Author: "Dossus L." / Publication Type: Electronic Resources - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Dossus L."' showing total 220 results

Start Over Author "Dossus L." Publication Type Electronic Resources

220 results on '"Dossus L."'

1. Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition

Author: Botteri, E, Peveri, G, Berstad, P, Bagnardi, V, Hoff, G, Heath, A, Cross, A, Vineis, P, Dossus, L, Johansson, M, Freisling, H, Matta, K, Huybrechts, I, Chen, S, B. Borch, K, Sandanger, T, H. Nost, T, Dahm, C, Antoniussen, C, Tin Tin, S, Fournier, A, Marques, C, Artaud, F, Sanchez, M, Guevara, M, Santiuste, C, Agudo, A, Bajracharya, R, Katzke, V, Ricceri, F, Agnoli, C, Bergmann, M, Schulze, M, Panico, S, Masala, G, Tjonneland, A, Olsen, A, Stocks, T, Manjer, J, Aizpurua-Atxega, A, Weiderpass, E, Riboli, E, Gunter, M, Ferrari, P, Botteri E., Peveri G., Berstad P., Bagnardi V., Hoff G., Heath A. K., Cross A. J., Vineis P., Dossus L., Johansson M., Freisling H., Matta K., Huybrechts I., Chen S. L. F., B. Borch K., Sandanger T. M., H. Nost T., Dahm C. C., Antoniussen C. S., Tin Tin S., Fournier A., Marques C., Artaud F., Sanchez M. -J., Guevara M., Santiuste C., Agudo A., Bajracharya R., Katzke V., Ricceri F., Agnoli C., Bergmann M. M., Schulze M. B., Panico S., Masala G., Tjonneland A., Olsen A., Stocks T., Manjer J., Aizpurua-Atxega A., Weiderpass E., Riboli E., Gunter M. J., Ferrari P., Botteri, E, Peveri, G, Berstad, P, Bagnardi, V, Hoff, G, Heath, A, Cross, A, Vineis, P, Dossus, L, Johansson, M, Freisling, H, Matta, K, Huybrechts, I, Chen, S, B. Borch, K, Sandanger, T, H. Nost, T, Dahm, C, Antoniussen, C, Tin Tin, S, Fournier, A, Marques, C, Artaud, F, Sanchez, M, Guevara, M, Santiuste, C, Agudo, A, Bajracharya, R, Katzke, V, Ricceri, F, Agnoli, C, Bergmann, M, Schulze, M, Panico, S, Masala, G, Tjonneland, A, Olsen, A, Stocks, T, Manjer, J, Aizpurua-Atxega, A, Weiderpass, E, Riboli, E, Gunter, M, Ferrari, P, Botteri E., Peveri G., Berstad P., Bagnardi V., Hoff G., Heath A. K., Cross A. J., Vineis P., Dossus L., Johansson M., Freisling H., Matta K., Huybrechts I., Chen S. L. F., B. Borch K., Sandanger T. M., H. Nost T., Dahm C. C., Antoniussen C. S., Tin Tin S., Fournier A., Marques C., Artaud F., Sanchez M. -J., Guevara M., Santiuste C., Agudo A., Bajracharya R., Katzke V., Ricceri F., Agnoli C., Bergmann M. M., Schulze M. B., Panico S., Masala G., Tjonneland A., Olsen A., Stocks T., Manjer J., Aizpurua-Atxega A., Weiderpass E., Riboli E., Gunter M. J., and Ferrari P.
Abstract: In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers—including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others—using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95–0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07–1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65–0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.
Published: 2024

2. Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition

Author: Yammine, S G, Huybrechts, I, Biessy, C, Dossus, L, Panico, S, Sánchez, M J, Benetou, V, Turzanski-Fortner, R, Katzke, V, Idahl, A, Skeie, G, Olsen, K Standahl, Tjønneland, A, Halkjaer, J, Colorado-Yohar, S, Heath, A K, Sonestedt, E, Sartor, H, Schulze, M B, Palli, D, Crous-Bou, M, Dorronsoro, A, Overvad, K, Gurrea, A Barricarte, Severi, G, Vermeulen, R C H, Sandanger, T M, Travis, R C, Key, T, Amiano, P, Van Guelpen, B, Johansson, M, Sund, M, Tumino, R, Wareham, N, Sacerdote, C, Krogh, V, Brennan, P, Riboli, E, Weiderpass, E, Gunter, M J, Chajès, V, Yammine, S G, Huybrechts, I, Biessy, C, Dossus, L, Panico, S, Sánchez, M J, Benetou, V, Turzanski-Fortner, R, Katzke, V, Idahl, A, Skeie, G, Olsen, K Standahl, Tjønneland, A, Halkjaer, J, Colorado-Yohar, S, Heath, A K, Sonestedt, E, Sartor, H, Schulze, M B, Palli, D, Crous-Bou, M, Dorronsoro, A, Overvad, K, Gurrea, A Barricarte, Severi, G, Vermeulen, R C H, Sandanger, T M, Travis, R C, Key, T, Amiano, P, Van Guelpen, B, Johansson, M, Sund, M, Tumino, R, Wareham, N, Sacerdote, C, Krogh, V, Brennan, P, Riboli, E, Weiderpass, E, Gunter, M J, and Chajès, V
Published: 2023

3. Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition

Author: Yammine, S.G., Huybrechts, I., Biessy, C., Dossus, L., Panico, S., Sánchez, M.J., Benetou, V., Turzanski-Fortner, R., Katzke, V., Idahl, Annika, Skeie, G., Olsen, K. Standahl, Tjønneland, A., Halkjaer, J., Colorado-Yohar, S., Heath, A.K., Sonestedt, E., Sartor, H., Schulze, M.B., Palli, D., Crous-Bou, M., Dorronsoro, A., Overvad, K., Gurrea, A. Barricarte, Severi, G., Vermeulen, R.C.H., Sandanger, T.M., Travis, R.C., Key, T., Amiano, P., van Guelpen, Bethany, Johansson, M., Sund, Malin, Tumino, R., Wareham, N., Sacerdote, C., Krogh, V., Brennan, P., Riboli, E., Weiderpass, E., Gunter, M.J., Chajès, V., Yammine, S.G., Huybrechts, I., Biessy, C., Dossus, L., Panico, S., Sánchez, M.J., Benetou, V., Turzanski-Fortner, R., Katzke, V., Idahl, Annika, Skeie, G., Olsen, K. Standahl, Tjønneland, A., Halkjaer, J., Colorado-Yohar, S., Heath, A.K., Sonestedt, E., Sartor, H., Schulze, M.B., Palli, D., Crous-Bou, M., Dorronsoro, A., Overvad, K., Gurrea, A. Barricarte, Severi, G., Vermeulen, R.C.H., Sandanger, T.M., Travis, R.C., Key, T., Amiano, P., van Guelpen, Bethany, Johansson, M., Sund, Malin, Tumino, R., Wareham, N., Sacerdote, C., Krogh, V., Brennan, P., Riboli, E., Weiderpass, E., Gunter, M.J., and Chajès, V.
Published: 2023
Full Text: View/download PDF

4. Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition

Author: Yammine, S.G. Huybrechts, I. Biessy, C. Dossus, L. Panico, S. Sánchez, M.J. Benetou, V. Turzanski-Fortner, R. Katzke, V. Idahl, A. Skeie, G. Olsen, K.S. Tjønneland, A. Halkjaer, J. Colorado-Yohar, S. Heath, A.K. Sonestedt, E. Sartor, H. Schulze, M.B. Palli, D. Crous-Bou, M. Dorronsoro, A. Overvad, K. Gurrea, A.B. Severi, G. Vermeulen, R.C.H. Sandanger, T.M. Travis, R.C. Key, T. Amiano, P. Van Guelpen, B. Johansson, M. Sund, M. Tumino, R. Wareham, N. Sacerdote, C. Krogh, V. Brennan, P. Riboli, E. Weiderpass, E. Gunter, M.J. Chajès, V. and Yammine, S.G. Huybrechts, I. Biessy, C. Dossus, L. Panico, S. Sánchez, M.J. Benetou, V. Turzanski-Fortner, R. Katzke, V. Idahl, A. Skeie, G. Olsen, K.S. Tjønneland, A. Halkjaer, J. Colorado-Yohar, S. Heath, A.K. Sonestedt, E. Sartor, H. Schulze, M.B. Palli, D. Crous-Bou, M. Dorronsoro, A. Overvad, K. Gurrea, A.B. Severi, G. Vermeulen, R.C.H. Sandanger, T.M. Travis, R.C. Key, T. Amiano, P. Van Guelpen, B. Johansson, M. Sund, M. Tumino, R. Wareham, N. Sacerdote, C. Krogh, V. Brennan, P. Riboli, E. Weiderpass, E. Gunter, M.J. Chajès, V.
Published: 2023

5. Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition

Author: Yammine, S. G., Huybrechts, I., Biessy, C., Dossus, L., Panico, S., Sanchez, M. J., Benetou, V., Turzanski-Fortner, R., Katzke, V., Idahl, A., Skeie, G., Olsen, K. Standahl, Tjonneland, A., Halkjaer, J., Colorado-Yohar, S., Heath, A. K., Sonestedt, E., Sartor, H., Schulze, M. B., Palli, D., Crous-Bou, M., Dorronsoro, A., Overvad, K., Gurrea, A. Barricarte, Severi, G., Vermeulen, R. C. H., Sandanger, T. M., Travis, R. C., Key, T., Amiano, P., Van Guelpen, B., Johansson, M., Sund, M., Tumino, R., Wareham, N., Sacerdote, C., Krogh, V., Brennan, P., Riboli, E., Weiderpass, E., Gunter, M. J., Chajes, V., Yammine, S. G., Huybrechts, I., Biessy, C., Dossus, L., Panico, S., Sanchez, M. J., Benetou, V., Turzanski-Fortner, R., Katzke, V., Idahl, A., Skeie, G., Olsen, K. Standahl, Tjonneland, A., Halkjaer, J., Colorado-Yohar, S., Heath, A. K., Sonestedt, E., Sartor, H., Schulze, M. B., Palli, D., Crous-Bou, M., Dorronsoro, A., Overvad, K., Gurrea, A. Barricarte, Severi, G., Vermeulen, R. C. H., Sandanger, T. M., Travis, R. C., Key, T., Amiano, P., Van Guelpen, B., Johansson, M., Sund, M., Tumino, R., Wareham, N., Sacerdote, C., Krogh, V., Brennan, P., Riboli, E., Weiderpass, E., Gunter, M. J., and Chajes, V.
Abstract: BackgroundDiet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).MethodsThis analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons.ResultsConsumption of n-6 gamma-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintile(Q5-Q1)=0.77, 95% CI = 0.64; 0.92, p(trend)=0.01, q-value = 0.15). This association was mainly driven by gamma-linolenic acid derived from plant sources (HRper unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HRper unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 alpha-linolenic acid from vegetable sources and endometrial cancer risk (HRper unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk.ConclusionOur results suggest that higher consumption of gamma-linolenic acid and alpha-linoleic acid from plant sources may be associated with lower risk of endometrial cancer.
Published: 2023

6. Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition

Author: Yammine, S.G., Huybrechts, I., Biessy, C., Dossus, L., Panico, S., Sánchez, M.J., Benetou, V., Turzanski-Fortner, R., Katzke, V., Idahl, Annika, Skeie, G., Olsen, K. Standahl, Tjønneland, A., Halkjaer, J., Colorado-Yohar, S., Heath, A.K., Sonestedt, E., Sartor, H., Schulze, M.B., Palli, D., Crous-Bou, M., Dorronsoro, A., Overvad, K., Gurrea, A. Barricarte, Severi, G., Vermeulen, R.C.H., Sandanger, T.M., Travis, R.C., Key, T., Amiano, P., van Guelpen, Bethany, Johansson, M., Sund, Malin, Tumino, R., Wareham, N., Sacerdote, C., Krogh, V., Brennan, P., Riboli, E., Weiderpass, E., Gunter, M.J., Chajès, V., Yammine, S.G., Huybrechts, I., Biessy, C., Dossus, L., Panico, S., Sánchez, M.J., Benetou, V., Turzanski-Fortner, R., Katzke, V., Idahl, Annika, Skeie, G., Olsen, K. Standahl, Tjønneland, A., Halkjaer, J., Colorado-Yohar, S., Heath, A.K., Sonestedt, E., Sartor, H., Schulze, M.B., Palli, D., Crous-Bou, M., Dorronsoro, A., Overvad, K., Gurrea, A. Barricarte, Severi, G., Vermeulen, R.C.H., Sandanger, T.M., Travis, R.C., Key, T., Amiano, P., van Guelpen, Bethany, Johansson, M., Sund, Malin, Tumino, R., Wareham, N., Sacerdote, C., Krogh, V., Brennan, P., Riboli, E., Weiderpass, E., Gunter, M.J., and Chajès, V.
Published: 2023
Full Text: View/download PDF

7. 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

8. 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

9. 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

10. Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition

Author: IRAS OH Epidemiology Chemical Agents, Yammine, S G, Huybrechts, I, Biessy, C, Dossus, L, Panico, S, Sánchez, M J, Benetou, V, Turzanski-Fortner, R, Katzke, V, Idahl, A, Skeie, G, Olsen, K Standahl, Tjønneland, A, Halkjaer, J, Colorado-Yohar, S, Heath, A K, Sonestedt, E, Sartor, H, Schulze, M B, Palli, D, Crous-Bou, M, Dorronsoro, A, Overvad, K, Gurrea, A Barricarte, Severi, G, Vermeulen, R C H, Sandanger, T M, Travis, R C, Key, T, Amiano, P, Van Guelpen, B, Johansson, M, Sund, M, Tumino, R, Wareham, N, Sacerdote, C, Krogh, V, Brennan, P, Riboli, E, Weiderpass, E, Gunter, M J, Chajès, V, IRAS OH Epidemiology Chemical Agents, Yammine, S G, Huybrechts, I, Biessy, C, Dossus, L, Panico, S, Sánchez, M J, Benetou, V, Turzanski-Fortner, R, Katzke, V, Idahl, A, Skeie, G, Olsen, K Standahl, Tjønneland, A, Halkjaer, J, Colorado-Yohar, S, Heath, A K, Sonestedt, E, Sartor, H, Schulze, M B, Palli, D, Crous-Bou, M, Dorronsoro, A, Overvad, K, Gurrea, A Barricarte, Severi, G, Vermeulen, R C H, Sandanger, T M, Travis, R C, Key, T, Amiano, P, Van Guelpen, B, Johansson, M, Sund, M, Tumino, R, Wareham, N, Sacerdote, C, Krogh, V, Brennan, P, Riboli, E, Weiderpass, E, Gunter, M J, and Chajès, V
Published: 2023

11. Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition

Author: IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, Yammine, S G, Huybrechts, I, Biessy, C, Dossus, L, Panico, S, Sánchez, M J, Benetou, V, Turzanski-Fortner, R, Katzke, V, Idahl, A, Skeie, G, Olsen, K Standahl, Tjønneland, A, Halkjaer, J, Colorado-Yohar, S, Heath, A K, Sonestedt, E, Sartor, H, Schulze, M B, Palli, D, Crous-Bou, M, Dorronsoro, A, Overvad, K, Gurrea, A Barricarte, Severi, G, Vermeulen, R C H, Sandanger, T M, Travis, R C, Key, T, Amiano, P, Van Guelpen, B, Johansson, M, Sund, M, Tumino, R, Wareham, N, Sacerdote, C, Krogh, V, Brennan, P, Riboli, E, Weiderpass, E, Gunter, M J, Chajès, V, IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, Yammine, S G, Huybrechts, I, Biessy, C, Dossus, L, Panico, S, Sánchez, M J, Benetou, V, Turzanski-Fortner, R, Katzke, V, Idahl, A, Skeie, G, Olsen, K Standahl, Tjønneland, A, Halkjaer, J, Colorado-Yohar, S, Heath, A K, Sonestedt, E, Sartor, H, Schulze, M B, Palli, D, Crous-Bou, M, Dorronsoro, A, Overvad, K, Gurrea, A Barricarte, Severi, G, Vermeulen, R C H, Sandanger, T M, Travis, R C, Key, T, Amiano, P, Van Guelpen, B, Johansson, M, Sund, M, Tumino, R, Wareham, N, Sacerdote, C, Krogh, V, Brennan, P, Riboli, E, Weiderpass, E, Gunter, M J, and Chajès, V
Published: 2023

12. Metabolically defined body size and body shape phenotypes and risk of postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition

Author: Epi Kanker, Cancer, JC onderzoeksprogramma Kanker, Epi Kanker Team C, Mahamat-Saleh, Y., Rinaldi, S., Kaaks, R., Biessy, C., Gonzalez-Gil, E. M., Murphy, N., Le Cornet, C., Huerta, J. M., Sieri, S., Tjønneland, A., Mellemkjær, L., Guevara, M., Overvad, K., Perez-Cornago, A., Tin Tin, S., Padroni, L., Simeon, V., Masala, G., May, A., Monninkhof, E., Christakoudi, S., Heath, A. K., Tsilidis, K., Agudo, A., Schulze, M. B., Rothwell, J., Cadeau, C., Severi, S., Weiderpass, E., Gunter, M. J., Dossus, L., Epi Kanker, Cancer, JC onderzoeksprogramma Kanker, Epi Kanker Team C, Mahamat-Saleh, Y., Rinaldi, S., Kaaks, R., Biessy, C., Gonzalez-Gil, E. M., Murphy, N., Le Cornet, C., Huerta, J. M., Sieri, S., Tjønneland, A., Mellemkjær, L., Guevara, M., Overvad, K., Perez-Cornago, A., Tin Tin, S., Padroni, L., Simeon, V., Masala, G., May, A., Monninkhof, E., Christakoudi, S., Heath, A. K., Tsilidis, K., Agudo, A., Schulze, M. B., Rothwell, J., Cadeau, C., Severi, S., Weiderpass, E., Gunter, M. J., and Dossus, L.
Published: 2023

13. Metabolically defined body size and body shape phenotypes and risk of postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition

Author: Mahamat-Saleh, Y., Rinaldi, S., Kaaks, R., Biessy, C., Gonzalez-Gil, E. M., Murphy, N., Le Cornet, C., Huerta, J. M., Sieri, S., Tjønneland, A., Mellemkjær, L., Guevara, M., Overvad, K., Perez-Cornago, A., Tin Tin, S., Padroni, L., Simeon, V., Masala, G., May, A., Monninkhof, E., Christakoudi, S., Heath, A. K., Tsilidis, K., Agudo, A., Schulze, M. B., Rothwell, J., Cadeau, C., Severi, S., Weiderpass, E., Gunter, M. J., Dossus, L., Mahamat-Saleh, Y., Rinaldi, S., Kaaks, R., Biessy, C., Gonzalez-Gil, E. M., Murphy, N., Le Cornet, C., Huerta, J. M., Sieri, S., Tjønneland, A., Mellemkjær, L., Guevara, M., Overvad, K., Perez-Cornago, A., Tin Tin, S., Padroni, L., Simeon, V., Masala, G., May, A., Monninkhof, E., Christakoudi, S., Heath, A. K., Tsilidis, K., Agudo, A., Schulze, M. B., Rothwell, J., Cadeau, C., Severi, S., Weiderpass, E., Gunter, M. J., and Dossus, L.
Abstract: Background: Excess body fatness and hyperinsulinemia are both associated with an increased risk of postmenopausal breast cancer. However, whether women with high body fatness but normal insulin levels or those with normal body fatness and high levels of insulin are at elevated risk of breast cancer is not known. We investigated the associations of metabolically defined body size and shape phenotypes with the risk of postmenopausal breast cancer in a nested case–control study within the European Prospective Investigation into Cancer and Nutrition. Methods: Concentrations of C-peptide—a marker for insulin secretion—were measured at inclusion prior to cancer diagnosis in serum from 610 incident postmenopausal breast cancer cases and 1130 matched controls. C-peptide concentrations among the control participants were used to define metabolically healthy (MH; in first tertile) and metabolically unhealthy (MU; >1st tertile) status. We created four metabolic health/body size phenotype categories by combining the metabolic health definitions with normal weight (NW; BMI < 25 kg/m2, or WC < 80 cm, or WHR < 0.8) and overweight or obese (OW/OB; BMI ≥ 25 kg/m2, or WC ≥ 80 cm, or WHR ≥ 0.8) status for each of the three anthropometric measures separately: (1) MHNW, (2) MHOW/OB, (3) MUNW, and (4) MUOW/OB. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). Results: Women classified as MUOW/OB were at higher risk of postmenopausal breast cancer compared to MHNW women considering BMI (OR = 1.58, 95% CI = 1.14–2.19) and WC (OR = 1.51, 95% CI = 1.09–2.08) cut points and there was also a suggestive increased risk for the WHR (OR = 1.29, 95% CI = 0.94–1.77) definition. Conversely, women with the MHOW/OB and MUNW were not at statistically significant elevated risk of postmenopausal breast cancer risk compared to MHNW women. Conclusion: These findings suggest that being overweight or obese and metabol
Published: 2023

14. Metabolically defined body size and body shape phenotypes and risk of postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition

Author: Mahamat-Saleh, Y., Rinaldi, S., Kaaks, R., Biessy, C., Gonzalez-Gil, E. M., Murphy, N., Le Cornet, C., Huerta, J. M., Sieri, S., Tjønneland, A., Mellemkjær, L., Guevara, M., Overvad, K., Perez-Cornago, A., Tin Tin, S., Padroni, L., Simeon, V., Masala, G., May, A., Monninkhof, E., Christakoudi, S., Heath, A. K., Tsilidis, K., Agudo, A., Schulze, M. B., Rothwell, J., Cadeau, C., Severi, S., Weiderpass, E., Gunter, M. J., Dossus, L., Mahamat-Saleh, Y., Rinaldi, S., Kaaks, R., Biessy, C., Gonzalez-Gil, E. M., Murphy, N., Le Cornet, C., Huerta, J. M., Sieri, S., Tjønneland, A., Mellemkjær, L., Guevara, M., Overvad, K., Perez-Cornago, A., Tin Tin, S., Padroni, L., Simeon, V., Masala, G., May, A., Monninkhof, E., Christakoudi, S., Heath, A. K., Tsilidis, K., Agudo, A., Schulze, M. B., Rothwell, J., Cadeau, C., Severi, S., Weiderpass, E., Gunter, M. J., and Dossus, L.
Abstract: Background: Excess body fatness and hyperinsulinemia are both associated with an increased risk of postmenopausal breast cancer. However, whether women with high body fatness but normal insulin levels or those with normal body fatness and high levels of insulin are at elevated risk of breast cancer is not known. We investigated the associations of metabolically defined body size and shape phenotypes with the risk of postmenopausal breast cancer in a nested case–control study within the European Prospective Investigation into Cancer and Nutrition. Methods: Concentrations of C-peptide—a marker for insulin secretion—were measured at inclusion prior to cancer diagnosis in serum from 610 incident postmenopausal breast cancer cases and 1130 matched controls. C-peptide concentrations among the control participants were used to define metabolically healthy (MH; in first tertile) and metabolically unhealthy (MU; >1st tertile) status. We created four metabolic health/body size phenotype categories by combining the metabolic health definitions with normal weight (NW; BMI < 25 kg/m2, or WC < 80 cm, or WHR < 0.8) and overweight or obese (OW/OB; BMI ≥ 25 kg/m2, or WC ≥ 80 cm, or WHR ≥ 0.8) status for each of the three anthropometric measures separately: (1) MHNW, (2) MHOW/OB, (3) MUNW, and (4) MUOW/OB. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). Results: Women classified as MUOW/OB were at higher risk of postmenopausal breast cancer compared to MHNW women considering BMI (OR = 1.58, 95% CI = 1.14–2.19) and WC (OR = 1.51, 95% CI = 1.09–2.08) cut points and there was also a suggestive increased risk for the WHR (OR = 1.29, 95% CI = 0.94–1.77) definition. Conversely, women with the MHOW/OB and MUNW were not at statistically significant elevated risk of postmenopausal breast cancer risk compared to MHNW women. Conclusion: These findings suggest that being overweight or obese and metabol
Published: 2023

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

Author: Wang, X, Kapoor, PM, Auer, PL, Dennis, J, Dunning, AM, Wang, Q, Lush, M, Michailidou, K, Bolla, MK, Aronson, KJ, Murphy, RA, Brooks-Wilson, A, Lee, DG, Guenel, P, Truong, T, Mulot, C, Teras, LR, Patel, A, Dossus, L, Kaaks, R, Hoppe, R, Bruening, T, Hamann, U, Czene, K, Gabrielson, M, Hall, P, Eriksson, M, Jung, A, Becher, H, Couch, FJ, Larson, NL, Olson, JE, Ruddy, KJ, Giles, GG, MacInnis, RJ, Southey, MC, Le Marchand, L, Wilkens, LR, Haiman, CA, Olsson, H, Augustinsson, A, Krueger, U, Wagner, P, Scott, C, Winham, SJ, Vachon, CM, Perou, CM, Olshan, AF, Troester, MA, Hunter, DJ, Eliassen, HA, Tamimi, RM, Brantley, K, Andrulis, IL, Figueroa, J, Chanock, SJ, Ahearn, TU, Evans, GD, Newman, WG, VanVeen, EM, Howell, A, Wolk, A, Hakansson, N, Ziogas, A, Jones, ME, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Kitahara, CM, Linet, M, Prentice, RL, Easton, DF, Milne, RL, Kraft, P, Chang-Claude, J, Lindstrom, S, Wang, X, Kapoor, PM, Auer, PL, Dennis, J, Dunning, AM, Wang, Q, Lush, M, Michailidou, K, Bolla, MK, Aronson, KJ, Murphy, RA, Brooks-Wilson, A, Lee, DG, Guenel, P, Truong, T, Mulot, C, Teras, LR, Patel, A, Dossus, L, Kaaks, R, Hoppe, R, Bruening, T, Hamann, U, Czene, K, Gabrielson, M, Hall, P, Eriksson, M, Jung, A, Becher, H, Couch, FJ, Larson, NL, Olson, JE, Ruddy, KJ, Giles, GG, MacInnis, RJ, Southey, MC, Le Marchand, L, Wilkens, LR, Haiman, CA, Olsson, H, Augustinsson, A, Krueger, U, Wagner, P, Scott, C, Winham, SJ, Vachon, CM, Perou, CM, Olshan, AF, Troester, MA, Hunter, DJ, Eliassen, HA, Tamimi, RM, Brantley, K, Andrulis, IL, Figueroa, J, Chanock, SJ, Ahearn, TU, Evans, GD, Newman, WG, VanVeen, EM, Howell, A, Wolk, A, Hakansson, N, Ziogas, A, Jones, ME, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Kitahara, CM, Linet, M, Prentice, RL, Easton, DF, Milne, RL, Kraft, P, Chang-Claude, J, and Lindstrom, S
Abstract: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10-8 as genome-wide significant, and p-values < 1 × 10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10-7), which showed genome-wide significant interaction (p-value = 3.8 × 10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.
Published: 2022

16. 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

17. Cigarette Smoking and Endometrial Cancer Risk: Observational and Mendelian Randomization Analyses.

Author: Dimou, N, Omiyale, W, Biessy, C, Viallon, V, Kaaks, R, O'Mara, TA, Aglago, EK, Ardanaz, E, Bergmann, MM, Bondonno, NP, Braaten, T, Colorado-Yohar, SM, Crous-Bou, M, Dahm, CC, Fortner, RT, Gram, IT, Harlid, S, Heath, AK, Idahl, A, Kvaskoff, M, Nøst, TH, Overvad, K, Palli, D, Perez-Cornago, A, Sacerdote, C, Sánchez, M-J, Schulze, MB, Severi, G, Simeon, V, Tagliabue, G, Tjønneland, A, Truong, T, Tumino, R, Johansson, M, Weiderpass, E, Murphy, N, Gunter, MJ, Lacey, B, Allen, NE, Dossus, L, Dimou, N, Omiyale, W, Biessy, C, Viallon, V, Kaaks, R, O'Mara, TA, Aglago, EK, Ardanaz, E, Bergmann, MM, Bondonno, NP, Braaten, T, Colorado-Yohar, SM, Crous-Bou, M, Dahm, CC, Fortner, RT, Gram, IT, Harlid, S, Heath, AK, Idahl, A, Kvaskoff, M, Nøst, TH, Overvad, K, Palli, D, Perez-Cornago, A, Sacerdote, C, Sánchez, M-J, Schulze, MB, Severi, G, Simeon, V, Tagliabue, G, Tjønneland, A, Truong, T, Tumino, R, Johansson, M, Weiderpass, E, Murphy, N, Gunter, MJ, Lacey, B, Allen, NE, and Dossus, L
Abstract: BACKGROUND: Current epidemiologic evidence indicates that smoking is associated with a lower endometrial cancer risk. However, it is unknown if this association is causal or confounded. To further elucidate the role of smoking in endometrial cancer risk, we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS: The observational analyses included 286,415 participants enrolled in the European Prospective Investigation into Cancer and Nutrition and 179,271 participants in the UK Biobank, and multivariable Cox proportional hazards models were used. In two-sample MR analyses, genetic variants robustly associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants) were selected and their association with endometrial cancer risk (12,906 cancer/108,979 controls from the Endometrial Cancer Association Consortium) was examined. RESULTS: In the observational analysis, lifetime amount of smoking and ever having smoked regularly were associated with a lower endometrial cancer risk. In the MR analysis accounting for body mass index, a genetic predisposition to a higher lifetime amount of smoking was not associated with endometrial cancer risk (OR per 1-SD increment: 1.15; 95% confidence interval: 0.91-1.44). Genetic predisposition to ever having smoked regularly was not associated with risk of endometrial cancer. CONCLUSIONS: Smoking was inversely associated with endometrial cancer in the observational analyses, although unsupported by the MR. Additional studies are required to better understand the possible confounders and mechanisms underlying the observed associations between smoking and endometrial cancer. IMPACT: The results from this analysis indicate that smoking is unlikely to be causally linked with endometrial cancer risk.
Published: 2022

18. Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition.

Author: Breeur, M, Ferrari, P, Dossus, L, Jenab, M, Johansson, M, Rinaldi, S, Travis, RC, His, M, Key, TJ, Schmidt, JA, Overvad, K, Tjønneland, A, Kyrø, C, Rothwell, JA, Laouali, N, Severi, G, Kaaks, R, Katzke, V, Schulze, MB, Eichelmann, F, Palli, D, Grioni, S, Panico, S, Tumino, R, Sacerdote, C, Bueno-de-Mesquita, B, Olsen, KS, Sandanger, TM, Nøst, TH, Quirós, JR, Bonet, C, Barranco, MR, Chirlaque, M-D, Ardanaz, E, Sandsveden, M, Manjer, J, Vidman, L, Rentoft, M, Muller, D, Tsilidis, K, Heath, AK, Keun, H, Adamski, J, Keski-Rahkonen, P, Scalbert, A, Gunter, MJ, Viallon, V, Breeur, M, Ferrari, P, Dossus, L, Jenab, M, Johansson, M, Rinaldi, S, Travis, RC, His, M, Key, TJ, Schmidt, JA, Overvad, K, Tjønneland, A, Kyrø, C, Rothwell, JA, Laouali, N, Severi, G, Kaaks, R, Katzke, V, Schulze, MB, Eichelmann, F, Palli, D, Grioni, S, Panico, S, Tumino, R, Sacerdote, C, Bueno-de-Mesquita, B, Olsen, KS, Sandanger, TM, Nøst, TH, Quirós, JR, Bonet, C, Barranco, MR, Chirlaque, M-D, Ardanaz, E, Sandsveden, M, Manjer, J, Vidman, L, Rentoft, M, Muller, D, Tsilidis, K, Heath, AK, Keun, H, Adamski, J, Keski-Rahkonen, P, Scalbert, A, Gunter, MJ, and Viallon, V
Abstract: BACKGROUND: Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. METHODS: We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. RESULTS: Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. CONCLUSIONS: These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.
Published: 2022

19. Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis

Author: Bouras, E. (Emmanouil), Karhunen, V. (Ville), Gill, D. (Dipender), Huang, J. (Jian), Haycock, P. C. (Philip C.), Gunter, M. J. (Marc J.), Johansson, M. (Mattias), Brennan, P. (Paul), Key, T. (Tim), Lewis, S. J. (Sarah J.), Martin, R. M. (Richard M.), Murphy, N. (Neil), Platz, E. A. (Elizabeth A.), Travis, R. (Ruth), Yarmolinsky, J. (James), Zuber, V. (Verena), Martin, P. (Paul), Katsoulis, M. (Michail), Freisling, H. (Heinz), Nost, T. H. (Therese Haugdahl), Schulze, M. B. (Matthias B.), Dossus, L. (Laure), Hung, R. J. (Rayjean J.), Amos, C. I. (Christopher, I), Ahola-Olli, A. (Ari), Palaniswamy, S. (Saranya), Mannikko, M. (Minna), Auvinen, J. (Juha), Herzig, K.-H. (Karl-Heinz), Keinänen-Kiukaanniemi, S. (Sirkka), Lehtimäki, T. (Terho), Salomaa, V. (Veikko), Raitakari, O. (Olli), Salmi, M. (Marko), Jalkanen, S. (Sirpa), Järvelin, M.-R. (Marjo-Riitta), Dehghan, A. (Abbas), Tsilidis, K. K. (Konstantinos K.), Bouras, E. (Emmanouil), Karhunen, V. (Ville), Gill, D. (Dipender), Huang, J. (Jian), Haycock, P. C. (Philip C.), Gunter, M. J. (Marc J.), Johansson, M. (Mattias), Brennan, P. (Paul), Key, T. (Tim), Lewis, S. J. (Sarah J.), Martin, R. M. (Richard M.), Murphy, N. (Neil), Platz, E. A. (Elizabeth A.), Travis, R. (Ruth), Yarmolinsky, J. (James), Zuber, V. (Verena), Martin, P. (Paul), Katsoulis, M. (Michail), Freisling, H. (Heinz), Nost, T. H. (Therese Haugdahl), Schulze, M. B. (Matthias B.), Dossus, L. (Laure), Hung, R. J. (Rayjean J.), Amos, C. I. (Christopher, I), Ahola-Olli, A. (Ari), Palaniswamy, S. (Saranya), Mannikko, M. (Minna), Auvinen, J. (Juha), Herzig, K.-H. (Karl-Heinz), Keinänen-Kiukaanniemi, S. (Sirkka), Lehtimäki, T. (Terho), Salomaa, V. (Veikko), Raitakari, O. (Olli), Salmi, M. (Marko), Jalkanen, S. (Sirpa), Järvelin, M.-R. (Marjo-Riitta), Dehghan, A. (Abbas), and Tsilidis, K. K. (Konstantinos K.)
Abstract: Background: Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiolog
Published: 2022

20. 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

21. 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, NV, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, NBCS Collaborators, Collée, JM, CTS Consortium, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dörk, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, Giles, GG, González-Neira, A, Guénel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, ABCTB Investigators, kConFab/AOCS Investigators, 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, JV, 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, Pylkäs, 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, NV, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, NBCS Collaborators, Collée, JM, CTS Consortium, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dörk, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, Giles, GG, González-Neira, A, Guénel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, ABCTB Investigators, kConFab/AOCS Investigators, 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, JV, 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, Pylkäs, 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

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, NV, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, NBCS Collaborators, Collée, JM, CTS Consortium, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dörk, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, Giles, GG, González-Neira, A, Guénel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, ABCTB Investigators, kConFab/AOCS Investigators, 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, JV, 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, Pylkäs, 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, NV, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, NBCS Collaborators, Collée, JM, CTS Consortium, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dörk, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, Giles, GG, González-Neira, A, Guénel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, ABCTB Investigators, kConFab/AOCS Investigators, 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, JV, 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, Pylkäs, 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. Prospective analysis of circulating metabolites and endometrial cancer risk

Author: Dossus, L., Kouloura, E., Biessy, C., Viallon, V., Siskos, A.P., Dimou, N., Rinaldi, S., Merritt, M.A., Allen, N., Fortner, R., Kaaks, R., Weiderpass, E., Gram, I.T., Rothwell, J.A., Lécuyer, L., Severi, G., Schulze, M.B., Nøst, T.H., Crous-Bou, M., Sánchez, M.-J., Amiano, P., Colorado-Yohar, S.M., Gurrea, A.B., Schmidt, J.A., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Mattiello, A., Vermeulen, R., Heath, A.K., Christakoudi, S., Tsilidis, K.K., Travis, R.C., Gunter, M.J., Keun, H.C., Dossus, L., Kouloura, E., Biessy, C., Viallon, V., Siskos, A.P., Dimou, N., Rinaldi, S., Merritt, M.A., Allen, N., Fortner, R., Kaaks, R., Weiderpass, E., Gram, I.T., Rothwell, J.A., Lécuyer, L., Severi, G., Schulze, M.B., Nøst, T.H., Crous-Bou, M., Sánchez, M.-J., Amiano, P., Colorado-Yohar, S.M., Gurrea, A.B., Schmidt, J.A., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Mattiello, A., Vermeulen, R., Heath, A.K., Christakoudi, S., Tsilidis, K.K., Travis, R.C., Gunter, M.J., and Keun, H.C.
Abstract: Background: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. Results: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR1SD: 1.18, 95% CI: 1.05–1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80–0.99; OR1SD: 0.89, 95% CI: 0.79–1.00 and OR1SD: 0.91, 95% CI: 0.81–1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR1SD: 1.14, 95% CI: 1.02–1.28) and that of short chain to free acylcarnitines (OR1SD: 1.12, 95% CI: 1.00–1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. Conclusion: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention.
Published: 2021

24. A New Pipeline for the Normalization and Pooling of Metabolomics Data

Author: Viallon, V., His, M., Rinaldi, S., Breeur, M., Gicquiau, A., Hemon, B., Overvad, K., Tjønneland, A., Rostgaard-Hansen, A.L., Rothwell, J.A., Lecuyer, L., Severi, G., Kaaks, R., Johnson, T., Schulze, M.B., Palli, D., Agnoli, C., Panico, S., Tumino, R., Ricceri, F., Monique Verschuren, W.M., Engelfriet, P., Onland-Moret, C., Vermeulen, R., Nøst, T.H., Urbarova, I., Zamora-Ros, R., Rodriguez-Barranco, M., Amiano, P., Huerta, J.M., Ardanaz, E., Melander, O., Ottoson, F., Vidman, L., Rentoft, M., Schmidt, J.A., Travis, R.C., Weiderpass, E., Johansson, M., Dossus, L., Jenab, M., Gunter, M.J., Bermejo, J.L., Scherer, D., Salek, R.M., Keski-Rahkonen, P., Ferrari, P., Viallon, V., His, M., Rinaldi, S., Breeur, M., Gicquiau, A., Hemon, B., Overvad, K., Tjønneland, A., Rostgaard-Hansen, A.L., Rothwell, J.A., Lecuyer, L., Severi, G., Kaaks, R., Johnson, T., Schulze, M.B., Palli, D., Agnoli, C., Panico, S., Tumino, R., Ricceri, F., Monique Verschuren, W.M., Engelfriet, P., Onland-Moret, C., Vermeulen, R., Nøst, T.H., Urbarova, I., Zamora-Ros, R., Rodriguez-Barranco, M., Amiano, P., Huerta, J.M., Ardanaz, E., Melander, O., Ottoson, F., Vidman, L., Rentoft, M., Schmidt, J.A., Travis, R.C., Weiderpass, E., Johansson, M., Dossus, L., Jenab, M., Gunter, M.J., Bermejo, J.L., Scherer, D., Salek, R.M., Keski-Rahkonen, P., and Ferrari, P.
Abstract: Pooling metabolomics data across studies is often desirable to increase the statistical power of the analysis. However, this can raise methodological challenges as several preanalytical and analytical factors could introduce differences in measured concentrations and variability between datasets. Specifically, different studies may use variable sample types (e.g., serum versus plasma) collected, treated, and stored according to different protocols, and assayed in different laboratories using different instruments. To address these issues, a new pipeline was developed to normalize and pool metabolomics data through a set of sequential steps: (i) exclusions of the least informative observations and metabolites and removal of outliers; imputation of missing data; (ii) identification of the main sources of variability through principal component partial R-square (PC-PR2) analysis; (iii) application of linear mixed models to remove unwanted variability, including samples’ originating study and batch, and preserve biological variations while accounting for potential differences in the residual variances across studies. This pipeline was applied to targeted metabolomics data acquired using Biocrates AbsoluteIDQ kits in eight case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Comprehensive examination of metabolomics measurements indicated that the pipeline improved the comparability of data across the studies. Our pipeline can be adapted to normalize other molecular data, including biomarkers as well as proteomics data, and could be used for pooling molecular datasets, for example in international consortia, to limit biases introduced by inter-study variability. This versatility of the pipeline makes our work of potential interest to molecular epidemiologists.
Published: 2021

25. 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., 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., 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., Le Marchand L., Lejbkowicz F., Li J., Long J., Lophatananon A., Lubinski J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Matsuo K., Mavroudis D., Mayes R., Menon U., Milne R.L., Mohd Taib N.A., 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., van den Ouweland A.M.W., 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., 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., 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., 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., Le Marchand L., Lejbkowicz F., Li J., Long J., Lophatananon A., Lubinski J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Matsuo K., Mavroudis D., Mayes R., Menon U., Milne R.L., Mohd Taib N.A., 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., van den Ouweland A.M.W., 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., and Fletcher O.
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 x 10-31).Copyright © 2021 The Authors
Published: 2021

26. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

Author: Morra A., Escala-Garcia M., Beesley J., Keeman R., Canisius S., Ahearn T.U., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Augustinsson A., Beane Freeman L.E., Becher H., Beckmann M.W., Behrens S., Bojesen S.E., Bolla M.K., Brenner H., Bruning T., Buys S.S., Caan B., Campa D., Canzian F., Castelao J.E., Chang-Claude J., Chanock S.J., Cheng T.-Y.D., Clarke C.L., Colonna S.V., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Dennis J., Dork T., Dossus L., Dunning A.M., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fritschi L., Gago-Dominguez M., Garcia-Saenz J.A., Giles G.G., Grip M., Guenel P., Gundert M., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hart S.N., Hartikainen J.M., Hartmann A., He W., Hooning M.J., Hoppe R., Hopper J.L., Howell A., Hunter D.J., Jager A., Jakubowska A., Janni W., John E.M., Jung A.Y., Kaaks R., Keupers M., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Kurian A.W., Lacey J.V., Lambrechts D., Le Marchand L., Lindblom A., Linet M., Luben R.N., Lubinski J., Lush M., Mannermaa A., Manoochehri M., Margolin S., Martens J.W.M., Martinez M.E., Mavroudis D., Michailidou K., Milne R.L., Mulligan A.M., Muranen T.A., Nevanlinna H., Newman W.G., Nielsen S.F., Nordestgaard B.G., Olshan A.F., Olsson H., Orr N., Park-Simon T.-W., Patel A.V., Peissel B., Peterlongo P., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Rack B., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Ruebner M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Scott C., Shah M., Smichkoska S., Southey M.C., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teras L.R., Terry M.B., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Truong T., Vachon C.M., Wang Q., Hurson A.N., Winqvist R., Wolk A., Ziogas A., Brauch H., Garcia-Closas M., Pharoah P.D.P., Easton D.F., Chenevix-Trench G., Schmidt M.K., Morra A., Escala-Garcia M., Beesley J., Keeman R., Canisius S., Ahearn T.U., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Augustinsson A., Beane Freeman L.E., Becher H., Beckmann M.W., Behrens S., Bojesen S.E., Bolla M.K., Brenner H., Bruning T., Buys S.S., Caan B., Campa D., Canzian F., Castelao J.E., Chang-Claude J., Chanock S.J., Cheng T.-Y.D., Clarke C.L., Colonna S.V., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Dennis J., Dork T., Dossus L., Dunning A.M., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fritschi L., Gago-Dominguez M., Garcia-Saenz J.A., Giles G.G., Grip M., Guenel P., Gundert M., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hart S.N., Hartikainen J.M., Hartmann A., He W., Hooning M.J., Hoppe R., Hopper J.L., Howell A., Hunter D.J., Jager A., Jakubowska A., Janni W., John E.M., Jung A.Y., Kaaks R., Keupers M., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Kurian A.W., Lacey J.V., Lambrechts D., Le Marchand L., Lindblom A., Linet M., Luben R.N., Lubinski J., Lush M., Mannermaa A., Manoochehri M., Margolin S., Martens J.W.M., Martinez M.E., Mavroudis D., Michailidou K., Milne R.L., Mulligan A.M., Muranen T.A., Nevanlinna H., Newman W.G., Nielsen S.F., Nordestgaard B.G., Olshan A.F., Olsson H., Orr N., Park-Simon T.-W., Patel A.V., Peissel B., Peterlongo P., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Rack B., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Ruebner M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Scott C., Shah M., Smichkoska S., Southey M.C., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teras L.R., Terry M.B., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Truong T., Vachon C.M., Wang Q., Hurson A.N., Winqvist R., Wolk A., Ziogas A., Brauch H., Garcia-Closas M., Pharoah P.D.P., Easton D.F., Chenevix-Trench G., and Schmidt M.K.
Abstract: BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHOD(S): We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP <0.15). RESULT(S): Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSION(S): We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on br
Published: 2021

27. A New Pipeline for the Normalization and Pooling of Metabolomics Data

Author: IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Sub Inorganic Chemistry and Catalysis, Viallon, V., His, M., Rinaldi, S., Breeur, M., Gicquiau, A., Hemon, B., Overvad, K., Tjønneland, A., Rostgaard-Hansen, A.L., Rothwell, J.A., Lecuyer, L., Severi, G., Kaaks, R., Johnson, T., Schulze, M.B., Palli, D., Agnoli, C., Panico, S., Tumino, R., Ricceri, F., Monique Verschuren, W.M., Engelfriet, P., Onland-Moret, C., Vermeulen, R., Nøst, T.H., Urbarova, I., Zamora-Ros, R., Rodriguez-Barranco, M., Amiano, P., Huerta, J.M., Ardanaz, E., Melander, O., Ottoson, F., Vidman, L., Rentoft, M., Schmidt, J.A., Travis, R.C., Weiderpass, E., Johansson, M., Dossus, L., Jenab, M., Gunter, M.J., Bermejo, J.L., Scherer, D., Salek, R.M., Keski-Rahkonen, P., Ferrari, P., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Sub Inorganic Chemistry and Catalysis, Viallon, V., His, M., Rinaldi, S., Breeur, M., Gicquiau, A., Hemon, B., Overvad, K., Tjønneland, A., Rostgaard-Hansen, A.L., Rothwell, J.A., Lecuyer, L., Severi, G., Kaaks, R., Johnson, T., Schulze, M.B., Palli, D., Agnoli, C., Panico, S., Tumino, R., Ricceri, F., Monique Verschuren, W.M., Engelfriet, P., Onland-Moret, C., Vermeulen, R., Nøst, T.H., Urbarova, I., Zamora-Ros, R., Rodriguez-Barranco, M., Amiano, P., Huerta, J.M., Ardanaz, E., Melander, O., Ottoson, F., Vidman, L., Rentoft, M., Schmidt, J.A., Travis, R.C., Weiderpass, E., Johansson, M., Dossus, L., Jenab, M., Gunter, M.J., Bermejo, J.L., Scherer, D., Salek, R.M., Keski-Rahkonen, P., and Ferrari, P.
Published: 2021

28. Prospective analysis of circulating metabolites and endometrial cancer risk

Author: Sub Inorganic Chemistry and Catalysis, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Dossus, L., Kouloura, E., Biessy, C., Viallon, V., Siskos, A.P., Dimou, N., Rinaldi, S., Merritt, M.A., Allen, N., Fortner, R., Kaaks, R., Weiderpass, E., Gram, I.T., Rothwell, J.A., Lécuyer, L., Severi, G., Schulze, M.B., Nøst, T.H., Crous-Bou, M., Sánchez, M.-J., Amiano, P., Colorado-Yohar, S.M., Gurrea, A.B., Schmidt, J.A., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Mattiello, A., Vermeulen, R., Heath, A.K., Christakoudi, S., Tsilidis, K.K., Travis, R.C., Gunter, M.J., Keun, H.C., Sub Inorganic Chemistry and Catalysis, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Dossus, L., Kouloura, E., Biessy, C., Viallon, V., Siskos, A.P., Dimou, N., Rinaldi, S., Merritt, M.A., Allen, N., Fortner, R., Kaaks, R., Weiderpass, E., Gram, I.T., Rothwell, J.A., Lécuyer, L., Severi, G., Schulze, M.B., Nøst, T.H., Crous-Bou, M., Sánchez, M.-J., Amiano, P., Colorado-Yohar, S.M., Gurrea, A.B., Schmidt, J.A., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Mattiello, A., Vermeulen, R., Heath, A.K., Christakoudi, S., Tsilidis, K.K., Travis, R.C., Gunter, M.J., and Keun, H.C.
Published: 2021

29. 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., 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., 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., Le Marchand L., Lejbkowicz F., Li J., Long J., Lophatananon A., Lubinski J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Matsuo K., Mavroudis D., Mayes R., Menon U., Milne R.L., Mohd Taib N.A., 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., van den Ouweland A.M.W., 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., 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., 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., 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., Le Marchand L., Lejbkowicz F., Li J., Long J., Lophatananon A., Lubinski J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Matsuo K., Mavroudis D., Mayes R., Menon U., Milne R.L., Mohd Taib N.A., 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., van den Ouweland A.M.W., 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., and Fletcher O.
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 x 10-31).Copyright © 2021 The Authors
Published: 2021

30. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

Author: Morra A., Escala-Garcia M., Beesley J., Keeman R., Canisius S., Ahearn T.U., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Augustinsson A., Beane Freeman L.E., Becher H., Beckmann M.W., Behrens S., Bojesen S.E., Bolla M.K., Brenner H., Bruning T., Buys S.S., Caan B., Campa D., Canzian F., Castelao J.E., Chang-Claude J., Chanock S.J., Cheng T.-Y.D., Clarke C.L., Colonna S.V., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Dennis J., Dork T., Dossus L., Dunning A.M., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fritschi L., Gago-Dominguez M., Garcia-Saenz J.A., Giles G.G., Grip M., Guenel P., Gundert M., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hart S.N., Hartikainen J.M., Hartmann A., He W., Hooning M.J., Hoppe R., Hopper J.L., Howell A., Hunter D.J., Jager A., Jakubowska A., Janni W., John E.M., Jung A.Y., Kaaks R., Keupers M., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Kurian A.W., Lacey J.V., Lambrechts D., Le Marchand L., Lindblom A., Linet M., Luben R.N., Lubinski J., Lush M., Mannermaa A., Manoochehri M., Margolin S., Martens J.W.M., Martinez M.E., Mavroudis D., Michailidou K., Milne R.L., Mulligan A.M., Muranen T.A., Nevanlinna H., Newman W.G., Nielsen S.F., Nordestgaard B.G., Olshan A.F., Olsson H., Orr N., Park-Simon T.-W., Patel A.V., Peissel B., Peterlongo P., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Rack B., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Ruebner M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Scott C., Shah M., Smichkoska S., Southey M.C., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teras L.R., Terry M.B., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Truong T., Vachon C.M., Wang Q., Hurson A.N., Winqvist R., Wolk A., Ziogas A., Brauch H., Garcia-Closas M., Pharoah P.D.P., Easton D.F., Chenevix-Trench G., Schmidt M.K., Morra A., Escala-Garcia M., Beesley J., Keeman R., Canisius S., Ahearn T.U., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Augustinsson A., Beane Freeman L.E., Becher H., Beckmann M.W., Behrens S., Bojesen S.E., Bolla M.K., Brenner H., Bruning T., Buys S.S., Caan B., Campa D., Canzian F., Castelao J.E., Chang-Claude J., Chanock S.J., Cheng T.-Y.D., Clarke C.L., Colonna S.V., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Dennis J., Dork T., Dossus L., Dunning A.M., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fritschi L., Gago-Dominguez M., Garcia-Saenz J.A., Giles G.G., Grip M., Guenel P., Gundert M., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hart S.N., Hartikainen J.M., Hartmann A., He W., Hooning M.J., Hoppe R., Hopper J.L., Howell A., Hunter D.J., Jager A., Jakubowska A., Janni W., John E.M., Jung A.Y., Kaaks R., Keupers M., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Kurian A.W., Lacey J.V., Lambrechts D., Le Marchand L., Lindblom A., Linet M., Luben R.N., Lubinski J., Lush M., Mannermaa A., Manoochehri M., Margolin S., Martens J.W.M., Martinez M.E., Mavroudis D., Michailidou K., Milne R.L., Mulligan A.M., Muranen T.A., Nevanlinna H., Newman W.G., Nielsen S.F., Nordestgaard B.G., Olshan A.F., Olsson H., Orr N., Park-Simon T.-W., Patel A.V., Peissel B., Peterlongo P., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Rack B., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Ruebner M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Scott C., Shah M., Smichkoska S., Southey M.C., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teras L.R., Terry M.B., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Truong T., Vachon C.M., Wang Q., Hurson A.N., Winqvist R., Wolk A., Ziogas A., Brauch H., Garcia-Closas M., Pharoah P.D.P., Easton D.F., Chenevix-Trench G., and Schmidt M.K.
Abstract: BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHOD(S): We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP <0.15). RESULT(S): Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSION(S): We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on br
Published: 2021

31. Use of systemic glucocorticoids and risk of breast cancer in a prospective cohort of postmenopausal women.

Author: Cairat, M, Al Rahmoun, M, Gunter, MJ, Heudel, P-E, Severi, G, Dossus, L, Fournier, A, Cairat, M, Al Rahmoun, M, Gunter, MJ, Heudel, P-E, Severi, G, Dossus, L, and Fournier, A
Abstract: BACKGROUND: Glucocorticoids could theoretically decrease breast cancer risk through their anti-inflammatory effects or increase risk through immunosuppression. However, epidemiological evidence is limited regarding the associations between glucocorticoid use and breast cancer risk. METHODS: We investigated the association between systemic glucocorticoid use and breast cancer incidence in the E3N cohort, which includes 98,995 women with information on various characteristics collected from repeated questionnaires complemented with drug reimbursement data available from 2004. Women with at least two reimbursements of systemic glucocorticoids in any previous 3-month period since January 1, 2004, were defined as exposed. We considered exposure as a time-varying parameter, and we used multivariable Cox regression models to estimate hazard ratios (HRs) of breast cancer. We performed a competing risk analysis using a cause-specific hazard approach to study the heterogeneity by tumour subtype/stage/grade. RESULTS: Among 62,512 postmenopausal women (median age at inclusion of 63 years old), 2864 developed breast cancer during a median follow-up of 9 years (between years 2004 and 2014). Compared with non-exposure, glucocorticoid exposure was not associated with overall breast cancer risk [HR = 0.94 (0.85-1.05)]; however, it was associated with a higher risk of in situ breast cancer and a lower risk of invasive breast cancer [HRinsitu = 1.34 (1.01-1.78); HRinvasive = 0.86 (0.76-0.97); Phomogeneity = 0.01]. Regarding the risk of invasive breast cancer, glucocorticoid exposure was inversely associated with oestrogen receptor (ER)-positive breast cancer [HRER+ = 0.82 (0.72-0.94); HRER- = 1.21 (0.88-1.66); Phomogeneity = 0.03]; it was also inversely associated with the risk of stage 1 or stage 2 tumours but positively associated with the risk of stage 3/4 breast cancers [HRstage1 = 0.87 (0.75-1.01); HRstage2 = 0.67 (0.52-0.86); HRstage3/4 = 1.49 (1.02-2.20); Phomogeneity = 0.01].
Published: 2021

32. Adiposity and Endometrial Cancer Risk in Postmenopausal Women: A Sequential Causal Mediation Analysis

Author: Dashti, SG, English, DR, Simpson, JA, Karahalios, A, Moreno-Betancur, M, Biessy, C, Rinaldi, S, Ferrari, P, Tjonneland, A, Halkjaer, J, Dahm, CC, Vistisen, HT, Menegaux, F, Perduca, V, Severi, G, Aleksandrova, K, Schulze, MB, Masala, G, Sieri, S, Tumino, R, Macciotta, A, Panico, S, Hiensch, AE, May, AM, Quiros, JR, Agudo, A, Sanchez, M-J, Amiano, P, Colorado-Yohar, S, Ardanaz, E, Allen, NE, Weiderpass, E, Fortner, RT, Christakoudi, S, Tsilidis, KK, Riboli, E, Kaaks, R, Gunter, MJ, Viallon, V, Dossus, L, Dashti, SG, English, DR, Simpson, JA, Karahalios, A, Moreno-Betancur, M, Biessy, C, Rinaldi, S, Ferrari, P, Tjonneland, A, Halkjaer, J, Dahm, CC, Vistisen, HT, Menegaux, F, Perduca, V, Severi, G, Aleksandrova, K, Schulze, MB, Masala, G, Sieri, S, Tumino, R, Macciotta, A, Panico, S, Hiensch, AE, May, AM, Quiros, JR, Agudo, A, Sanchez, M-J, Amiano, P, Colorado-Yohar, S, Ardanaz, E, Allen, NE, Weiderpass, E, Fortner, RT, Christakoudi, S, Tsilidis, KK, Riboli, E, Kaaks, R, Gunter, MJ, Viallon, V, and Dossus, L
Abstract: BACKGROUND: Adiposity increases endometrial cancer risk, possibly through inflammation, hyperinsulinemia, and increasing estrogens. We aimed to quantify the mediating effects of adiponectin (anti-inflammatory adipocytokine); IL6, IL1-receptor antagonist, TNF receptor 1 and 2, and C-reactive protein (inflammatory status biomarkers); C-peptide (hyperinsulinemia biomarker); and free estradiol and estrone (estrogen biomarkers) in the adiposity-endometrial cancer link in postmenopausal women. METHODS: We used data from a case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Eligible women did not have cancer, hysterectomy, and diabetes; did not use oral contraceptives or hormone therapy; and were postmenopausal at recruitment. Mediating pathways from adiposity to endometrial cancer were investigated by estimating natural indirect (NIE) and direct (NDE) effects using sequential mediation analysis. RESULTS: The study included 163 cases and 306 controls. The adjusted OR for endometrial cancer for body mass index (BMI) ≥30 versus ≥18.5-<25 kg/m2 was 2.51 (95% confidence interval, 1.26-5.02). The ORsNIE were 1.95 (1.01-3.74) through all biomarkers [72% proportion mediated (PM)] decomposed as: 1.35 (1.06-1.73) through pathways originating with adiponectin (33% PM); 1.13 (0.71-1.80) through inflammation beyond (the potential influence of) adiponectin (13% PM); 1.05 (0.88-1.24) through C-peptide beyond adiponectin and inflammation (5% PM); and 1.22 (0.89-1.67) through estrogens beyond preceding biomarkers (21% PM). The ORNDE not through biomarkers was 1.29 (0.54-3.09). Waist circumference gave similar results. CONCLUSIONS: Reduced adiponectin and increased inflammatory biomarkers, C-peptide, and estrogens mediated approximately 70% of increased odds of endometrial cancer in women with obesity versus normal weight. IMPACT: If replicated, these results could have implications for identifying targets for intervention to reduce endometria
Published: 2021

33. Lifestyle correlates of eight breast cancer-related metabolites: a cross-sectional study within the EPIC cohort

Author: His, M, Viallon, V, Dossus, L, Schmidt, JA, Travis, RC, Gunter, MJ, Overvad, K, Kyro, C, Tjonneland, A, Lecuyer, L, Rothwell, JA, Severi, G, Johnson, T, Katzke, V, Schulze, MB, Masala, G, Sieri, S, Panico, S, Tumino, R, Macciotta, A, Boer, JMA, Monninkhof, EM, Olsen, KS, Nost, TH, Sandanger, TM, Agudo, A, Sanchez, M-J, Amiano, P, Colorado-Yohar, SM, Ardanaz, E, Vidman, L, Winkvist, A, Heath, AK, Weiderpass, E, Huybrechts, I, Rinaldi, S, His, M, Viallon, V, Dossus, L, Schmidt, JA, Travis, RC, Gunter, MJ, Overvad, K, Kyro, C, Tjonneland, A, Lecuyer, L, Rothwell, JA, Severi, G, Johnson, T, Katzke, V, Schulze, MB, Masala, G, Sieri, S, Panico, S, Tumino, R, Macciotta, A, Boer, JMA, Monninkhof, EM, Olsen, KS, Nost, TH, Sandanger, TM, Agudo, A, Sanchez, M-J, Amiano, P, Colorado-Yohar, SM, Ardanaz, E, Vidman, L, Winkvist, A, Heath, AK, Weiderpass, E, Huybrechts, I, and Rinaldi, S
Abstract: BACKGROUND: Metabolomics is a promising molecular tool for identifying novel etiological pathways leading to cancer. In an earlier prospective study among pre- and postmenopausal women not using exogenous hormones, we observed a higher risk of breast cancer associated with higher blood concentrations of one metabolite (acetylcarnitine) and a lower risk associated with higher blood concentrations of seven others (arginine, asparagine, phosphatidylcholines (PCs) aa C36:3, ae C34:2, ae C36:2, ae C36:3, and ae C38:2). METHODS: To identify determinants of these breast cancer-related metabolites, we conducted a cross-sectional analysis to identify their lifestyle and anthropometric correlates in 2358 women, who were previously included as controls in case-control studies nested within the European Prospective Investigation into Cancer and Nutrition cohort and not using exogenous hormones at blood collection. Associations of each metabolite concentration with 42 variables were assessed using linear regression models in a discovery set of 1572 participants. Significant associations were evaluated in a validation set (n = 786). RESULTS: For the metabolites previously associated with a lower risk of breast cancer, concentrations of PCs ae C34:2, C36:2, C36:3, and C38:2 were negatively associated with adiposity and positively associated with total and saturated fat intakes. PC ae C36:2 was also negatively associated with alcohol consumption and positively associated with two scores reflecting adherence to a healthy lifestyle. Asparagine concentration was negatively associated with adiposity. Arginine and PC aa C36:3 concentrations were not associated to any of the factors examined. For the metabolite previously associated with a higher risk of breast cancer, acetylcarnitine, a positive association with age was observed. CONCLUSIONS: These associations may indicate possible mechanisms underlying associations between lifestyle and anthropometric factors, and risk of breast cance
Published: 2021

34. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Morra, A, Escala-Garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Augustinsson, A, Freeman, LEB, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Bruening, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Cheng, T-YD, Clarke, CL, Colonna, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dork, T, Dossus, L, Dunning, AM, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, Gago-Dominguez, M, Garcia-Saenz, JA, Giles, GG, Grip, M, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, Janni, W, John, EM, Jung, AY, Kaaks, R, Keupers, M, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, Michailidou, K, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Olshan, AF, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peissel, B, Peterlongo, P, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Presneau, N, Rack, B, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Lubinski, J, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teras, LR, Terry, MB, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Hurson, AN, Winqvist, R, Wolk, A, Ziogas, A, Brauch, H, Garcia-Closas, M, Pharoah, PDP, Easton, DF, Chenevix-Trench, G, Schmidt, MK, Morra, A, Escala-Garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Augustinsson, A, Freeman, LEB, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Bruening, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Cheng, T-YD, Clarke, CL, Colonna, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dork, T, Dossus, L, Dunning, AM, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, Gago-Dominguez, M, Garcia-Saenz, JA, Giles, GG, Grip, M, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, Janni, W, John, EM, Jung, AY, Kaaks, R, Keupers, M, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, Michailidou, K, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Olshan, AF, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peissel, B, Peterlongo, P, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Presneau, N, Rack, B, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Lubinski, J, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teras, LR, Terry, MB, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Hurson, AN, Winqvist, R, Wolk, A, Ziogas, A, Brauch, H, Garcia-Closas, M, Pharoah, PDP, Easton, DF, Chenevix-Trench, G, and Schmidt, MK
Abstract: BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast
Published: 2021

35. Investigation of circulating metabolites associated with breast cancer risk by untargeted metabolomics: a case-control study nested within the French E3N cohort.

Author: Jobard, E, Dossus, L, Baglietto, L, Fornili, M, Lécuyer, L, Mancini, FR, Gunter, MJ, Trédan, O, Boutron-Ruault, M-C, Elena-Herrmann, B, Severi, G, Rothwell, JA, Jobard, E, Dossus, L, Baglietto, L, Fornili, M, Lécuyer, L, Mancini, FR, Gunter, MJ, Trédan, O, Boutron-Ruault, M-C, Elena-Herrmann, B, Severi, G, and Rothwell, JA
Abstract: BACKGROUND: Perturbations in circulating metabolites prior to a breast cancer diagnosis are not well characterised. We aimed to gain more detailed knowledge to help understand and prevent the disease. METHODS: Baseline plasma samples from 791 breast cancer cases and 791 matched controls from the E3N (EPIC-France) cohort were profiled by nuclear magnetic resonance (NMR)-based untargeted metabolomics. Partial least-squares discriminant analysis (PLS-DA) models were built from NMR profiles to predict disease outcome, and odds ratios and false discovery rate (FDR)-adjusted CIs were calculated for 43 identified metabolites by conditional logistic regression. RESULTS: Breast cancer onset was predicted in the premenopausal subgroup with modest accuracy (AUC 0.61, 95% CI: 0.49-0.73), and 10 metabolites associated with risk, particularly histidine (OR = 1.70 per SD increase, FDR-adjusted CI 1.19-2.41), N-acetyl glycoproteins (OR = 1.53, FDR-adjusted CI 1.18-1.97), glycerol (OR = 1.55, FDR-adjusted CI 1.11-2.18) and ethanol (OR = 1.44, FDR-adjusted CI 1.05-1.97). No predictive capacity or significant metabolites were found overall or for postmenopausal women. CONCLUSIONS: Perturbed metabolism compared to controls was observed in premenopausal but not postmenopausal cases. Histidine and NAC have known involvement in inflammatory pathways, and the robust association of ethanol with risk suggests the involvement of alcohol intake.
Published: 2021

36. Y Prospective analysis of circulating metabolites and endometrial cancer risk

Author: Dossus, L, Kouloura, E, Biessy, C, Viallon, V, Siskos, AP, Dimou, N, Rinaldi, S, Merritt, MA, Allen, N, Fortner, R, Kaaks, R, Weiderpass, E, Gram, IT, Rothwell, JA, Lecuyer, L, Severi, G, Schulze, MB, Nost, TH, Crous-Bou, M, Sanchez, M-J, Amiano, P, Colorado-Yohar, SM, Gurrea, AB, Schmidt, JA, Palli, D, Agnoli, C, Tumino, R, Sacerdote, C, Mattiello, A, Vermeulen, R, Heath, AK, Christakoud, S, Tsilidis, KK, Travis, RC, Gunter, MJ, Keun, HC, Dossus, L, Kouloura, E, Biessy, C, Viallon, V, Siskos, AP, Dimou, N, Rinaldi, S, Merritt, MA, Allen, N, Fortner, R, Kaaks, R, Weiderpass, E, Gram, IT, Rothwell, JA, Lecuyer, L, Severi, G, Schulze, MB, Nost, TH, Crous-Bou, M, Sanchez, M-J, Amiano, P, Colorado-Yohar, SM, Gurrea, AB, Schmidt, JA, Palli, D, Agnoli, C, Tumino, R, Sacerdote, C, Mattiello, A, Vermeulen, R, Heath, AK, Christakoud, S, Tsilidis, KK, Travis, RC, Gunter, MJ, and Keun, HC
Abstract: BACKGROUND: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. RESULTS: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR1SD: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80-0.99; OR1SD: 0.89, 95% CI: 0.79-1.00 and OR1SD: 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR1SD: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR1SD: 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. CONCLUSION: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention.
Published: 2021

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

Author: Baxter, JS, Johnson, N, Tomczyk, K, Gillespie, A, Maguire, S, Brough, R, Fachal, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Brucker, SY, Cai, Q, Campa, D, Canzian, F, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Choi, J-Y, Clarke, CL, Collaborators, N, Colonna, S, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gao, C, Garcia-Closas, M, Garcia-Saenz, JA, Ghoussaini, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Guendert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hatse, S, Hauke, J, Hollestelle, A, Hoppe, R, Hopper, JL, Hou, M-F, Ito, H, Iwasaki, M, Jager, A, Jakubowska, A, Janni, W, John, EM, Joseph, V, Jung, A, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kosma, V-M, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Larson, NL, Larsson, SC, Le Marchand, L, Lejbkowicz, F, Li, J, Long, J, Lophatananon, A, LubiNski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Matsuo, K, Mavroudis, D, Mayes, R, Menon, U, Milne, RL, Taib, NAM, Muir, K, Muranen, TA, Murphy, RA, Nevanlinna, H, O'Brien, KM, Offit, K, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Patel, A, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Pylkas, K, Rack, B, Rennert, G, Romero, A, Ruebner, M, Ruediger, T, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Toland, AE, Tomlinson, I, Truong, T, Tseng, C-C, Untch, M, Vachon, CM, van den Ouweland, AMW, Wang, SS, Weinberg, CR, Wendt, C, Winham, SJ, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Zheng, W, Ziogas, A, Pharoah, PDP, Dunning, AM, Easton, DF, Pettitt, SJ, Lord, CJ, Haider, S, Orr, N, Fletcher, O, Baxter, JS, Johnson, N, Tomczyk, K, Gillespie, A, Maguire, S, Brough, R, Fachal, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Brucker, SY, Cai, Q, Campa, D, Canzian, F, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Choi, J-Y, Clarke, CL, Collaborators, N, Colonna, S, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gao, C, Garcia-Closas, M, Garcia-Saenz, JA, Ghoussaini, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Guendert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hatse, S, Hauke, J, Hollestelle, A, Hoppe, R, Hopper, JL, Hou, M-F, Ito, H, Iwasaki, M, Jager, A, Jakubowska, A, Janni, W, John, EM, Joseph, V, Jung, A, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kosma, V-M, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Larson, NL, Larsson, SC, Le Marchand, L, Lejbkowicz, F, Li, J, Long, J, Lophatananon, A, LubiNski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Matsuo, K, Mavroudis, D, Mayes, R, Menon, U, Milne, RL, Taib, NAM, Muir, K, Muranen, TA, Murphy, RA, Nevanlinna, H, O'Brien, KM, Offit, K, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Patel, A, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Pylkas, K, Rack, B, Rennert, G, Romero, A, Ruebner, M, Ruediger, T, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Toland, AE, Tomlinson, I, Truong, T, Tseng, C-C, Untch, M, Vachon, CM, van den Ouweland, AMW, Wang, SS, Weinberg, CR, Wendt, C, Winham, SJ, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Zheng, W, Ziogas, A, Pharoah, PDP, Dunning, AM, Easton, DF, Pettitt, SJ, Lord, CJ, Haider, S, Orr, N, and Fletcher, O
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).
Published: 2021

38. A New Pipeline for the Normalization and Pooling of Metabolomics Data

Author: Viallon, V, His, M, Rinaldi, S, Breeur, M, Gicquiau, A, Hemon, B, Overvad, K, Tjonneland, A, Rostgaard-Hansen, AL, Rothwell, JA, Lecuyer, L, Severi, G, Kaaks, R, Johnson, T, Schulze, MB, Palli, D, Agnoli, C, Panico, S, Tumino, R, Ricceri, F, Verschuren, WMM, Engelfriet, P, Onland-Moret, C, Vermeulen, R, Nost, TH, Urbarova, I, Zamora-Ros, R, Rodriguez-Barranco, M, Amiano, P, Huerta, JM, Ardanaz, E, Melander, O, Ottoson, F, Vidman, L, Rentoft, M, Schmidt, JA, Travis, RC, Weiderpass, E, Johansson, M, Dossus, L, Jenab, M, Gunter, MJ, Bermejo, JL, Scherer, D, Salek, RM, Keski-Rahkonen, P, Ferrari, P, Viallon, V, His, M, Rinaldi, S, Breeur, M, Gicquiau, A, Hemon, B, Overvad, K, Tjonneland, A, Rostgaard-Hansen, AL, Rothwell, JA, Lecuyer, L, Severi, G, Kaaks, R, Johnson, T, Schulze, MB, Palli, D, Agnoli, C, Panico, S, Tumino, R, Ricceri, F, Verschuren, WMM, Engelfriet, P, Onland-Moret, C, Vermeulen, R, Nost, TH, Urbarova, I, Zamora-Ros, R, Rodriguez-Barranco, M, Amiano, P, Huerta, JM, Ardanaz, E, Melander, O, Ottoson, F, Vidman, L, Rentoft, M, Schmidt, JA, Travis, RC, Weiderpass, E, Johansson, M, Dossus, L, Jenab, M, Gunter, MJ, Bermejo, JL, Scherer, D, Salek, RM, Keski-Rahkonen, P, and Ferrari, P
Abstract: Pooling metabolomics data across studies is often desirable to increase the statistical power of the analysis. However, this can raise methodological challenges as several preanalytical and analytical factors could introduce differences in measured concentrations and variability between datasets. Specifically, different studies may use variable sample types (e.g., serum versus plasma) collected, treated, and stored according to different protocols, and assayed in different laboratories using different instruments. To address these issues, a new pipeline was developed to normalize and pool metabolomics data through a set of sequential steps: (i) exclusions of the least informative observations and metabolites and removal of outliers; imputation of missing data; (ii) identification of the main sources of variability through principal component partial R-square (PC-PR2) analysis; (iii) application of linear mixed models to remove unwanted variability, including samples' originating study and batch, and preserve biological variations while accounting for potential differences in the residual variances across studies. This pipeline was applied to targeted metabolomics data acquired using Biocrates AbsoluteIDQ kits in eight case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Comprehensive examination of metabolomics measurements indicated that the pipeline improved the comparability of data across the studies. Our pipeline can be adapted to normalize other molecular data, including biomarkers as well as proteomics data, and could be used for pooling molecular datasets, for example in international consortia, to limit biases introduced by inter-study variability. This versatility of the pipeline makes our work of potential interest to molecular epidemiologists.
Published: 2021

39. Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Author: Christakoudi, S, Pagoni, P, Ferrari, P, Cross, AJ, Tzoulaki, I, Muller, DC, Weiderpass, E, Freisling, H, Murphy, N, Dossus, L, Turzanski Fortner, R, Agudo, A, Overvad, K, Perez-Cornago, A, Key, TJ, Brennan, P, Johansson, M, Tjonneland, A, Halkjaer, J, Boutron-Ruault, M-C, Artaud, F, Severi, G, Kaaks, R, Schulze, MB, Bergmann, MM, Masala, G, Grioni, S, Simeon, V, Tumino, R, Sacerdote, C, Skeie, G, Rylander, C, Borch, KB, Quiros, JR, Rodriguez-Barranco, M, Chirlaque, M-D, Ardanaz, E, Amiano, P, Drake, I, Stocks, T, Haggstrom, C, Harlid, S, Ellingjord-Dale, M, Riboli, E, Tsilidis, KK, Christakoudi, S, Pagoni, P, Ferrari, P, Cross, AJ, Tzoulaki, I, Muller, DC, Weiderpass, E, Freisling, H, Murphy, N, Dossus, L, Turzanski Fortner, R, Agudo, A, Overvad, K, Perez-Cornago, A, Key, TJ, Brennan, P, Johansson, M, Tjonneland, A, Halkjaer, J, Boutron-Ruault, M-C, Artaud, F, Severi, G, Kaaks, R, Schulze, MB, Bergmann, MM, Masala, G, Grioni, S, Simeon, V, Tumino, R, Sacerdote, C, Skeie, G, Rylander, C, Borch, KB, Quiros, JR, Rodriguez-Barranco, M, Chirlaque, M-D, Ardanaz, E, Amiano, P, Drake, I, Stocks, T, Haggstrom, C, Harlid, S, Ellingjord-Dale, M, Riboli, E, and Tsilidis, KK
Abstract: Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
Published: 2021

40. Prospective analysis of circulating metabolites and endometrial cancer risk

Author: Sub Inorganic Chemistry and Catalysis, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Dossus, L., Kouloura, E., Biessy, C., Viallon, V., Siskos, A.P., Dimou, N., Rinaldi, S., Merritt, M.A., Allen, N., Fortner, R., Kaaks, R., Weiderpass, E., Gram, I.T., Rothwell, J.A., Lécuyer, L., Severi, G., Schulze, M.B., Nøst, T.H., Crous-Bou, M., Sánchez, M.-J., Amiano, P., Colorado-Yohar, S.M., Gurrea, A.B., Schmidt, J.A., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Mattiello, A., Vermeulen, R., Heath, A.K., Christakoudi, S., Tsilidis, K.K., Travis, R.C., Gunter, M.J., Keun, H.C., Sub Inorganic Chemistry and Catalysis, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Dossus, L., Kouloura, E., Biessy, C., Viallon, V., Siskos, A.P., Dimou, N., Rinaldi, S., Merritt, M.A., Allen, N., Fortner, R., Kaaks, R., Weiderpass, E., Gram, I.T., Rothwell, J.A., Lécuyer, L., Severi, G., Schulze, M.B., Nøst, T.H., Crous-Bou, M., Sánchez, M.-J., Amiano, P., Colorado-Yohar, S.M., Gurrea, A.B., Schmidt, J.A., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Mattiello, A., Vermeulen, R., Heath, A.K., Christakoudi, S., Tsilidis, K.K., Travis, R.C., Gunter, M.J., and Keun, H.C.
Published: 2021

41. A New Pipeline for the Normalization and Pooling of Metabolomics Data

Author: IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Sub Inorganic Chemistry and Catalysis, Viallon, V., His, M., Rinaldi, S., Breeur, M., Gicquiau, A., Hemon, B., Overvad, K., Tjønneland, A., Rostgaard-Hansen, A.L., Rothwell, J.A., Lecuyer, L., Severi, G., Kaaks, R., Johnson, T., Schulze, M.B., Palli, D., Agnoli, C., Panico, S., Tumino, R., Ricceri, F., Monique Verschuren, W.M., Engelfriet, P., Onland-Moret, C., Vermeulen, R., Nøst, T.H., Urbarova, I., Zamora-Ros, R., Rodriguez-Barranco, M., Amiano, P., Huerta, J.M., Ardanaz, E., Melander, O., Ottoson, F., Vidman, L., Rentoft, M., Schmidt, J.A., Travis, R.C., Weiderpass, E., Johansson, M., Dossus, L., Jenab, M., Gunter, M.J., Bermejo, J.L., Scherer, D., Salek, R.M., Keski-Rahkonen, P., Ferrari, P., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Sub Inorganic Chemistry and Catalysis, Viallon, V., His, M., Rinaldi, S., Breeur, M., Gicquiau, A., Hemon, B., Overvad, K., Tjønneland, A., Rostgaard-Hansen, A.L., Rothwell, J.A., Lecuyer, L., Severi, G., Kaaks, R., Johnson, T., Schulze, M.B., Palli, D., Agnoli, C., Panico, S., Tumino, R., Ricceri, F., Monique Verschuren, W.M., Engelfriet, P., Onland-Moret, C., Vermeulen, R., Nøst, T.H., Urbarova, I., Zamora-Ros, R., Rodriguez-Barranco, M., Amiano, P., Huerta, J.M., Ardanaz, E., Melander, O., Ottoson, F., Vidman, L., Rentoft, M., Schmidt, J.A., Travis, R.C., Weiderpass, E., Johansson, M., Dossus, L., Jenab, M., Gunter, M.J., Bermejo, J.L., Scherer, D., Salek, R.M., Keski-Rahkonen, P., and Ferrari, P.
Published: 2021

42. 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. (Joseph S.), Johnson, N. (Nichola), Tomczyk, K. (Katarzyna), Gillespie, A. (Andrea), Maguire, S. (Sarah), Brough, R. (Rachel), Fachal, L. (Laura), Michailidou, K. (Kyriaki), 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), Becher, H. (Heiko), 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), Brucker, S. Y. (Sara Y.), Cai, Q. (Qiuyin), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chan, T. L. (Tsun L.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Choi, J.-Y. (Ji-Yeob), Clarke, C. L. (Christine L.), Collaborators, N. (Nbcs), Colonna, S. (Sarah), Conroy, D. M. (Don M.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Doerk, T. (Thilo), Dossus, L. (Laure), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Engel, C. (Christoph), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Flyger, H. (Henrik), Gago-Dominguez, M. (Manuela), Gao, C. (Chi), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Ghoussaini, M. (Maya), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Gonzalez-Neira, A. (Anna), Guenel, P. (Pascal), Guendert, M. (Melanie), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), Hartman, M. (Mikael), Hatse, S. (Sigrid), Hauke, J. (Jan), Hollestelle, A. (Antoinette), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Hou, M.-F. (Ming-Feng), Ito, H. (Hidemi), Iwasaki, M. (Motoki), Jager, A. (Agnes), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Joseph, V. (Vijai), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kang, D. (Daehee), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kim, S.-W. (Sung-Won), Kosma, V.-M. (Veli-Matti), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kubelka-Sabit, K. (Katerina), Kurian, A. W. (Allison W.), Kwong, A. (Ava), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Larson, N. L. (Nicole L.), Larsson, S. C. (Susanna C.), Le Marchand, L. (Loic), Lejbkowicz, F. (Flavio), Li, J. (Jingmei), Long, J. (Jirong), Lophatananon, A. (Artitaya), LubiNski, J. (Jan), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Matsuo, K. (Keitaro), Mavroudis, D. (Dimitrios), Mayes, R. (Rebecca), Menon, U. (Usha), Milne, R. L. (Roger L.), Taib, N. A. (Nur Aishah Mohd), Muir, K. (Kenneth), Muranen, T. A. (Taru A.), Murphy, R. A. (Rachel A.), Nevanlinna, H. (Heli), O'Brien, K. M. (Katie M.), Offit, K. (Kenneth), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Park, S. K. (Sue K.), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peterlongo, P. (Paolo), Peto, J. (Julian), Plaseska-Karanfilska, D. (Dijana), Presneau, N. (Nadege), Pylkäs, K. (Katri), Rack, B. (Brigitte), Rennert, G. (Gad), Romero, A. (Atocha), Ruebner, M. (Matthias), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Shah, M. (Mitul), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Southey, M. C. (Melissa C.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teo, S. H. (Soo Hwang), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Toland, A. E. (Amanda E.), Tomlinson, I. (Ian), Truong, T. (Therese), Tseng, C.-C. (Chiu-Chen), Untch, M. (Michael), Vachon, C. M. (Celine M.), van den Ouweland, A. M. (Ans M. W.), Wang, S. S. (Sophia S.), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Winham, S. J. (Stacey J.), Winqvist, R. (Robert), Wolk, A. (Alicja), Wu, A. H. (Anna H.), Yamaji, T. (Taiki), Zheng, W. (Wei), Ziogas, A. (Argyrios), Pharoah, P. D. (Paul D. P.), Dunning, A. M. (Alison M.), Easton, D. F. (Douglas F.), Pettitt, S. J. (Stephen J.), Lord, C. J. (Christopher J.), Haider, S. (Syed), Orr, N. (Nick), Fletcher, O. (Olivia), Baxter, J. S. (Joseph S.), Johnson, N. (Nichola), Tomczyk, K. (Katarzyna), Gillespie, A. (Andrea), Maguire, S. (Sarah), Brough, R. (Rachel), Fachal, L. (Laura), Michailidou, K. (Kyriaki), 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), Becher, H. (Heiko), 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), Brucker, S. Y. (Sara Y.), Cai, Q. (Qiuyin), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chan, T. L. (Tsun L.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Choi, J.-Y. (Ji-Yeob), Clarke, C. L. (Christine L.), Collaborators, N. (Nbcs), Colonna, S. (Sarah), Conroy, D. M. (Don M.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Doerk, T. (Thilo), Dossus, L. (Laure), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Engel, C. (Christoph), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Flyger, H. (Henrik), Gago-Dominguez, M. (Manuela), Gao, C. (Chi), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Ghoussaini, M. (Maya), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Gonzalez-Neira, A. (Anna), Guenel, P. (Pascal), Guendert, M. (Melanie), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), Hartman, M. (Mikael), Hatse, S. (Sigrid), Hauke, J. (Jan), Hollestelle, A. (Antoinette), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Hou, M.-F. (Ming-Feng), Ito, H. (Hidemi), Iwasaki, M. (Motoki), Jager, A. (Agnes), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Joseph, V. (Vijai), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kang, D. (Daehee), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kim, S.-W. (Sung-Won), Kosma, V.-M. (Veli-Matti), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kubelka-Sabit, K. (Katerina), Kurian, A. W. (Allison W.), Kwong, A. (Ava), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Larson, N. L. (Nicole L.), Larsson, S. C. (Susanna C.), Le Marchand, L. (Loic), Lejbkowicz, F. (Flavio), Li, J. (Jingmei), Long, J. (Jirong), Lophatananon, A. (Artitaya), LubiNski, J. (Jan), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Matsuo, K. (Keitaro), Mavroudis, D. (Dimitrios), Mayes, R. (Rebecca), Menon, U. (Usha), Milne, R. L. (Roger L.), Taib, N. A. (Nur Aishah Mohd), Muir, K. (Kenneth), Muranen, T. A. (Taru A.), Murphy, R. A. (Rachel A.), Nevanlinna, H. (Heli), O'Brien, K. M. (Katie M.), Offit, K. (Kenneth), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Park, S. K. (Sue K.), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peterlongo, P. (Paolo), Peto, J. (Julian), Plaseska-Karanfilska, D. (Dijana), Presneau, N. (Nadege), Pylkäs, K. (Katri), Rack, B. (Brigitte), Rennert, G. (Gad), Romero, A. (Atocha), Ruebner, M. (Matthias), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Shah, M. (Mitul), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Southey, M. C. (Melissa C.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teo, S. H. (Soo Hwang), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Toland, A. E. (Amanda E.), Tomlinson, I. (Ian), Truong, T. (Therese), Tseng, C.-C. (Chiu-Chen), Untch, M. (Michael), Vachon, C. M. (Celine M.), van den Ouweland, A. M. (Ans M. W.), Wang, S. S. (Sophia S.), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Winham, S. J. (Stacey J.), Winqvist, R. (Robert), Wolk, A. (Alicja), Wu, A. H. (Anna H.), Yamaji, T. (Taiki), Zheng, W. (Wei), Ziogas, A. (Argyrios), Pharoah, P. D. (Paul D. P.), Dunning, A. M. (Alison M.), Easton, D. F. (Douglas F.), Pettitt, S. J. (Stephen J.), Lord, C. J. (Christopher J.), Haider, S. (Syed), Orr, N. (Nick), and Fletcher, O. (Olivia)
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).
Published: 2021

43. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Morra, A. (Anna), Escala-Garcia, M. (Maria), Beesley, J. (Jonathan), Keeman, R. (Renske), Canisius, S. (Sander), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Auer, P. L. (Paul L.), Augustinsson, A. (Annelie), Freeman, L. E. (Laura E. Beane), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Brenner, H. (Hermann), Bruening, T. (Thomas), Buys, S. S. (Saundra S.), Caan, B. (Bette), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Cheng, T. D. (Ting-Yuan David), Clarke, C. L. (Christine L.), Colonna, S. V. (Sarah, V), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Dennis, J. (Joe), Dork, T. (Thilo), Dossus, L. (Laure), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Flyger, H. (Henrik), Fritschi, L. (Lin), Gago-Dominguez, M. (Manuela), Garcia-Saenz, J. A. (Jose A.), Giles, G. G. (Graham G.), Grip, M. (Mervi), Guenel, P. (Pascal), Guendert, M. (Melanie), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hart, S. N. (Steven N.), Hartikainen, J. M. (Jaana M.), Hartmann, A. (Arndt), He, W. (Wei), Hooning, M. J. (Maartje J.), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Howell, A. (Anthony), Hunter, D. J. (David J.), Jager, A. (Agnes), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jung, A. Y. (Audrey Y.), Kaaks, R. (Rudolf), Keupers, M. (Machteld), Kitahara, C. M. (Cari M.), Koutros, S. (Stella), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lindblom, A. (Annika), Linet, M. (Martha), Luben, R. N. (Robert N.), Lush, M. (Michael), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Martens, J. W. (John W. M.), Martinez, M. E. (Maria Elena), Mavroudis, D. (Dimitrios), Michailidou, K. (Kyriaki), Milne, R. L. (Roger L.), Mulligan, A. M. (Anna Marie), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Orr, N. (Nick), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peissel, B. (Bernard), Peterlongo, P. (Paolo), Plaseska-Karanfilska, D. (Dijana), Prajzendanc, K. (Karolina), Prentice, R. (Ross), Presneau, N. (Nadege), Rack, B. (Brigitte), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Romero, A. (Atocha), Roylance, R. (Rebecca), Lubinski, J. (Jan), Ruebner, M. (Matthias), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Scott, C. (Christopher), Shah, M. (Mitul), Smichkoska, S. (Snezhana), Southey, M. C. (Melissa C.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), Wang, Q. (Qin), Hurson, A. N. (Amber N.), Winqvist, R. (Robert), Wolk, A. (Alicja), Ziogas, A. (Argyrios), Brauch, H. (Hiltrud), Garcia-Closas, M. (Montserrat), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Chenevix-Trench, G. (Georgia), Schmidt, M. K. (Marjanka K.), Morra, A. (Anna), Escala-Garcia, M. (Maria), Beesley, J. (Jonathan), Keeman, R. (Renske), Canisius, S. (Sander), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Auer, P. L. (Paul L.), Augustinsson, A. (Annelie), Freeman, L. E. (Laura E. Beane), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Brenner, H. (Hermann), Bruening, T. (Thomas), Buys, S. S. (Saundra S.), Caan, B. (Bette), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Cheng, T. D. (Ting-Yuan David), Clarke, C. L. (Christine L.), Colonna, S. V. (Sarah, V), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Dennis, J. (Joe), Dork, T. (Thilo), Dossus, L. (Laure), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Flyger, H. (Henrik), Fritschi, L. (Lin), Gago-Dominguez, M. (Manuela), Garcia-Saenz, J. A. (Jose A.), Giles, G. G. (Graham G.), Grip, M. (Mervi), Guenel, P. (Pascal), Guendert, M. (Melanie), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hart, S. N. (Steven N.), Hartikainen, J. M. (Jaana M.), Hartmann, A. (Arndt), He, W. (Wei), Hooning, M. J. (Maartje J.), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Howell, A. (Anthony), Hunter, D. J. (David J.), Jager, A. (Agnes), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jung, A. Y. (Audrey Y.), Kaaks, R. (Rudolf), Keupers, M. (Machteld), Kitahara, C. M. (Cari M.), Koutros, S. (Stella), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lindblom, A. (Annika), Linet, M. (Martha), Luben, R. N. (Robert N.), Lush, M. (Michael), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Martens, J. W. (John W. M.), Martinez, M. E. (Maria Elena), Mavroudis, D. (Dimitrios), Michailidou, K. (Kyriaki), Milne, R. L. (Roger L.), Mulligan, A. M. (Anna Marie), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Orr, N. (Nick), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peissel, B. (Bernard), Peterlongo, P. (Paolo), Plaseska-Karanfilska, D. (Dijana), Prajzendanc, K. (Karolina), Prentice, R. (Ross), Presneau, N. (Nadege), Rack, B. (Brigitte), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Romero, A. (Atocha), Roylance, R. (Rebecca), Lubinski, J. (Jan), Ruebner, M. (Matthias), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Scott, C. (Christopher), Shah, M. (Mitul), Smichkoska, S. (Snezhana), Southey, M. C. (Melissa C.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), Wang, Q. (Qin), Hurson, A. N. (Amber N.), Winqvist, R. (Robert), Wolk, A. (Alicja), Ziogas, A. (Argyrios), Brauch, H. (Hiltrud), Garcia-Closas, M. (Montserrat), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Chenevix-Trench, G. (Georgia), and Schmidt, M. K. (Marjanka K.)
Abstract: Background: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP & 0.15). Results: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic varia
Published: 2021

44. Prospective analysis of circulating metabolites and endometrial cancer risk

Author: Sub Inorganic Chemistry and Catalysis, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Dossus, L., Kouloura, E., Biessy, C., Viallon, V., Siskos, A.P., Dimou, N., Rinaldi, S., Merritt, M.A., Allen, N., Fortner, R., Kaaks, R., Weiderpass, E., Gram, I.T., Rothwell, J.A., Lécuyer, L., Severi, G., Schulze, M.B., Nøst, T.H., Crous-Bou, M., Sánchez, M.-J., Amiano, P., Colorado-Yohar, S.M., Gurrea, A.B., Schmidt, J.A., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Mattiello, A., Vermeulen, R., Heath, A.K., Christakoudi, S., Tsilidis, K.K., Travis, R.C., Gunter, M.J., Keun, H.C., Sub Inorganic Chemistry and Catalysis, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Dossus, L., Kouloura, E., Biessy, C., Viallon, V., Siskos, A.P., Dimou, N., Rinaldi, S., Merritt, M.A., Allen, N., Fortner, R., Kaaks, R., Weiderpass, E., Gram, I.T., Rothwell, J.A., Lécuyer, L., Severi, G., Schulze, M.B., Nøst, T.H., Crous-Bou, M., Sánchez, M.-J., Amiano, P., Colorado-Yohar, S.M., Gurrea, A.B., Schmidt, J.A., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Mattiello, A., Vermeulen, R., Heath, A.K., Christakoudi, S., Tsilidis, K.K., Travis, R.C., Gunter, M.J., and Keun, H.C.
Published: 2021

45. A New Pipeline for the Normalization and Pooling of Metabolomics Data

Author: IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Sub Inorganic Chemistry and Catalysis, Viallon, V., His, M., Rinaldi, S., Breeur, M., Gicquiau, A., Hemon, B., Overvad, K., Tjønneland, A., Rostgaard-Hansen, A.L., Rothwell, J.A., Lecuyer, L., Severi, G., Kaaks, R., Johnson, T., Schulze, M.B., Palli, D., Agnoli, C., Panico, S., Tumino, R., Ricceri, F., Monique Verschuren, W.M., Engelfriet, P., Onland-Moret, C., Vermeulen, R., Nøst, T.H., Urbarova, I., Zamora-Ros, R., Rodriguez-Barranco, M., Amiano, P., Huerta, J.M., Ardanaz, E., Melander, O., Ottoson, F., Vidman, L., Rentoft, M., Schmidt, J.A., Travis, R.C., Weiderpass, E., Johansson, M., Dossus, L., Jenab, M., Gunter, M.J., Bermejo, J.L., Scherer, D., Salek, R.M., Keski-Rahkonen, P., Ferrari, P., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Sub Inorganic Chemistry and Catalysis, Viallon, V., His, M., Rinaldi, S., Breeur, M., Gicquiau, A., Hemon, B., Overvad, K., Tjønneland, A., Rostgaard-Hansen, A.L., Rothwell, J.A., Lecuyer, L., Severi, G., Kaaks, R., Johnson, T., Schulze, M.B., Palli, D., Agnoli, C., Panico, S., Tumino, R., Ricceri, F., Monique Verschuren, W.M., Engelfriet, P., Onland-Moret, C., Vermeulen, R., Nøst, T.H., Urbarova, I., Zamora-Ros, R., Rodriguez-Barranco, M., Amiano, P., Huerta, J.M., Ardanaz, E., Melander, O., Ottoson, F., Vidman, L., Rentoft, M., Schmidt, J.A., Travis, R.C., Weiderpass, E., Johansson, M., Dossus, L., Jenab, M., Gunter, M.J., Bermejo, J.L., Scherer, D., Salek, R.M., Keski-Rahkonen, P., and Ferrari, P.
Published: 2021

46. Mediation analysis of the alcohol-postmenopausal breast cancer relationship by sex hormones in the EPIC cohort

Author: Assi, N. Rinaldi, S. Viallon, V. Dashti, S.G. Dossus, L. Fournier, A. Cervenka, I. Kvaskoff, M. Turzanski-Fortner, R. Bergmann, M. Boeing, H. Panico, S. Ricceri, F. Palli, D. Tumino, R. Grioni, S. Sánchez Pérez, M.J. Chirlaque, M.-D. Bonet, C. Gurrea, A.B. Amiano Etxezarreta, P. Merino, S. Bueno de Mesquita, H.B. van Gils, C.H. Onland-Moret, C. Tjønneland, A. Overvad, K. Trichopoulou, A. Martimianaki, G. Karakatsani, A. Key, T. Christakoudi, S. Ellingjord-Dale, M. Tsilidis, K. Riboli, E. Kaaks, R. Gunter, M.J. Ferrari, P. and Assi, N. Rinaldi, S. Viallon, V. Dashti, S.G. Dossus, L. Fournier, A. Cervenka, I. Kvaskoff, M. Turzanski-Fortner, R. Bergmann, M. Boeing, H. Panico, S. Ricceri, F. Palli, D. Tumino, R. Grioni, S. Sánchez Pérez, M.J. Chirlaque, M.-D. Bonet, C. Gurrea, A.B. Amiano Etxezarreta, P. Merino, S. Bueno de Mesquita, H.B. van Gils, C.H. Onland-Moret, C. Tjønneland, A. Overvad, K. Trichopoulou, A. Martimianaki, G. Karakatsani, A. Key, T. Christakoudi, S. Ellingjord-Dale, M. Tsilidis, K. Riboli, E. Kaaks, R. Gunter, M.J. Ferrari, P.
Abstract: Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex-hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol-consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol-related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor-positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1-standard deviation (1-SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol-related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1-SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol-BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association. © 2019 UICC
Published: 2020

47. Dietary and circulating fatty acids and ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition

Author: Yammine, S. Huybrechts, I. Biessy, C. Dossus, L. Aglago, E.K. Naudin, S. Ferrari, P. Weiderpass, E. Tjønneland, A. Hansen, L. Overvad, K. Mancini, F.R. Boutron-Ruault, M.-C. Kvaskoff, M. Fortner, R.T. Kaaks, R. Schulze, M.B. Boeing, H. Trichopoulou, A. Karakatsani, A. Vecchia, C.L. Benetou, V. Masala, G. Krogh, V. Mattiello, A. Macciotta, A. Gram, I.T. Skeie, G. Quiros, J.R. Agudo, A. Sanchez, M.-J. Chirlaque, M.-D. Ardanaz, E. Gil, L. Sartor, H. Drake, I. Idahl, A. Lundin, E. Aune, D. Ward, H. Merritt, M.A. Allen, N.E. Gunter, M.J. Chajes, V. and Yammine, S. Huybrechts, I. Biessy, C. Dossus, L. Aglago, E.K. Naudin, S. Ferrari, P. Weiderpass, E. Tjønneland, A. Hansen, L. Overvad, K. Mancini, F.R. Boutron-Ruault, M.-C. Kvaskoff, M. Fortner, R.T. Kaaks, R. Schulze, M.B. Boeing, H. Trichopoulou, A. Karakatsani, A. Vecchia, C.L. Benetou, V. Masala, G. Krogh, V. Mattiello, A. Macciotta, A. Gram, I.T. Skeie, G. Quiros, J.R. Agudo, A. Sanchez, M.-J. Chirlaque, M.-D. Ardanaz, E. Gil, L. Sartor, H. Drake, I. Idahl, A. Lundin, E. Aune, D. Ward, H. Merritt, M.A. Allen, N.E. Gunter, M.J. Chajes, V.
Abstract: Background: Fatty acids impact obesity, estrogens, and inflammation, which are risk factors for ovarian cancer. Few epidemiologic studies have investigated the association of fatty acids with ovarian cancer. Methods: Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,486 incident ovarian cancer cases were identified. Cox proportional hazard models with adjustment for ovarian cancer risk factors were used to estimate HRs of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate ORs of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case–control analysis. Results: A positive association was found between ovarian cancer and intake of industrial trans elaidic acid [HR comparing fifth with first quintileQ5-Q1 ¼ 1.29; 95% confidence interval (CI) ¼ 1.03–1.62; Ptrend ¼ 0.02, q-value ¼ 0.06]. Dietary intakes of n-6 linoleic acid (HRQ5-Q1 ¼ 1.10; 95% CI ¼ 1.01–1.21; Ptrend ¼ 0.03) and n-3 a-linolenic acid (HRQ5-Q1 ¼ 1.18; 95% CI ¼ 1.05–1.34; Ptrend ¼ 0.007) from deep-frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (OR comparing third with first tertileT3-T1 ¼ 1.39; 95% CI ¼ 0.99–1.94; Ptrend ¼ 0.06) and a-linolenic acids (ORT3-T1 ¼ 1.30; 95% CI ¼ 0.98–1.72; Ptrend ¼ 0.06). Conclusions: Our results suggest that higher intakes and circulating levels of industrial trans elaidic acid, and higher intakes of linoleic acid and a-linolenic acid from deep-frying fat, may be associated with greater risk of ovarian cancer. Impact: If causal, eliminating industrial trans-fatty acids could offer a straightforward public health action for reducing ovarian cancer risk. © 2020 American Association for Cancer Research.
Published: 2020

48. Theoretical potential for endometrial cancer prevention through primary risk factor modification: Estimates from the EPIC cohort

Author: Fortner, R.T. Hüsing, A. Dossus, L. Tjønneland, A. Overvad, K. Dahm, C.C. Arveux, P. Fournier, A. Kvaskoff, M. Schulze, M.B. Bergmann, M. Trichopoulou, A. Karakatsani, A. La Vecchia, C. Masala, G. Pala, V. Mattiello, A. Tumino, R. Ricceri, F. van Gils, C.H. Monninkhof, E.M. Bonet, C. Quirós, J.R. Sanchez, M.-J. Rodríguez-Palacios, D.-Á. Gurrea, A.B. Amiano, P. Allen, N.E. Travis, R.C. Gunter, M.J. Viallon, V. Weiderpass, E. Riboli, E. Kaaks, R. and Fortner, R.T. Hüsing, A. Dossus, L. Tjønneland, A. Overvad, K. Dahm, C.C. Arveux, P. Fournier, A. Kvaskoff, M. Schulze, M.B. Bergmann, M. Trichopoulou, A. Karakatsani, A. La Vecchia, C. Masala, G. Pala, V. Mattiello, A. Tumino, R. Ricceri, F. van Gils, C.H. Monninkhof, E.M. Bonet, C. Quirós, J.R. Sanchez, M.-J. Rodríguez-Palacios, D.-Á. Gurrea, A.B. Amiano, P. Allen, N.E. Travis, R.C. Gunter, M.J. Viallon, V. Weiderpass, E. Riboli, E. Kaaks, R.
Abstract: Endometrial cancer (EC) incidence rates vary ~10-fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low-risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow-up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m2), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m2) and HT use (to all non-HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks. © 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC
Published: 2020

49. Exogenous hormone use and cutaneous melanoma risk in women: The European Prospective Investigation into Cancer and Nutrition

Author: Cervenka, I. Al Rahmoun, M. Mahamat-Saleh, Y. Fournier, A. Boutron-Ruault, M.-C. Severi, G. Caini, S. Palli, D. Ghiasvand, R. Veierod, M.B. Botteri, E. Tjønneland, A. Olsen, A. Fortner, R.T. Kaaks, R. Schulze, M.B. Panico, S. Trichopoulou, A. Dessinioti, C. Niforou, K. Sieri, S. Tumino, R. Sacerdote, C. Bueno-de-Mesquita, B. Sandanger, T.M. Colorado-Yohar, S. Sánchez, M.J. Gil Majuelo, L. Lujan-Barroso, L. Ardanaz, E. Merino, S. Isaksson, K. Butt, S. Ljuslinder, I. Jansson, M. Travis, R.C. Khaw, K.-T. Weiderpass, E. Dossus, L. Rinaldi, S. Kvaskoff, M. and Cervenka, I. Al Rahmoun, M. Mahamat-Saleh, Y. Fournier, A. Boutron-Ruault, M.-C. Severi, G. Caini, S. Palli, D. Ghiasvand, R. Veierod, M.B. Botteri, E. Tjønneland, A. Olsen, A. Fortner, R.T. Kaaks, R. Schulze, M.B. Panico, S. Trichopoulou, A. Dessinioti, C. Niforou, K. Sieri, S. Tumino, R. Sacerdote, C. Bueno-de-Mesquita, B. Sandanger, T.M. Colorado-Yohar, S. Sánchez, M.J. Gil Majuelo, L. Lujan-Barroso, L. Ardanaz, E. Merino, S. Isaksson, K. Butt, S. Ljuslinder, I. Jansson, M. Travis, R.C. Khaw, K.-T. Weiderpass, E. Dossus, L. Rinaldi, S. Kvaskoff, M.
Abstract: Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992–2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00–1.26), with no detected heterogeneity across countries (phomogeneity = 0.42). This risk increased linearly with duration of use (ptrend = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97–1.43), which was heterogeneous across countries (phomogeneity = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations. © 2019 UICC
Published: 2020

50. The risk of ovarian cancer increases with an increase in the lifetime number of ovulatory cycles: An analysis from the Ovarian Cancer Cohort Consortium (OC3).

Author: Rohan T.E., Sandler D.P., Schairer C., Schouten L.J., Setiawan V.W., Swerdlow A.J., Travis R.C., Trichopoulou A., Van Den Brandt P.A., Visvanathan K., Wilkens L.R., Wolk A., Zeleniuch-Jacquotte A., Wentzensen N., Trabert B., Tworoger S.S., O'Brien K.M., Townsend M.K., Fortner R.T., Iversen E.S., Hartge P., White E., Amiano P., Arslan A.A., Bernstein L., Brinton L.A., Buring J.E., Dossus L., Fraser G.E., Gaudet M.M., Giles G.G., Gram I.T., Harris H.R., Bolton J.H., Idahl A., Jones M.E., Kaaks R., Kirsh V.A., Knutsen S.F., Kvaskoff M., Lacey J.V., Lee I.-M., Milne R.L., Onland-Moret N.C., Overvad K., Patel A.V., Peters U., Poynter J.N., Riboli E., Robien K., Rohan T.E., Sandler D.P., Schairer C., Schouten L.J., Setiawan V.W., Swerdlow A.J., Travis R.C., Trichopoulou A., Van Den Brandt P.A., Visvanathan K., Wilkens L.R., Wolk A., Zeleniuch-Jacquotte A., Wentzensen N., Trabert B., Tworoger S.S., O'Brien K.M., Townsend M.K., Fortner R.T., Iversen E.S., Hartge P., White E., Amiano P., Arslan A.A., Bernstein L., Brinton L.A., Buring J.E., Dossus L., Fraser G.E., Gaudet M.M., Giles G.G., Gram I.T., Harris H.R., Bolton J.H., Idahl A., Jones M.E., Kaaks R., Kirsh V.A., Knutsen S.F., Kvaskoff M., Lacey J.V., Lee I.-M., Milne R.L., Onland-Moret N.C., Overvad K., Patel A.V., Peters U., Poynter J.N., Riboli E., and Robien K.
Abstract: Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than womenin the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. Significance: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approx
Published: 2020

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Publication Year Range

Publication Type

Database

Publisher

220 results on '"Dossus L."'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources