen A.H., Engel C., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Barberan V., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Gehrig A., Georgoulias V., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hart S.N., He W., Hogervorst F.B.L., Hollestelle A., Hopper J.L., Horcasitas D.J., Hulick P.J., Hunter D.J., Imyanitov E.N., Fox S., Campbell I., Spurdle A., Webb P., de Fazio A., Tassell M., Kirk J., Lindeman G., Price M., Southey M., Milne R., Deb S., Bowtell D., van der Hout A.H., van den Ouweland A.M.W., Mensenkamp A.R., van Deurzen C.H.M., Kets C.M., Seynaeve C., van Asperen C.J., Aalfs C.M., Gomez Garcia E.B., van Leeuwen F.E., de Bock G.H., Meijers-Heijboer H.E.J., Obdeijn I.M., Collee J.M., Gille J.J.P., Oosterwijk J.C., Wijnen J.T., van der Kolk L.E., Hooning M.J., Ausems M.G.E.M., Mourits M.J.E., Blok M.J., Rookus M.A., Adank M.A., van der Luijt R.B., van Cronenburg T.C.T.E.F., van der Pol C.C., Russell N.S., Siesling S., Overbeek L., Wijnands R., de Lange J.L., Clarke C., Graham D., Sachchithananthan M., Marsh D., Scott R., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Simpson P., Jager A., Jakubowska A., James P.A., Jensen U.B., John E.M., Jones M.E., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Kosma V.-M., Kraft P., Kurian A.W., Laitman Y., Lambrechts D., Le Marchand L., Lester J., Lesueur F., Lindstrom T., Lopez-Fernandez A., Loud J.T., Luccarini C., Mannermaa A., Manoukian S., Margolin S., Martens J.W.M., Mebirouk N., Meindl A., Miller A., Milne R.L., Montagna M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nielsen F.C., O'Brien K.M., Olopade O.I., Olson J.E., Olsson H., Osorio A., Ottini L., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peshkin B., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Polley E.C., Poppe B., Presneau N., Pujana M.A., Punie K., Radice P., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Robson M., Romero A., Rossing M., Saloustros E., Sandler D.P., Santella R., Scheuner M.T., Schmidt M.K., Schmidt G., Scott C., Sharma P., Soucy P., Southey M.C., Spinelli J.J., Steinsnyder Z., Stone J., Stoppa-Lyonnet D., Swerdlow A., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Trainer A.H., Truong T., Tung N., Vachon C.M., Vega A., Vijai J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wolk A., Yadav S., Yang X.R., Yannoukakos D., Zheng W., Ziogas A., Zorn K.K., Park S.K., Thomassen M., Offit K., Schmutzler R.K., Couch F.J., Simard J., Chenevix-Trench G., Easton D.F., Andrieu N., Antoniou A.C., Coignard J., Lush M., Beesley J., O'Mara T.A., Dennis J., Tyrer J.P., Barnes D.R., McGuffog L., Leslie G., Bolla M.K., Agata S., Ahearn T., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Arnold N., Aronson K.J., Arun B.K., Augustinsson A., Azzollini J., Barrowdale D., Baynes C., Becher H., Bermisheva M., Bernstein L., Bialkowska K., Blomqvist C., Bojesen S.E., Bonanni B., Borg A., Brauch H., Brenner H., Burwinkel B., Buys S.S., Caldes T., Caligo M.A., Campa D., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chung W.K., Claes K.B.M., Clarke C.L., Bertrand O., Caputo S., Dupre A., Le Mentec M., Belotti M., Birot A.-M., Buecher B., Fourme E., Gauthier-Villars M., Golmard L., Houdayer C., Moncoutier V., de Pauw A., Saule C., Sinilnikova O., Mazoyer S., Damiola F., Barjhoux L., Verny-Pierre C., Leone M., Boutry-Kryza N., Calender A., Giraud S., Caron O., Guillaud-Bataille M., Bressac-de-Paillerets B., Bignon Y.-J., Uhrhammer N., Lasset C., Bonadona V., Berthet P., Vaur D., Castera L., Popovici C., Sobol H., Bourdon V., Noguchi T., Remenieras A., Nogues C., Coupier I., Pujol P., Dumont A., Revillion F., Adenis C., Muller D., Barouk-Simonet E., Bonnet F., Bubien V., Sevenet N., Longy M., Toulas C., Guimbaud R., Gladieff L., Feillel V., Leroux D., Dreyfus H., Rebischung C., Peysselon M., Coron F., Faivre L., Baurand A., Jacquot C., Bertolone G., Lizard S., Prieur F., Lebrun M., Kientz C., Ferrer S.F., Mari V., Venat-Bouvet L., Delnatte C., Bezieau S., Mortemousque I., Coulet F., Colas C., Soubrier F., Warcoin M., Sokolowska J., Bronner M., Collonge-Rame M.-A., Damette A., Gesta P., Lallaoui H., Chiesa J., Molina-Gomes D., Ingster O., Gregory H., Miedzybrodzka Z., Morrison P.J., Ong K.-R., Donaldson A., Rogers M.T., Kennedy M.J., Porteous M.E., Brewer C., Davidson R., Izatt L., Brady A., Barwell J., Adlard J., Foo C., Lalloo F., Side L.E., Eason J., Henderson A., Walker L., Eeles R.A., Cook J., Snape K., Eccles D., Murray A., McCann E., Conroy D.M., Czene K., Daly M.B., Devilee P., Diez O., Ding Y.C., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Eliassen A.H., Engel C., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Barberan V., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Gehrig A., Georgoulias V., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hart S.N., He W., Hogervorst F.B.L., Hollestelle A., Hopper J.L., Horcasitas D.J., Hulick P.J., Hunter D.J., Imyanitov E.N., Fox S., Campbell I., Spurdle A., Webb P., de Fazio A., Tassell M., Kirk J., Lindeman G., Price M., Southey M., Milne R., Deb S., Bowtell D., van der Hout A.H., van den Ouweland A.M.W., Mensenkamp A.R., van Deurzen C.H.M., Kets C.M., Seynaeve C., van Asperen C.J., Aalfs C.M., Gomez Garcia E.B., van Leeuwen F.E., de Bock G.H., Meijers-Heijboer H.E.J., Obdeijn I.M., Collee J.M., Gille J.J.P., Oosterwijk J.C., Wijnen J.T., van der Kolk L.E., Hooning M.J., Ausems M.G.E.M., Mourits M.J.E., Blok M.J., Rookus M.A., Adank M.A., van der Luijt R.B., van Cronenburg T.C.T.E.F., van der Pol C.C., Russell N.S., Siesling S., Overbeek L., Wijnands R., de Lange J.L., Clarke C., Graham D., Sachchithananthan M., Marsh D., Scott R., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Simpson P., Jager A., Jakubowska A., James P.A., Jensen U.B., John E.M., Jones M.E., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Kosma V.-M., Kraft P., Kurian A.W., Laitman Y., Lambrechts D., Le Marchand L., Lester J., Lesueur F., Lindstrom T., Lopez-Fernandez A., Loud J.T., Luccarini C., Mannermaa A., Manoukian S., Margolin S., Martens J.W.M., Mebirouk N., Meindl A., Miller A., Milne R.L., Montagna M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nielsen F.C., O'Brien K.M., Olopade O.I., Olson J.E., Olsson H., Osorio A., Ottini L., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peshkin B., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Polley E.C., Poppe B., Presneau N., Pujana M.A., Punie K., Radice P., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Robson M., Romero A., Rossing M., Saloustros E., Sandler D.P., Santella R., Scheuner M.T., Schmidt M.K., Schmidt G., Scott C., Sharma P., Soucy P., Southey M.C., Spinelli J.J., Steinsnyder Z., Stone J., Stoppa-Lyonnet D., Swerdlow A., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Trainer A.H., Truong T., Tung N., Vachon C.M., Vega A., Vijai J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wolk A., Yadav S., Yang X.R., Yannoukakos D., Zheng W., Ziogas A., Zorn K.K., Park S.K., Thomassen M., Offit K., Schmutzler R.K., Couch F.J., Simard J., Chenevix-Trench G., Easton D.F., Andrieu N., and Antoniou A.C.
Abstract: The original version of this Article contained an error in the spelling of the author Heiko Becher, which was incorrectly given as Heko Becher. This has now been corrected in both the PDF and HTML versions of the Article.Copyright © 2021, The Author(s).
Published: 2021

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