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2,266 results on '"Kaaks,R"'

1. Compositional clusters in the nasal microbiome as predictors of SARS-CoV-2 infection - results from the German National Cohort (NAKO) study

Author

Kleine Bardenhorst, S, Six-Merker, J, Peters, A, Krist, L, Keil, T, Nimptsch, K, Pischon, T, Gastell, S, Schulze, MB, Wolters, M, Günther, K, Schikowski, T, Schmidt, B, Stang, A, Michels, KB, Klee, B, Mikolajczyk, R, Harth, V, Obi, N, Lange, B, Klett-Tammen, CJ, Lieb, W, Becher, H, Kaaks, R, Karch, A, Berger, K, Nauck, M, Khattak M, N, Baurecht, H, Leitzmann, M, Holleczek, B, Brenner, H, Kemmling, Y, Panreck, L, Vital, M, Rübsamen, N, Kleine Bardenhorst, S, Six-Merker, J, Peters, A, Krist, L, Keil, T, Nimptsch, K, Pischon, T, Gastell, S, Schulze, MB, Wolters, M, Günther, K, Schikowski, T, Schmidt, B, Stang, A, Michels, KB, Klee, B, Mikolajczyk, R, Harth, V, Obi, N, Lange, B, Klett-Tammen, CJ, Lieb, W, Becher, H, Kaaks, R, Karch, A, Berger, K, Nauck, M, Khattak M, N, Baurecht, H, Leitzmann, M, Holleczek, B, Brenner, H, Kemmling, Y, Panreck, L, Vital, M, and Rübsamen, N

Published
2024

2. Patient-reported fatigue up to five years after radiotherapy in an international multicentre cohort study of men with non-metastatic prostate cancer

Author

Heumann, P, Rosas, JC, Aguado-Barrera, ME, Azria, D, Briers, E, Kaaks, R, López-Pleguezuelos, C, Rancati, T, Rattay, T, Rosenstein, B, Sperk, E, Stobart, H, Talbot, C, Vega, A, Ward, T, Webb, A, West, CM, Chang-Claude, J, Seibold, P, Heumann, P, Rosas, JC, Aguado-Barrera, ME, Azria, D, Briers, E, Kaaks, R, López-Pleguezuelos, C, Rancati, T, Rattay, T, Rosenstein, B, Sperk, E, Stobart, H, Talbot, C, Vega, A, Ward, T, Webb, A, West, CM, Chang-Claude, J, and Seibold, P

Published
2024

3. Common symptoms and post-COVID associated symptoms in Germany - results from the NAKO study

Author

Diexer, S, Purschke, O, Fricke, J, Ahnert, P, Gabrysch, S, Gottschick, C, Bohn, B, Brenner, H, Buck, C, Castell, S, Gastell, S, Greiser, KH, Harth, V, Heise, JK, Holleczek, B, Kaaks, R, Krist, L, Leitzmann, MF, Meinke-Franze, C, Michels, KB, Moreno, I, Obi, N, Panreck, L, Peters, A, Pischon, T, Schikowski, T, Schmidt, B, Standl, M, Stang, A, Völzke, H, Weber, A, Zeeb, H, Karch, A, Mikolajczyk, R, Diexer, S, Purschke, O, Fricke, J, Ahnert, P, Gabrysch, S, Gottschick, C, Bohn, B, Brenner, H, Buck, C, Castell, S, Gastell, S, Greiser, KH, Harth, V, Heise, JK, Holleczek, B, Kaaks, R, Krist, L, Leitzmann, MF, Meinke-Franze, C, Michels, KB, Moreno, I, Obi, N, Panreck, L, Peters, A, Pischon, T, Schikowski, T, Schmidt, B, Standl, M, Stang, A, Völzke, H, Weber, A, Zeeb, H, Karch, A, and Mikolajczyk, R

Published
2024

9. Changes in Lifestyle and Risk of Colorectal Cancer in the European Prospective Investigation Into Cancer and Nutrition

Author

Botteri, E, Peveri, G, Berstad, P, Bagnardi, V, Chen, S, Sandanger, T, Hoff, G, Dahm, C, Antoniussen, C, Tjonneland, A, Eriksen, A, Skeie, G, Perez-Cornago, A, Huerta, J, Jakszyn, P, Harlid, S, Sundstrom, B, Barricarte, A, Monninkhof, E, Derksen, J, Schulze, M, Bueno-De-Mesquita, B, Sanchez, M, Cross, A, Tsilidis, K, De Magistris, M, Kaaks, R, Katzke, V, Rothwell, J, Laouali, N, Severi, G, Amiano, P, Contiero, P, Sacerdote, C, Goldberg, M, Touvier, M, Freisling, H, Viallon, V, Weiderpass, E, Riboli, E, Gunter, M, Jenab, M, Ferrari, P, Botteri E., Peveri G., Berstad P., Bagnardi V., Chen S. L. F., Sandanger T. M., Hoff G., Dahm C. C., Antoniussen C. S., Tjonneland A., Eriksen A. K., Skeie G., Perez-Cornago A., Huerta J. M., Jakszyn P., Harlid S., Sundstrom B., Barricarte A., Monninkhof E. M., Derksen J. W. G., Schulze M. B., Bueno-De-Mesquita B., Sanchez M. -J., Cross A. J., Tsilidis K. K., De Magistris M. S., Kaaks R., Katzke V., Rothwell J. A., Laouali N., Severi G., Amiano P., Contiero P., Sacerdote C., Goldberg M., Touvier M., Freisling H., Viallon V., Weiderpass E., Riboli E., Gunter M. J., Jenab M., Ferrari P., Botteri, E, Peveri, G, Berstad, P, Bagnardi, V, Chen, S, Sandanger, T, Hoff, G, Dahm, C, Antoniussen, C, Tjonneland, A, Eriksen, A, Skeie, G, Perez-Cornago, A, Huerta, J, Jakszyn, P, Harlid, S, Sundstrom, B, Barricarte, A, Monninkhof, E, Derksen, J, Schulze, M, Bueno-De-Mesquita, B, Sanchez, M, Cross, A, Tsilidis, K, De Magistris, M, Kaaks, R, Katzke, V, Rothwell, J, Laouali, N, Severi, G, Amiano, P, Contiero, P, Sacerdote, C, Goldberg, M, Touvier, M, Freisling, H, Viallon, V, Weiderpass, E, Riboli, E, Gunter, M, Jenab, M, Ferrari, P, Botteri E., Peveri G., Berstad P., Bagnardi V., Chen S. L. F., Sandanger T. M., Hoff G., Dahm C. C., Antoniussen C. S., Tjonneland A., Eriksen A. K., Skeie G., Perez-Cornago A., Huerta J. M., Jakszyn P., Harlid S., Sundstrom B., Barricarte A., Monninkhof E. M., Derksen J. W. G., Schulze M. B., Bueno-De-Mesquita B., Sanchez M. -J., Cross A. J., Tsilidis K. K., De Magistris M. S., Kaaks R., Katzke V., Rothwell J. A., Laouali N., Severi G., Amiano P., Contiero P., Sacerdote C., Goldberg M., Touvier M., Freisling H., Viallon V., Weiderpass E., Riboli E., Gunter M. J., Jenab M., and Ferrari P.

Abstract

Introduction: We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multicountry European cohort. Methods: We used baseline and follow-up questionnaire data from the European Prospective Investigation into Cancer cohort to assess changes in lifestyle habits and their associations with CRC development. We calculated a healthy lifestyle index (HLI) score based on smoking status, alcohol consumption, body mass index, and physical activity collected at the 2 time points. HLI ranged from 0 (most unfavorable) to 16 (most favorable). We estimated the association between HLI changes and CRC risk using Cox regression models and reported hazard ratios (HR) with 95% confidence intervals (CI). Results: Among 295,865 participants, 2,799 CRC cases were observed over a median of 7.8 years. The median time between questionnaires was 5.7 years. Each unit increase in HLI from the baseline to the follow-up assessment was associated with a statistically significant 3% lower CRC risk. Among participants in the top tertile at baseline (HLI > 11), those in the bottom tertile at follow-up (HLI ≤ 9) had a higher CRC risk (HR 1.34; 95% CI 1.02-1.75) than those remaining in the top tertile. Among individuals in the bottom tertile at baseline, those in the top tertile at follow-up had a lower risk (HR 0.77; 95% CI 0.59-1.00) than those remaining in the bottom tertile. Discussion: Improving adherence to a healthy lifestyle was inversely associated with CRC risk, while worsening adherence was positively associated with CRC risk. These results justify and support recommendations for healthy lifestyle changes and healthy lifestyle maintenance for CRC prevention.

Published
2023

10. Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium

Author

Kreimer, A.R., Ferreiro-Iglesias, A., Nygard, M., Bender, N., Schroeder, L., Hildesheim, A., Robbins, H.A., Pawlita, M., Langseth, H., Schlecht, N.F., Tinker, L.F., Agalliu, I., Smoller, S.W., Ness-Jensen, E., Hveem, K., D’Souza, G., Visvanathan, K., May, B., Ursin, G., Weiderpass, E., Giles, G.G., Milne, R.L., Cai, Q., Blot, W.J., Zheng, W., Weinstein, S.J., Albanes, D., Brenner, N., Hoffman-Bolton, J., Kaaks, R., Barricarte, A., Tjønneland, A., Sacerdote, C., Trichopoulou, A., Vermeulen, R.C.H., Huang, W.-Y., Freedman, N.D., Brennan, P., Waterboer, T., and Johansson, M.

Published
2019
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11. The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case–control and Mendelian randomization study in the European prospective investigation into cancer and nutrition

Author

Smith Byrne, K., Appleby, P.N., Key, T.J., Holmes, M.V., Fensom, G.K., Agudo, A., Ardanaz, E., Boeing, H., Bueno-de-Mesquita, H.B., Chirlaque, M.D., Kaaks, R., Larrañaga, N., Palli, D., Perez-Cornago, A., Quirós, J.R., Ricceri, F., Sánchez, M.J., Tagliabue, G., Tsilidis, K.K., Tumino, R., Fortner, R.T., Ferrari, P., Riboli, E., Lilja, H., and Travis, R.C.

Published
2019
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12. Dietary intake of acrylamide and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort

Author

Obón-Santacana, M, Kaaks, R, Slimani, N, Lujan-Barroso, L, Freisling, H, Ferrari, P, Dossus, L, Chabbert-Buffet, N, Baglietto, L, Fortner, RT, Boeing, H, Tjønneland, A, Olsen, A, Overvad, K, Menéndez, V, Molina-Montes, E, Larrañaga, N, Chirlaque, M-D, Ardanaz, E, Khaw, K-T, Wareham, N, Travis, RC, Lu, Y, Merritt, MA, Trichopoulou, A, Benetou, V, Trichopoulos, D, Saieva, C, Sieri, S, Tumino, R, Sacerdote, C, Galasso, R, Bueno-de-Mesquita, HB, Wirfält, E, Ericson, U, Idahl, A, Ohlson, N, Skeie, G, Gram, IT, Weiderpass, E, Onland-Moret, NC, Riboli, E, and Duell, EJ

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Nutrition, Clinical Research, Prevention, Cancer, Aetiology, 2.2 Factors relating to the physical environment, Cardiovascular, Acrylamide, Cohort Studies, Diet, Eating, Endometrial Neoplasms, Female, Humans, Middle Aged, Nutritional Status, Prospective Studies, Risk, Risk Factors, Smoking, acrylamide, endometrial cancer, type-I endometrial cancer, cohort, nutrition, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThree prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The objective of this study was to evaluate the association between acrylamide intake and EC risk: for overall EC, for type-I EC, and in never smokers and never users of oral contraceptives (OCs). Smoking is a source of acrylamide, and OC use is a protective factor for EC risk.MethodsCox regression was used to estimate hazard ratios (HRs) for the association between acrylamide intake and EC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Acrylamide intake was estimated from the EU acrylamide monitoring database, which was matched with EPIC questionnaire-based food consumption data. Acrylamide intake was energy adjusted using the residual method.ResultsNo associations were observed between acrylamide intake and overall EC (n=1382) or type-I EC risk (n=627). We observed increasing relative risks for type-I EC with increasing acrylamide intake among women who both never smoked and were non-users of OCs (HRQ5vsQ1: 1.97, 95% CI: 1.08-3.62; likelihood ratio test (LRT) P-value: 0.01, n=203).ConclusionsDietary intake of acrylamide was not associated with overall or type-I EC risk; however, positive associations with type I were observed in women who were both non-users of OCs and never smokers.

Published
2014

15. A prospective evaluation of plasma phospholipid fatty acids and breast cancer risk in the EPIC study

Author

Chajès, V., Assi, N., Biessy, C., Ferrari, P., Rinaldi, S., Slimani, N., Lenoir, G.M., Baglietto, L., His, M., Boutron-Ruault, M.C., Trichopoulou, A., Lagiou, P., Katsoulis, M., Kaaks, R., Kühn, T., Panico, S., Pala, V., Masala, G., Bueno-de-Mesquita, H.B., Peeters, P.H., van Gils, C., Hjartåker, A., Standahl Olsen, K., Borgund Barnung, R., Barricarte, A., Redondo-Sanchez, D., Menéndez, V., Amiano, P., Wennberg, M., Key, T., Khaw, K.T., Merritt, M.A., Riboli, E., Gunter, M.J., and Romieu, I.

Published
2017
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16. A body shape index (ABSI) is associated inversely with post-menopausal progesterone-receptor-negative breast cancer risk in a large European cohort

Author

Christakoudi, S, Tsilidis, KK, Dossus, L, Rinaldi, S, Weiderpass, E, Antoniussen, CS, Dahm, CC, Tjønneland, A, Mellemkjær, L, Katzke, V, Kaaks, R, Schulze, MB, Masala, G, Grioni, S, Panico, S, Tumino, R, Sacerdote, C, May, AM, Monninkhof, EM, Quirós, JR, Bonet, C, Sánchez, M-J, Amiano, P, Chirlaque, M-D, Guevara, M, Rosendahl, AH, Stocks, T, Perez-Cornago, A, Tin Tin, S, Heath, AK, Aglago, EK, Peruchet-Noray, L, Freisling, H, and Riboli, E

Subjects
Breast Neoplasms/complications, Somatotypes, Hip Size, Triple Negative Breast Neoplasms/complications, Waist Size, Middle Aged, Body Mass Index, Postmenopause, ABSI, Body shape, Breast cancer, Risk Factors, Humans, Female, Prospective Studies, Obesity, Progesterone
Abstract

BACKGROUND: Associations of body shape with breast cancer risk, independent of body size, are unclear because waist and hip circumferences are correlated strongly positively with body mass index (BMI).METHODS: We evaluated body shape with the allometric "a body shape index" (ABSI) and hip index (HI), which compare waist and hip circumferences, correspondingly, among individuals with the same weight and height. We examined associations of ABSI, HI, and BMI (per one standard deviation increment) with breast cancer overall, and according to menopausal status at baseline, age at diagnosis, and oestrogen and progesterone receptor status (ER+/-PR+/-) in multivariable Cox proportional hazards models using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.RESULTS: During a mean follow-up of 14.0 years, 9011 incident breast cancers were diagnosed among 218,276 women. Although there was little evidence for association of ABSI with breast cancer overall (hazard ratio HR = 0.984; 95% confidence interval: 0.961-1.007), we found borderline inverse associations for post-menopausal women (HR = 0.971; 0.942-1.000; n = 5268 cases) and breast cancers diagnosed at age ≥ 55 years (HR = 0.976; 0.951-1.002; n = 7043) and clear inverse associations for ER + PR- subtypes (HR = 0.894; 0.822-0.971; n = 726) and ER-PR- subtypes (HR = 0.906; 0.835-0.983 n = 759). There were no material associations with HI. BMI was associated strongly positively with breast cancer overall (HR = 1.074; 1.049-1.098), for post-menopausal women (HR = 1.117; 1.085-1.150), for cancers diagnosed at age ≥ 55 years (HR = 1.104; 1.076-1.132), and for ER + PR + subtypes (HR = 1.122; 1.080-1.165; n = 3101), but not for PR- subtypes.CONCLUSIONS: In the EPIC cohort, abdominal obesity evaluated with ABSI was not associated with breast cancer risk overall but was associated inversely with the risk of post-menopausal PR- breast cancer. Our findings require validation in other cohorts and with a larger number of PR- breast cancer cases.

Published
2023

17. 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., primary, Rinaldi, S., additional, Kaaks, R., additional, Biessy, C., additional, Gonzalez‐Gil, E. M., additional, Murphy, N., additional, Le Cornet, C., additional, Huerta, J. M., additional, Sieri, S., additional, Tjønneland, A., additional, Mellemkjær, L., additional, Guevara, M., additional, Overvad, K., additional, Perez‐Cornago, A., additional, Tin Tin, S., additional, Padroni, L., additional, Simeon, V., additional, Masala, G., additional, May, A., additional, Monninkhof, E., additional, Christakoudi, S., additional, Heath, A. K., additional, Tsilidis, K., additional, Agudo, A., additional, Schulze, M. B., additional, Rothwell, J., additional, Cadeau, C., additional, Severi, S., additional, Weiderpass, E., additional, Gunter, M. J., additional, and Dossus, L., additional

Published
2023
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18. 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

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

Author

Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, Michailidou, K, Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, and Michailidou, K

Abstract

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

Published
2023

20. 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

21. 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

22. Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

Author

Fu, Z., Brooks, M.M., Irvin, S., Jordan, S., Aben, K.K.H., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Brooks-Wilson, A., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cushing-Haugen, K.L., Doherty, J.A., Ekici, A.B., Fasching, P.A., Fortner, R.T., Gayther, S.A., Gentry-Maharaj, A., Giles, G.G., Goode, E.L., Goodman, M.T., Harris, H.R., Hein, A., Kaaks, R., Kiemeney, L.A., Köbel, M., Kotsopoulos, J., Le, N.D., Lee, A.W.C., Matsuo, K., McGuire, V., McLaughlin, J.R., Menon, U., Milne, R.L., Moysich, K.B., Pearce, C.L., Pike, M.C., Qin, B., Ramus, S.J., Riggan, M.J., Rothstein, J.H., Schildkraut, J.M., Sieh, W., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Altena, A.M. van, White, E., Whittemore, A.S., Wu, A.H., Zheng, W., Ziogas, Argyrios, Taylor, S.E., Tang, L., Songer, T., Wentzensen, N., Webb, P.M., Risch, H.A., Modugno, F., Fu, Z., Brooks, M.M., Irvin, S., Jordan, S., Aben, K.K.H., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Brooks-Wilson, A., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cushing-Haugen, K.L., Doherty, J.A., Ekici, A.B., Fasching, P.A., Fortner, R.T., Gayther, S.A., Gentry-Maharaj, A., Giles, G.G., Goode, E.L., Goodman, M.T., Harris, H.R., Hein, A., Kaaks, R., Kiemeney, L.A., Köbel, M., Kotsopoulos, J., Le, N.D., Lee, A.W.C., Matsuo, K., McGuire, V., McLaughlin, J.R., Menon, U., Milne, R.L., Moysich, K.B., Pearce, C.L., Pike, M.C., Qin, B., Ramus, S.J., Riggan, M.J., Rothstein, J.H., Schildkraut, J.M., Sieh, W., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Altena, A.M. van, White, E., Whittemore, A.S., Wu, A.H., Zheng, W., Ziogas, Argyrios, Taylor, S.E., Tang, L., Songer, T., Wentzensen, N., Webb, P.M., Risch, H.A., and Modugno, F.

Abstract

Item does not contain fulltext, BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. RESULTS: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. CONCLUSIONS: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

Published
2023

23. Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis

Author

Watts, EL, Perez-Cornago, A, Fensom, GK, Smith-Byrne, K, Noor, U, Andrews, CD, Gunter, MJ, Holmes, M, Martin, RM, Tsilidis, KK, Albanes, D, Barricarte, A, Bueno-de-Mesquita, HB, Cohn, BA, Deschasaux-Tanguy, M, Dimou, NL, Ferrucci, L, Flicker, L, Freedman, ND, Giles, GG, Giovannucci, EL, Haiman, CA, Hankey, GJ, Holly, JMP, Huang, J, Huang, W-Y, Hurwitz, LM, Kaaks, R, Kubo, T, Le Marchand, L, MacInnis, RJ, Mannisto, S, Metter, EJ, Mikami, K, Mucci, LA, Olsen, AW, Ozasa, K, Palli, D, Penney, KL, Platz, EA, Pollak, MN, Roobol, MJ, Schaefer, CA, Schenk, JM, Stattin, P, Tamakoshi, A, Thysell, E, Tsai, CJ, Touvier, M, Van Den Eeden, SK, Weiderpass, E, Weinstein, SJ, Wilkens, LR, Yeap, BB, Allen, NE, Key, TJ, Travis, RC, Watts, EL, Perez-Cornago, A, Fensom, GK, Smith-Byrne, K, Noor, U, Andrews, CD, Gunter, MJ, Holmes, M, Martin, RM, Tsilidis, KK, Albanes, D, Barricarte, A, Bueno-de-Mesquita, HB, Cohn, BA, Deschasaux-Tanguy, M, Dimou, NL, Ferrucci, L, Flicker, L, Freedman, ND, Giles, GG, Giovannucci, EL, Haiman, CA, Hankey, GJ, Holly, JMP, Huang, J, Huang, W-Y, Hurwitz, LM, Kaaks, R, Kubo, T, Le Marchand, L, MacInnis, RJ, Mannisto, S, Metter, EJ, Mikami, K, Mucci, LA, Olsen, AW, Ozasa, K, Palli, D, Penney, KL, Platz, EA, Pollak, MN, Roobol, MJ, Schaefer, CA, Schenk, JM, Stattin, P, Tamakoshi, A, Thysell, E, Tsai, CJ, Touvier, M, Van Den Eeden, SK, Weiderpass, E, Weinstein, SJ, Wilkens, LR, Yeap, BB, Allen, NE, Key, TJ, and Travis, RC

Abstract

BACKGROUND: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. METHODS: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. RESULTS: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. CONCLUSIONS: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.

Published
2023

24. Baseline and lifetime alcohol consumption and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).

Author

Mahamat-Saleh, Y, Al-Rahmoun, M, Severi, G, Ghiasvand, R, Veierod, MB, Caini, S, Palli, D, Botteri, E, Sacerdote, C, Ricceri, F, Lukic, M, Sánchez, MJ, Pala, V, Tumino, R, Chiodini, P, Amiano, P, Colorado-Yohar, S, Chirlaque, M-D, Ardanaz, E, Bonet, C, Katzke, V, Kaaks, R, Schulze, MB, Overvad, K, Dahm, CC, Antoniussen, CS, Tjønneland, A, Kyrø, C, Bueno-de-Mesquita, B, Manjer, J, Jansson, M, Esberg, A, Mori, N, Ferrari, P, Weiderpass, E, Boutron-Ruault, M-C, Kvaskoff, M, Mahamat-Saleh, Y, Al-Rahmoun, M, Severi, G, Ghiasvand, R, Veierod, MB, Caini, S, Palli, D, Botteri, E, Sacerdote, C, Ricceri, F, Lukic, M, Sánchez, MJ, Pala, V, Tumino, R, Chiodini, P, Amiano, P, Colorado-Yohar, S, Chirlaque, M-D, Ardanaz, E, Bonet, C, Katzke, V, Kaaks, R, Schulze, MB, Overvad, K, Dahm, CC, Antoniussen, CS, Tjønneland, A, Kyrø, C, Bueno-de-Mesquita, B, Manjer, J, Jansson, M, Esberg, A, Mori, N, Ferrari, P, Weiderpass, E, Boutron-Ruault, M-C, and Kvaskoff, M

Abstract

Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; Ptrend = .001), BCC (HR = 1.12, 95% CI = 1.01-1.23; Ptrend = .04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; Ptrend = .17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; Ptrend = .13; BCC: HR = 1.08, 95% CI = 1.00-1.17, Ptrend = .03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, Ptrend = .13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; Ptrend = .0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31; Ptrend = .14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer.

Published
2023

25. Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis

Author

Fu, Z, Brooks, MM, Irvin, S, Jordan, S, Aben, KKH, Anton-Culver, H, Bandera, E, Beckmann, MW, Berchuck, A, Brooks-Wilson, A, Chang-Claude, J, Cook, LS, Cramer, DW, Cushing-Haugen, KL, Doherty, JA, Ekici, AB, Fasching, PA, Fortner, RT, Gayther, SA, Gentry-Maharaj, A, Giles, GG, Goode, EL, Goodman, MT, Harris, HR, Hein, A, Kaaks, R, Kiemeney, LA, Koebel, M, Kotsopoulos, J, Le, ND, Lee, AW, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Milne, RL, Moysich, KB, Pearce, CL, Pike, MC, Qin, B, Ramus, SJ, Riggan, MJ, Rothstein, JH, Schildkraut, JM, Sieh, W, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, van Altena, AM, White, E, Whittemore, AS, Wu, AH, Zheng, W, Ziogas, A, Taylor, SE, Tang, L, Songer, T, Wentzensen, N, Webb, PM, Risch, HA, Modugno, F, Fu, Z, Brooks, MM, Irvin, S, Jordan, S, Aben, KKH, Anton-Culver, H, Bandera, E, Beckmann, MW, Berchuck, A, Brooks-Wilson, A, Chang-Claude, J, Cook, LS, Cramer, DW, Cushing-Haugen, KL, Doherty, JA, Ekici, AB, Fasching, PA, Fortner, RT, Gayther, SA, Gentry-Maharaj, A, Giles, GG, Goode, EL, Goodman, MT, Harris, HR, Hein, A, Kaaks, R, Kiemeney, LA, Koebel, M, Kotsopoulos, J, Le, ND, Lee, AW, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Milne, RL, Moysich, KB, Pearce, CL, Pike, MC, Qin, B, Ramus, SJ, Riggan, MJ, Rothstein, JH, Schildkraut, JM, Sieh, W, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, van Altena, AM, White, E, Whittemore, AS, Wu, AH, Zheng, W, Ziogas, A, Taylor, SE, Tang, L, Songer, T, Wentzensen, N, Webb, PM, Risch, HA, and Modugno, F

Abstract

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. RESULTS: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. CONCLUSIONS: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

Published
2023

26. Lipopolysaccharide-binding protein and future Parkinson's disease risk: a European prospective cohort.

Author

Zhao, Yujia, Walker, D.I., Lill, C.M., Bloem, B.R., Darweesh, S.K.L., Pinto-Pacheco, B., McNeil, B., Miller, G.W., Heath, A.K., Frissen, M.N., Petrova, D., Sánchez, M.J., Chirlaque, M.D., Guevara, M., Zibetti, M., Panico, S., Middleton, L., Katzke, V., Kaaks, R., Riboli, E., Masala, G., Sieri, S., Zamora-Ros, R., Amiano, P., Jenab, M., Peters, Susan, Vermeulen, R., Zhao, Yujia, Walker, D.I., Lill, C.M., Bloem, B.R., Darweesh, S.K.L., Pinto-Pacheco, B., McNeil, B., Miller, G.W., Heath, A.K., Frissen, M.N., Petrova, D., Sánchez, M.J., Chirlaque, M.D., Guevara, M., Zibetti, M., Panico, S., Middleton, L., Katzke, V., Kaaks, R., Riboli, E., Masala, G., Sieri, S., Zamora-Ros, R., Amiano, P., Jenab, M., Peters, Susan, and Vermeulen, R.

Abstract

Item does not contain fulltext, INTRODUCTION: Lipopolysaccharide (LPS) is the outer membrane component of Gram-negative bacteria. LPS-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS and has been used as a blood marker for LPS. LBP has recently been indicated to be associated with Parkinson's disease (PD) in small-scale retrospective case-control studies. We aimed to investigate the association between LBP blood levels with PD risk in a nested case-control study within a large European prospective cohort. METHODS: A total of 352 incident PD cases (55% males) were identified and one control per case was selected, matched by age at recruitment, sex and study center. LBP levels in plasma collected at recruitment, which was on average 7.8 years before diagnosis of the cases, were analyzed by enzyme linked immunosorbent assay. Odds ratios (ORs) were estimated for one unit increase of the natural log of LBP levels and PD incidence by conditional logistic regression. RESULTS: Plasma LBP levels were higher in prospective PD cases compared to controls (median (interquartile range) 26.9 (18.1-41.0) vs. 24.7 (16.6-38.4) µg/ml). The OR for PD incidence per one unit increase of log LBP was elevated (1.46, 95% CI 0.98-2.19). This association was more pronounced among women (OR 2.68, 95% CI 1.40-5.13) and overweight/obese subjects (OR 1.54, 95% CI 1.09-2.18). CONCLUSION: The findings suggest that higher plasma LBP levels may be associated with an increased risk of PD and may thus pinpoint to a potential role of endotoxemia in the pathogenesis of PD, particularly in women and overweight/obese individuals.

Published
2023

27. 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

28. 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

29. 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, T. A., Aglago, E. K., Ardanaz, E., Bergmann, M. M., Bondonno, N. P., Braaten, T., Colorado-Yohar, S. M., Crous-Bou, M., Dahm, C. C., Fortner, R. T., Gram, I. T., Harlid, S., Heath, A. K., Idahl, A., Kvaskoff, M., Nost, T. H., Overvad, K., Palli, D., Perez-Cornago, A., Sacerdote, C., Sanchez, M. -J., Schulze, M. B., Severi, G., Simeon, V., Tagliabue, G., Tjonneland, A., Truong, T., Tumino, R., Johansson, M., Weiderpass, E., Murphy, N., Gunter, M. J., Lacey, B., Allen, N. E., and Dossus, L.

Subjects
Epidemiology, ESTROGENS, Polymorphism, Single Nucleotide, BREAST, Article, Cigarette Smoking, Risk Factors, GENETIC-VARIANTS, REGRESSION, Humans, Genetic Predisposition to Disease, Prospective Studies, 11 Medical and Health Sciences, INDEX, Cancer och onkologi, IDENTIFICATION, WOMEN, Public Health, Global Health, Social Medicine and Epidemiology, Mendelian Randomization Analysis, Endometrial Neoplasms, OVERLAP, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Oncology, Cancer and Oncology, OBESITY, Female, SEX-HORMONES, Genome-Wide Association Study
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 twosampleMR analyses, genetic variants robustly associated with lifetime amount of smoking (n ¼ 126 variants) and ever having smoked regularly (n ¼ 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., World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, NIHR Imperial Biomedical Research Centre (BRC), Danish Cancer Society, Ligue Contre le Cancer (France) Institut Gustave Roussy (France) MutuelleGenerale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe German Cancer Research Center (DKFZ) (Germany) German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) (Germany) Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro Compagnia di San Paolo Consiglio Nazionale delle Ricerche (CNR), Netherlands Government Netherlands Government, World Cancer Research Fund International (WCRF), Netherlands Government, Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII) (Spain), Junta de Andalucia, Principality of Asturias Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain) Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society Swedish Research Council County Council of Skane (Sweden) County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) 1000143 MR/M012190/1 MR/N003284/1 MC-UU_12015/1 MC_UU_00006/ 1, Cancer Research UK C864/A14136 C18281/A29019

Published
2022

31. Plasma methionine, choline, betaine, and dimethylglycine in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Author

Nitter, M., Norgård, B., de Vogel, S., Eussen, S.J.P.M., Meyer, K., Ulvik, A., Ueland, P.M., Nygård, O., Vollset, S.E., Bjørge, T., Tjønneland, A., Hansen, L., Boutron-Ruault, M., Racine, A., Cottet, V., Kaaks, R., Kühn, T., Trichopoulou, A., Bamia, C., Naska, A., Grioni, S., Palli, D., Panico, S., Tumino, R., Vineis, P., Bueno-de-Mesquita, H.B., van Kranen, H., Peeters, P.H., Weiderpass, E., Dorronsoro, M., Jakszyn, P., Sánchez, M., Argüelles, M., Huerta, J.M., Barricarte, A., Johansson, M., Ljuslinder, I., Khaw, K., Wareham, N., Freisling, H., Duarte-Salles, T., Stepien, M., Gunter, M.J., and Riboli, E.

Published
2014
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32. Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort

Author

Tikk, K., Sookthai, D., Johnson, T., Rinaldi, S., Romieu, I., Tjønneland, A., Olsen, A., Overvad, K., Clavel-Chapelon, F., Baglietto, L., Boeing, H., Trichopoulou, A., Lagiou, P., Trichopoulos, D., Palli, D., Pala, V., Tumino, R., Rosso, S., Panico, S., Agudo, A., Menéndez, V., Sánchez, M.-J., Amiano, P., Huerta Castaño, J.M., Ardanaz, E., Bueno-de-Mesquita, H.B., Monninkhof, E., Onland-Moret, C., Andersson, A., Sund, M., Weiderpass, E., Khaw, K.-T., Key, T.J., Travis, R.C., Gunter, M.J., Riboli, E., Dossus, L., and Kaaks, R.

Published
2014
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33. Changes in body weight and obesity status in German adults: results of seven population-based prospective studies

Author

Haftenberger, M., Mensink, G.B.M., Herzog, B., Kluttig, A., Greiser, K.H., Merz, B., Nothlings, U., Schlesinger, S., Vogt, S., Thorand, B., Peters, A., Ittermann, T., Volzke, H., Schipf, S., Neamat-Allah, J., Kuhn, T., Kaaks, R., Boeing, H., Bachlechner, U., Scheidt-Nave, C., and Schienkiewitz, A.

Subjects
Obesity -- Physiological aspects, Body weight -- Health aspects, Food/cooking/nutrition, Health
Abstract

BACKGROUND/OBJECTIVES: The objective of this study was to quantify body weight changes in German adult populations during the past decades. SUBJECTS/METHODS: Longitudinal analysis of seven cohort studies covering different age ranges between 18 and 83 years. Baseline examinations were between 1994 and 2007 and follow-up durations between 4.0 and 11.9 years. For each study, mean change in body weight per year and 10-year change in body mass index (BMI) classification were analyzed. For the middle age group of 45-64 years, meta-analysis was conducted to obtain an overall estimate for Germany. RESULTS: Among men weight gain was highest in the youngest participants and decreased with advancing age. Among women weight gain was on a stable high level among those younger than 45 years and decreased at older age. Within 10 years, 30-40% of middle-aged participants with normal baseline weight became pre-obese or obese and 20-25% of those with pre-obesity at baseline became obese, whereas >80% of persons who were obese at baseline remained obese over time. The estimated average weight change in adults aged 45-64 years was 0.25 (95% confidence interval (CI): 0.18-0.33) kg/year among men and 0.24 (0.17-0.30) kg/year among women. CONCLUSIONS: We could observe a moderate weight gain over the past years in German middle-aged populations of 0.25 kg/year. Obesity prevention needs to be targeted to specific subgroups in the population, especially to younger adults, who seem to be most vulnerable for gaining weight. Obesity intervention needs to be improved, as the majority of obese adults remained obese over time. European Journal of Clinical Nutrition (2016) 70, 300-305; doi: 10.1038/ejcn.2015.179; published online 28 October 2015, INTRODUCTION During the past decades, the prevalence of overweight (body mass index, BMI [greater than or equal to] 25.0 kg/[m.sup.2]) and obesity (BMI [greater than or equal to] 30.0 kg/[m.sup.2]) [...]

Published
2016
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34. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe

Author

Hageman, S., Pennells, L., Ojeda, F., Kaptoge, S., Kuulasmaa, K., Vries, T. de, Xu, Z., Kee, F., Chung, R., Wood, A., McEvoy, J.W., Veronesi, G., Bolton, T., Dendale, P., Ference, B.A., Halle, M., Timmis, A., Vardas, P., Danesh, J., Graham, I., Salomaa, V., Visseren, F., Bacquer, D. de, Blankenberg, S., Dorresteijn, J., Angelantonio, E. di, Achenbach, S., Aleksandrova, K., Amiano, P., Amouyel, P., Andersson, J., Bakker, S.J.L., Costa, R.B.D., Beulens, J.W.J., Blaha, M., Bobak, M., Boer, J.M.A., Bonet, C., Bonnet, F., Boutron-Ruault, M.C., Braaten, T., Brenner, H., Brunner, F., Brunner, E.J., Brunstrom, M., Buring, J., Butterworth, A.S., Capkova, N., Cesana, G., Chrysohoou, C., Colorado-Yohar, S., Cook, N.R., Cooper, C., Dahm, C.C., Davidson, K., Dennison, E., Castelnuovo, A. di, Donfrancesco, C., Dorr, M., Dorynska, A., Eliasson, M., Engstrom, G., Ferrari, P., Ferrario, M., Ford, I., Fu, M., Gansevoort, R.T., Giampaoli, S., Gillum, R.F., Camara, A.G. de la, Grassi, G., Hansson, P.O., Huculeci, R., Hveem, K., Iacoviello, L., Ikram, M.K., Jorgensen, T., Joseph, B., Jousilahti, P., Jukema, J.W., Kaaks, R., Katzke, V., Kavousi, M., Kiechl, S., Klotsche, J., Konig, W., Kronmal, R.A., Kubinova, R., Kucharska-Newton, A., Lall, K., Lehmann, N., Leistner, D., Linneberg, A., Pablos, D.L., Lorenz, T., Lu, W.T., Luksiene, D., Lyngbakken, M., Magnussen, C., Malyutina, S., Ibanez, A.M., Masala, G., Mathiesen, E.B., Matsushita, K., Meade, T.W., Melander, O., Meyer, H.E., Moons, K.G.M., Moreno-Iribas, C., Muller, D., Munzel, T., Nikitin, Y., Nordestgaard, B.G., Omland, T., Onland, C., Overvad, K., Packard, C., Pajak, A., Palmieri, L., Panagiotakos, D., Panico, S., Perez-Cornago, A., Peters, A., Pietila, A., Pikhart, H., Psaty, B.M., Quarti-Trevano, F., Garcia, J.R.Q., Riboli, E., Ridker, P.M., Rodriguez, B., Rodriguez-Barranco, M., Rosengren, A., Roussel, R., Sacerdote, C., Sans, S., Sattar, N., Schiborn, C., Schmidt, B., Schottker, B., Schulze, M., Schwartz, J.E., Selmer, R.M., Shea, S., Shipley, M.J., Sieri, S., Soderberg, S., Sofat, R., Tamosiunas, A., Thorand, B., Tillmann, T., Tjonneland, A., Tong, T.Y.N., Trichopoulou, A., Tumino, R., Tunstall-Pedoe, H., Tybjaerg-Hansen, A., Tzoulaki, J., Heijden, A. van der, Schouw, Y.T. van der, Verschuren, W.M.M., Volzke, H., Waldeyer, C., Wareham, N.J., Weiderpass, E., Weidinger, F., Wild, P., Willeit, J., Willeit, P., Wilsgaard, T., Woodward, M., Zeller, T., Zhang, D.D., Zhou, B., SCORE2 Working Grp, ESC Cardiovasc Risk Collaboration, collaboration, SCORE2 working group and ESC Cardiovascular risk, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Epidemiology, Neurology, Achenbach, S, Aleksandrova, K, Amiano, P, San Sebastian, D, Amouyel, P, Andersson, J, Bakker, S, Da Providencia Costa, R, Beulens, J, Blaha, M, Bobak, M, Boer, J, Bonet, C, Bonnet, F, Boutron-Ruault, M, Braaten, T, Brenner, H, Brunner, F, Brunner, E, Brunström, M, Buring, J, Butterworth, A, Capkova, N, Cesana, G, Chrysohoou, C, Colorado-Yohar, S, Cook, N, Cooper, C, Dahm, C, Davidson, K, Dennison, E, Di Castelnuovo, A, Donfrancesco, C, Dörr, M, Doryńska, A, Eliasson, M, Engström, G, Ferrari, P, Ferrario, M, Ford, I, Fu, M, Gansevoort, R, Giampaoli, S, Gillum, R, Gómez de la Cámara, A, Grassi, G, Hansson, P, Huculeci, R, Hveem, K, Iacoviello, L, Ikram, M, Jørgensen, T, Joseph, B, Jousilahti, P, Wouter Jukema, J, Kaaks, R, Katzke, V, Kavousi, M, Kiechl, S, Klotsche, J, König, W, Kronmal, R, Kubinova, R, Kucharska-Newton, A, Läll, K, Lehmann, N, Leistner, D, Linneberg, A, Pablos, D, Lorenz, T, Lu, W, Luksiene, D, Lyngbakken, M, Magnussen, C, Malyutina, S, Ibañez, A, Masala, G, Mathiesen, E, Matsushita, K, Meade, T, Melander, O, Meyer, H, Moons, K, Moreno-Iribas, C, Muller, D, Münzel, T, Nikitin, Y, Nordestgaard, B, Omland, T, Onland, C, Overvad, K, Packard, C, Pająk, A, Palmieri, L, Panagiotakos, D, Panico, S, Perez-Cornago, A, Peters, A, Pietilä, A, Pikhart, H, Psaty, B, Quarti-Trevano, F, Garcia, J, Riboli, E, Ridker, P, Rodriguez, B, Rodriguez-Barranco, M, Rosengren, A, Roussel, R, Sacerdote, C, S, S, Sattar, N, Schiborn, C, Schmidt, B, Schöttker, B, Schulze, M, Schwartz, J, Selmer, R, Shea, S, Shipley, M, Sieri, S, Söderberg, S, Sofat, R, Tamosiunas, A, Thorand, B, Tillmann, T, Tjønneland, A, Tong, T, Trichopoulou, A, Tumino, R, Tunstall-Pedoe, H, Tybjaerg-Hansen, A, Tzoulaki, J, van der Heijden, A, van der Schouw, Y, Verschuren, W, Völzke, H, Waldeyer, C, Wareham, N, Weiderpass, E, Weidinger, F, Wild, P, Willeit, J, Willeit, P, Wilsgaard, T, Woodward, M, Zeller, T, Zhang, D, Zhou, B, and Apollo - University of Cambridge Repository

Subjects
Male, Cardiology, RATIONALE, Blood Pressure, Disease, 030204 cardiovascular system & hematology, PROFILE, ACUTE CORONARY EVENTS, VALIDATION, Europe/epidemiology, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, DESIGN, Clinical Research, Risk Factors, Diabetes mellitus, medicine, PARTICIPANTS, Humans, 030212 general & internal medicine, Risk factor, Aged, Primary prevention, business.industry, 10-year CVD risk, Incidence (epidemiology), Cardiovascular Diseases/epidemiology, Risk Prediction, Cardiovascular Disease, Primary Prevention, 10-year Cvd Risk, External validation, PRIMARY-CARE, Middle Aged, medicine.disease, Cardiovascular disease, Risk prediction, 3. Good health, Europe, Prediction algorithms, Blood pressure, Cardiovascular Diseases, Smoking status, Female, Cardiology and Cardiovascular Medicine, business, Algorithms, Demography
Abstract

Aims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe.Methods and results We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low- risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries.Conclusion SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe. Acknowledgements We thank investigators and participants of the several studies that contributed data to the Emerging Risk Factors Collaboration (ERFC). This research has been conducted using the UK Biobank Resource under Application Number 26865. Data from the Clinical Practice Research Datalink (CPRD) were obtained under licence from the UK Medicines and Healthcare products Regulatory Agency (protocol 162RMn2). CPRD uses data provided by patients and collected by the NHS as part of their care and support. We thank all EPIC participants and staff for their contribution to the study, the laboratory teams at the Medical Research Council Epidemiology Unit for sample management and Cambridge Genomic Services for genotyping, Sarah Spackman for data management and the team at the EPIC-CVD Coordinating Centre for study co-ordination and administration. Funding The ERFC co-ordinating centre was underpinned by programme grants from the British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946), BHF Centre of Research Excellence (RE/18/1/34212), the UK Medical Research Council (MR/L003120/1), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC1215-20014), with project-specific support received from the UK NIHR [*], British United Provident Association UK Foundation and an unrestricted educational grant from GlaxoSmithKline. A variety of funding sources have supported recruitment, follow-up, and laboratory measurements in the studies contributing data to the ERFC, which are listed on the ERFC website (www.phpc.cam.ac.uk/ceu/erfc/list-of-studies). *The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome. The MORGAM Project has received funding from EU projects MORGAM (Biomed BMH4-CT98-3183), GenomEUtwin (FP5, QLG2-CT-2002-01254), ENGAGE (FP7, HEALTH-F4-2007-201413),CHANCES (FP7, HEALTH-F3-2010-242244), BiomarCaRE (FP7,HEALTH-F2-2011-278913), euCanSHare (Horizon 2020, No. 825903) and AFFECT-EU (Horizon 2020, No. 847770); and Medical Research Council, London (G0601463, No. 80983: Biomarkers in the MORGAM Populations). This has supported central coordination, workshops and part of the activities of the MORGAM Data Centre, the MORGAM Laboratories and the MORGAM Participating Centres EPIC-CVD was funded by the European Research Council (268834), and the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). This work was supported by the Estonian Research Council grant PUTs (PRG687, PUT1660, PUT1665, PRG184), by European Union through the European Regional Development Fund project no. MOBERA5 (Norface Network project no 462.16.107), by the Green ICT programme under Norway Grants 2014 – 2021 (grant number EU53928), by the European Union through Horizon 2020 grant no. 810645 and through the European Regional Development Fund (Project No. 2014-2020.4.01.16-0125) and by the PRECISE4Q consortium. PRECISE4Q project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement 777107. This work was partly funded through the CoMorMent project. CoMorMent has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement 847776. The KORA study was initiated and financed by the Helmholtz Zentrum Mu¨nchen—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. The KORA study was supported by a research grant from the Virtual Institute of Diabetes Research (Helmholtz Zentrum Mu¨nchen), the Clinical Cooperation Group Diabetes between Ludwig-Maximilians-Universita¨t Mu¨nchen and Helmholtz Zentrum Mu¨nchen, and by the German Diabetes Center (DDZ). The HAPIEE project, Institute, was supported by grants from the Wellcome Trust (064947/Z/01/Z; WT081081) and US National Institute on Aging (1R01 and AG23522). The co-ordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Ge´ne´rale de l’Education Nationale, Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch 2448 SCORE2 working group and ESC Cardiovascular Risk Collaboration Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucı´a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Ska˚ne and Va¨sterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom)

Published
2021

35. Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: A multinational cohort study

Author

Freisling, H, Viallon, V, Lennon, H, Bagnardi, V, Ricci, C, Butterworth, A, Sweeting, M, Muller, D, Romieu, I, Bazelle, P, Kvaskoff, M, Arveux, P, Severi, G, Bamia, C, Kuhn, T, Kaaks, R, Bergmann, M, Boeing, H, Tjonneland, A, Olsen, A, Overvad, K, Dahm, C, Menendez, V, Agudo, A, Sanchez, M, Amiano, P, Santiuste, C, Gurrea, A, Tong, T, Schmidt, J, Tzoulaki, I, Tsilidis, K, Ward, H, Palli, D, Agnoli, C, Tumino, R, Ricceri, F, Panico, S, Picavet, H, Bakker, M, Monninkhof, E, Nilsson, P, Manjer, J, Rolandsson, O, Thysell, E, Weiderpass, E, Jenab, M, Riboli, E, Vineis, P, Danesh, J, Wareham, N, Gunter, M, Ferrari, P, Freisling H., Viallon V., Lennon H., Bagnardi V., Ricci C., Butterworth A. S., Sweeting M., Muller D., Romieu I., Bazelle P., Kvaskoff M., Arveux P., Severi G., Bamia C., Kuhn T., Kaaks R., Bergmann M., Boeing H., Tjonneland A., Olsen A., Overvad K., Dahm C. C., Menendez V., Agudo A., Sanchez M. -J., Amiano P., Santiuste C., Gurrea A. B., Tong T. Y. N., Schmidt J. A., Tzoulaki I., Tsilidis K. K., Ward H., Palli D., Agnoli C., Tumino R., Ricceri F., Panico S., Picavet H. S. J., Bakker M., Monninkhof E., Nilsson P., Manjer J., Rolandsson O., Thysell E., Weiderpass E., Jenab M., Riboli E., Vineis P., Danesh J., Wareham N. J., Gunter M. J., Ferrari P., Freisling, H, Viallon, V, Lennon, H, Bagnardi, V, Ricci, C, Butterworth, A, Sweeting, M, Muller, D, Romieu, I, Bazelle, P, Kvaskoff, M, Arveux, P, Severi, G, Bamia, C, Kuhn, T, Kaaks, R, Bergmann, M, Boeing, H, Tjonneland, A, Olsen, A, Overvad, K, Dahm, C, Menendez, V, Agudo, A, Sanchez, M, Amiano, P, Santiuste, C, Gurrea, A, Tong, T, Schmidt, J, Tzoulaki, I, Tsilidis, K, Ward, H, Palli, D, Agnoli, C, Tumino, R, Ricceri, F, Panico, S, Picavet, H, Bakker, M, Monninkhof, E, Nilsson, P, Manjer, J, Rolandsson, O, Thysell, E, Weiderpass, E, Jenab, M, Riboli, E, Vineis, P, Danesh, J, Wareham, N, Gunter, M, Ferrari, P, Freisling H., Viallon V., Lennon H., Bagnardi V., Ricci C., Butterworth A. S., Sweeting M., Muller D., Romieu I., Bazelle P., Kvaskoff M., Arveux P., Severi G., Bamia C., Kuhn T., Kaaks R., Bergmann M., Boeing H., Tjonneland A., Olsen A., Overvad K., Dahm C. C., Menendez V., Agudo A., Sanchez M. -J., Amiano P., Santiuste C., Gurrea A. B., Tong T. Y. N., Schmidt J. A., Tzoulaki I., Tsilidis K. K., Ward H., Palli D., Agnoli C., Tumino R., Ricceri F., Panico S., Picavet H. S. J., Bakker M., Monninkhof E., Nilsson P., Manjer J., Rolandsson O., Thysell E., Weiderpass E., Jenab M., Riboli E., Vineis P., Danesh J., Wareham N. J., Gunter M. J., and Ferrari P.

Abstract

Background: Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases. Methods: In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs. Results: During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and

Published
2020

36. Obesity is Associated With Increased Risk of Crohn's disease, but not Ulcerative Colitis: A Pooled Analysis of Five Prospective Cohort Studies

Author

Casey, K., Olen, O., Ludvigsson, J.F., Carbonnel, F., Oldenburg, B., Gunter, M.J., Tjønneland, A., Grip, O., Amian, P., Barricarte, A., Bergmann, M.M., Boutron-Ruault, M.-C., Cross, A., Hart, A.R., Kaaks, R., Key, T., Chirlaque López, M.D., Luben, Robert, Masala, G., Manjer, J., Olsen, A., Overvad, K., Palli, D., Riboli, E., Sánchez, M.J., Tumino, R., Vermeulen, R., Verschuren, W.M.M., Wareham, N., Ananthakrishnan, A., Burke, K., Lopes, E.W., Lochhead, P., Chan, A.T., Wolk, A., Khalili, H., Casey, K., Olen, O., Ludvigsson, J.F., Carbonnel, F., Oldenburg, B., Gunter, M.J., Tjønneland, A., Grip, O., Amian, P., Barricarte, A., Bergmann, M.M., Boutron-Ruault, M.-C., Cross, A., Hart, A.R., Kaaks, R., Key, T., Chirlaque López, M.D., Luben, Robert, Masala, G., Manjer, J., Olsen, A., Overvad, K., Palli, D., Riboli, E., Sánchez, M.J., Tumino, R., Vermeulen, R., Verschuren, W.M.M., Wareham, N., Ananthakrishnan, A., Burke, K., Lopes, E.W., Lochhead, P., Chan, A.T., Wolk, A., and Khalili, H.

Abstract

Background and Aims: It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC). Methods: We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs). Results: Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m2) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I2 = 0%) compared with normal BMI (18.5 to <25 kg/m2). Each 5 kg/m2 increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I2 = 0%). Similarly, with each 5 kg/m2 increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I2 = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I2 = 0%). No associations were observed between measures of obesity and risk of UC. Conclusions: In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC.

Published
2022

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

Author

Wang, X, Chen, H, Kapoor, PM, Su, Y-R, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Michailidou, K, Pharoah, PDP, Hopper, JL, Southey, MC, Koutros, S, Freeman, LEB, Stone, J, Rennert, G, Shibli, R, Murphy, RA, Aronson, K, Guenel, P, Truong, T, Teras, LR, Hodge, JM, Canzian, F, Kaaks, R, Brenner, H, Arndt, V, Hoppe, R, Lo, W-Y, Behrens, S, Mannermaa, A, Kosma, V-M, Jung, A, Becher, H, Glies, GG, Haiman, CA, Maskarinec, G, Scott, C, Winham, S, Simard, J, Goldberg, MS, Zheng, W, Long, J, Troester, MA, Love, MI, Peng, C, Tamimi, R, Eliassen, H, Garcia-Closas, M, Figueroa, J, Ahearn, T, Yang, R, Evans, DG, Howell, A, Hall, P, Czene, K, Wolk, A, Sandler, DP, Taylor, JA, Swerdlow, AJ, Orr, N, Lacey, JV, Wang, S, Olsson, H, Easton, DF, Milne, RL, Hsu, L, Kraft, P, Chang-Claude, J, Lindstroem, S, Wang, X, Chen, H, Kapoor, PM, Su, Y-R, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Michailidou, K, Pharoah, PDP, Hopper, JL, Southey, MC, Koutros, S, Freeman, LEB, Stone, J, Rennert, G, Shibli, R, Murphy, RA, Aronson, K, Guenel, P, Truong, T, Teras, LR, Hodge, JM, Canzian, F, Kaaks, R, Brenner, H, Arndt, V, Hoppe, R, Lo, W-Y, Behrens, S, Mannermaa, A, Kosma, V-M, Jung, A, Becher, H, Glies, GG, Haiman, CA, Maskarinec, G, Scott, C, Winham, S, Simard, J, Goldberg, MS, Zheng, W, Long, J, Troester, MA, Love, MI, Peng, C, Tamimi, R, Eliassen, H, Garcia-Closas, M, Figueroa, J, Ahearn, T, Yang, R, Evans, DG, Howell, A, Hall, P, Czene, K, Wolk, A, Sandler, DP, Taylor, JA, Swerdlow, AJ, Orr, N, Lacey, JV, Wang, S, Olsson, H, Easton, DF, Milne, RL, Hsu, L, Kraft, P, Chang-Claude, J, and Lindstroem, S

Abstract

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. METHODS: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. RESULTS: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE=4.44×10-6). CONCLUSION: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. IMPACT: Our study suggests a limited role of gene-environment interactions in breast cancer risk.

Published
2022

38. 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

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

Author

Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, Chatterjee, N, Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, and Chatterjee, N

Abstract

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

Published
2022

40. 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

41. Pre-diagnostic C-reactive protein concentrations, CRP genetic variation and mortality among individuals with colorectal cancer in Western European populations

Author

Nimptsch, K., Aleksandrova, K., Fedirko, V., Jenab, M., Gunter, M.J., Siersema, P.D., Wu, K., Katzke, V., Kaaks, R., Panico, S., Palli, D., May, A.M., Sieri, S., Bueno-de-Mesquita, B., Standahl, K., Sánchez, M.J., Perez-Cornago, A., Olsen, A., Tjønneland, A., Bonet, C.B., Dahm, C.C., Chirlaque, M.D., Fiano, V., Tumino, R., Gurrea, A.B., Boutron-Ruault, M.C., Menegaux, F., Severi, G., Guelpen, B. van, Lee, Y.A., Pischon, T., Nimptsch, K., Aleksandrova, K., Fedirko, V., Jenab, M., Gunter, M.J., Siersema, P.D., Wu, K., Katzke, V., Kaaks, R., Panico, S., Palli, D., May, A.M., Sieri, S., Bueno-de-Mesquita, B., Standahl, K., Sánchez, M.J., Perez-Cornago, A., Olsen, A., Tjønneland, A., Bonet, C.B., Dahm, C.C., Chirlaque, M.D., Fiano, V., Tumino, R., Gurrea, A.B., Boutron-Ruault, M.C., Menegaux, F., Severi, G., Guelpen, B. van, Lee, Y.A., and Pischon, T.

Abstract

Contains fulltext : 252185.pdf (Publisher’s version ) (Open Access), BACKGROUND: The role of elevated pre-diagnostic C-reactive protein (CRP) concentrations on mortality in individuals with colorectal cancer (CRC) remains unclear. METHODS: We investigated the association between pre-diagnostic high-sensitivity CRP concentrations and CRP genetic variation associated with circulating CRP and CRC-specific and all-cause mortality based on data from 1,235 individuals with CRC within the European Prospective Investigation into Cancer and Nutrition cohort using multivariable-adjusted Cox proportional hazards regression. RESULTS: During a median follow-up of 9.3 years, 455 CRC-specific deaths were recorded, out of 590 deaths from all causes. Pre-diagnostic CRP concentrations were not associated with CRC-specific (hazard ratio, HR highest versus lowest quintile 0.92, 95% confidence interval, CI 0.66, 1.28) or all-cause mortality (HR 0.91, 95% CI 0.68, 1.21). Genetic predisposition to higher CRP (weighted score based on alleles of four CRP SNPs associated with higher circulating CRP) was not significantly associated with CRC-specific mortality (HR per CRP-score unit 0.95, 95% CI 0.86, 1.05) or all-cause mortality (HR 0.98, 95% CI 0.90, 1.07). Among four investigated CRP genetic variants, only SNP rs1205 was significantly associated with CRC-specific (comparing the CT and CC genotypes with TT genotype, HR 0.54, 95% CI 0.35, 0.83 and HR 0.58, 95% CI 0.38, 0.88, respectively) and all-cause mortality (HR 0.58, 95% CI 0.40, 0.85 and 0.64, 95% CI 0.44, 0.92, respectively). CONCLUSIONS: The results of this prospective cohort study do not support a role of pre-diagnostic CRP concentrations on mortality in individuals with CRC. The observed associations with rs1205 deserve further scientific attention.

Published
2022

42. Pre-diagnostic C-reactive protein concentrations, CRP genetic variation and mortality among individuals with colorectal cancer in Western European populations.

Author

Nimptsch, K, Aleksandrova, K, Fedirko, V, Jenab, M, Gunter, MJ, Siersema, PD, Wu, K, Katzke, V, Kaaks, R, Panico, S, Palli, D, May, AM, Sieri, S, Bueno-de-Mesquita, B, Standahl, K, Sánchez, M-J, Perez-Cornago, A, Olsen, A, Tjønneland, A, Bonet, CB, Dahm, CC, Chirlaque, M-D, Fiano, V, Tumino, R, Gurrea, AB, Boutron-Ruault, M-C, Menegaux, F, Severi, G, van Guelpen, B, Lee, Y-A, Pischon, T, Nimptsch, K, Aleksandrova, K, Fedirko, V, Jenab, M, Gunter, MJ, Siersema, PD, Wu, K, Katzke, V, Kaaks, R, Panico, S, Palli, D, May, AM, Sieri, S, Bueno-de-Mesquita, B, Standahl, K, Sánchez, M-J, Perez-Cornago, A, Olsen, A, Tjønneland, A, Bonet, CB, Dahm, CC, Chirlaque, M-D, Fiano, V, Tumino, R, Gurrea, AB, Boutron-Ruault, M-C, Menegaux, F, Severi, G, van Guelpen, B, Lee, Y-A, and Pischon, T

Abstract

BACKGROUND: The role of elevated pre-diagnostic C-reactive protein (CRP) concentrations on mortality in individuals with colorectal cancer (CRC) remains unclear. METHODS: We investigated the association between pre-diagnostic high-sensitivity CRP concentrations and CRP genetic variation associated with circulating CRP and CRC-specific and all-cause mortality based on data from 1,235 individuals with CRC within the European Prospective Investigation into Cancer and Nutrition cohort using multivariable-adjusted Cox proportional hazards regression. RESULTS: During a median follow-up of 9.3 years, 455 CRC-specific deaths were recorded, out of 590 deaths from all causes. Pre-diagnostic CRP concentrations were not associated with CRC-specific (hazard ratio, HR highest versus lowest quintile 0.92, 95% confidence interval, CI 0.66, 1.28) or all-cause mortality (HR 0.91, 95% CI 0.68, 1.21). Genetic predisposition to higher CRP (weighted score based on alleles of four CRP SNPs associated with higher circulating CRP) was not significantly associated with CRC-specific mortality (HR per CRP-score unit 0.95, 95% CI 0.86, 1.05) or all-cause mortality (HR 0.98, 95% CI 0.90, 1.07). Among four investigated CRP genetic variants, only SNP rs1205 was significantly associated with CRC-specific (comparing the CT and CC genotypes with TT genotype, HR 0.54, 95% CI 0.35, 0.83 and HR 0.58, 95% CI 0.38, 0.88, respectively) and all-cause mortality (HR 0.58, 95% CI 0.40, 0.85 and 0.64, 95% CI 0.44, 0.92, respectively). CONCLUSIONS: The results of this prospective cohort study do not support a role of pre-diagnostic CRP concentrations on mortality in individuals with CRC. The observed associations with rs1205 deserve further scientific attention.

Published
2022

43. Absolute Risk of Oropharyngeal Cancer After an HPV16-E6 Serology Test and Potential Implications for Screening: Results From the Human Papillomavirus Cancer Cohort Consortium.

Author

Robbins, HA, Ferreiro-Iglesias, A, Waterboer, T, Brenner, N, Nygard, M, Bender, N, Schroeder, L, Hildesheim, A, Pawlita, M, D'Souza, G, Visvanathan, K, Langseth, H, Schlecht, NF, Tinker, LF, Agalliu, I, Wassertheil-Smoller, S, Ness-Jensen, E, Hveem, K, Grioni, S, Kaaks, R, Sánchez, M-J, Weiderpass, E, Giles, GG, Milne, RL, Cai, Q, Blot, WJ, Zheng, W, Weinstein, SJ, Albanes, D, Huang, W-Y, Freedman, ND, Kreimer, AR, Johansson, M, Brennan, P, Robbins, HA, Ferreiro-Iglesias, A, Waterboer, T, Brenner, N, Nygard, M, Bender, N, Schroeder, L, Hildesheim, A, Pawlita, M, D'Souza, G, Visvanathan, K, Langseth, H, Schlecht, NF, Tinker, LF, Agalliu, I, Wassertheil-Smoller, S, Ness-Jensen, E, Hveem, K, Grioni, S, Kaaks, R, Sánchez, M-J, Weiderpass, E, Giles, GG, Milne, RL, Cai, Q, Blot, WJ, Zheng, W, Weinstein, SJ, Albanes, D, Huang, W-Y, Freedman, ND, Kreimer, AR, Johansson, M, and Brennan, P

Abstract

PURPOSE: Seropositivity for the HPV16-E6 oncoprotein is a promising marker for early detection of oropharyngeal cancer (OPC), but the absolute risk of OPC after a positive or negative test is unknown. METHODS: We constructed an OPC risk prediction model that integrates (1) relative odds of OPC for HPV16-E6 serostatus and cigarette smoking from the human papillomavirus (HPV) Cancer Cohort Consortium (HPVC3), (2) US population risk factor data from the National Health Interview Survey, and (3) US sex-specific population rates of OPC and mortality. RESULTS: The nine HPVC3 cohorts included 365 participants with OPC with up to 10 years between blood draw and diagnosis and 5,794 controls. The estimated 10-year OPC risk for HPV16-E6 seropositive males at age 50 years was 17.4% (95% CI, 12.4 to 28.6) and at age 60 years was 27.1% (95% CI, 19.2 to 45.4). Corresponding 5-year risk estimates were 7.3% and 14.4%, respectively. For HPV16-E6 seropositive females, 10-year risk estimates were 3.6% (95% CI, 2.5 to 5.9) at age 50 years and 5.5% (95% CI, 3.8 to 9.2) at age 60 years and 5-year risk estimates were 1.5% and 2.7%, respectively. Over 30 years, after a seropositive result at age 50 years, an estimated 49.9% of males and 13.3% of females would develop OPC. By contrast, 10-year risks among HPV16-E6 seronegative people were very low, ranging from 0.01% to 0.25% depending on age, sex, and smoking status. CONCLUSION: We estimate that a substantial proportion of HPV16-E6 seropositive individuals will develop OPC, with 10-year risks of 17%-27% for males and 4%-6% for females age 50-60 years in the United States. This high level of risk may warrant periodic, minimally invasive surveillance after a positive HPV16-E6 serology test, particularly for males in high-incidence regions. However, an appropriate clinical protocol for surveillance remains to be established.

Published
2022

44. Prediagnosis Leisure-Time Physical Activity and Lung Cancer Survival: A Pooled Analysis of 11 Cohorts.

Author

Yang, JJ, Yu, D, White, E, Lee, DH, Blot, W, Robien, K, Sinha, R, Park, Y, Takata, Y, Gao, Y-T, Smith-Byrne, K, Monninkhof, EM, Kaaks, R, Langhammer, A, Borch, KB, Al-Shaar, L, Lan, Q, Sørgjerd, EP, Zhang, X, Zhu, C, Chirlaque, MD, Severi, G, Overvad, K, Sacerdote, C, Aune, D, Johansson, M, Smith-Warner, SA, Zheng, W, Shu, X-O, Yang, JJ, Yu, D, White, E, Lee, DH, Blot, W, Robien, K, Sinha, R, Park, Y, Takata, Y, Gao, Y-T, Smith-Byrne, K, Monninkhof, EM, Kaaks, R, Langhammer, A, Borch, KB, Al-Shaar, L, Lan, Q, Sørgjerd, EP, Zhang, X, Zhu, C, Chirlaque, MD, Severi, G, Overvad, K, Sacerdote, C, Aune, D, Johansson, M, Smith-Warner, SA, Zheng, W, and Shu, X-O

Abstract

BACKGROUND: Little is known about the association between physical activity before cancer diagnosis and survival among lung cancer patients. In this pooled analysis of 11 prospective cohorts, we investigated associations of prediagnosis leisure-time physical activity (LTPA) with all-cause and lung cancer-specific mortality among incident lung cancer patients. METHODS: Using self-reported data on regular engagement in exercise and sports activities collected at study enrollment, we assessed metabolic equivalent hours (MET-h) of prediagnosis LTPA per week. According to the Physical Activity Guidelines for Americans, prediagnosis LTPA was classified into inactivity, less than 8.3 and at least 8.3 MET-h per week (the minimum recommended range). Cox regression was used to estimate hazard ratios (HRs) and 95% confidence interval (CIs) for all-cause and lung cancer-specific mortality after adjustment for major prognostic factors and lifetime smoking history. RESULTS: Of 20 494 incident lung cancer patients, 16 864 died, including 13 596 deaths from lung cancer (overall 5-year relative survival rate = 20.9%, 95% CI = 20.3% to 21.5%). Compared with inactivity, prediagnosis LTPA of more than 8.3 MET-h per week was associated with a lower hazard of all-cause mortality (multivariable-adjusted HR = 0.93, 95% CI = 0.88 to 0.99), but not with lung cancer-specific mortality (multivariable-adjusted HR = 0.99, 95% CI = 0.95 to 1.04), among the overall population. Additive interaction was found by tumor stage (Pinteraction = .008 for all-cause mortality and .003 for lung cancer-specific mortality). When restricted to localized cancer, prediagnosis LTPA of at least 8.3 MET-h per week linked to 20% lower mortality: multivariable-adjusted HRs were 0.80 (95% CI = 0.67 to 0.97) for all-cause mortality and 0.80 (95% CI = 0.65 to 0.99) for lung cancer-specific mortality. CONCLUSIONS: Regular participation in LTPA that met or exceeded the minimum Physical Activity Guidelines was associated wi

Published
2022

45. Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia

Author

Watts, EL, Perez-Cornago, A, Fensom, GK, Smith-Byrne, K, Noor, U, Andrews, CD, Gunter, MJ, Holmes, M, Martin, RM, Tsilidis, KK, Albanes, D, Barricarte, A, Bueno-de-Mesquita, B, Chen, C, Cohn, BA, Dimou, NL, Ferrucci, L, Flicker, L, Freedman, ND, Giles, GG, Giovannucci, EL, Goodman, GE, Haiman, CA, Hankey, GJ, Huang, J, Huang, W-Y, Hurwitz, LM, Kaaks, R, Knekt, P, Kubo, T, Langseth, H, Laughlin, G, Le Marchand, L, Luostarinen, T, MacInnis, RJ, Maenpaa, HO, Mannisto, S, Metter, JE, Mikami, K, Mucci, LA, Olsen, AW, Ozasa, K, Palli, D, Penney, KL, Platz, EA, Rissanen, H, Sawada, N, Schenk, JM, Stattin, P, Tamakoshi, A, Thysell, E, Tsai, CJ, Tsugane, S, Vatten, L, Weiderpass, E, Weinstein, SJ, Wilkens, LR, Yeap, BB, Allen, NE, Key, TJ, Travis, RC, Watts, EL, Perez-Cornago, A, Fensom, GK, Smith-Byrne, K, Noor, U, Andrews, CD, Gunter, MJ, Holmes, M, Martin, RM, Tsilidis, KK, Albanes, D, Barricarte, A, Bueno-de-Mesquita, B, Chen, C, Cohn, BA, Dimou, NL, Ferrucci, L, Flicker, L, Freedman, ND, Giles, GG, Giovannucci, EL, Goodman, GE, Haiman, CA, Hankey, GJ, Huang, J, Huang, W-Y, Hurwitz, LM, Kaaks, R, Knekt, P, Kubo, T, Langseth, H, Laughlin, G, Le Marchand, L, Luostarinen, T, MacInnis, RJ, Maenpaa, HO, Mannisto, S, Metter, JE, Mikami, K, Mucci, LA, Olsen, AW, Ozasa, K, Palli, D, Penney, KL, Platz, EA, Rissanen, H, Sawada, N, Schenk, JM, Stattin, P, Tamakoshi, A, Thysell, E, Tsai, CJ, Tsugane, S, Vatten, L, Weiderpass, E, Weinstein, SJ, Wilkens, LR, Yeap, BB, Allen, NE, Key, TJ, and Travis, RC

Abstract

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

Published
2022

46. 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

47. Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

Author

Gaziano, L, Sun, L, Arnold, M, Bell, S, Cho, K, Kaptoge, SK, Song, RJ, Burgess, S, Posner, DC, Mosconi, K, Cohen, CR, Mason, AM, Bolton, TR, Tao, R, Allara, E, Schubert, P, Chen, L, Staley, JR, Staplin, N, Altay, S, Amiano, P, Arndt, PV, Arnlov, J, Barr, ELM, Bjorkelund, C, Boer, JMA, Brenner, H, Casiglia, E, Chiodini, P, Cooper, JA, Coresh, J, Cushman, M, Dankner, R, Davidson, KW, de Jongh, RT, Donfrancesco, C, Engstrom, G, Freisling, H, de la Camara, AG, Gudnason, V, Hankey, GJ, Hansson, P, Heath, AK, Hoorn, EJ, Imano, H, Jassal, SK, Kaaks, R, Katzke, V, Kauhanen, J, Kiechl, S, Koenig, W, Kronmal, RA, Kyro, C, Lawlor, DA, Ljungberg, B, MacDonald, C, Masala, G, Meisinger, C, Melander, O, Iribas, CM, Ninomiya, T, Nitsch, D, Nordestgaard, BG, OnlandMoret, C, Palmieri, L, Petrova, D, Garcia, JRQ, Rosengren, A, Sacerdote, C, Sakurai, M, Santiuste, C, Schulze, MB, Sieri, S, Sundstrom, J, Tikhonoff, V, Tjonneland, A, Tong, T, Tumino, R, Tzoulaki, I, van der Schouw, YT, Verschuren, WMM, Volzke, H, Wallace, RB, Wannamethee, SG, Weiderpass, E, Willeit, P, Woodward, M, Yamagishi, K, ZamoraRos, R, Akwo, EA, Pyarajan, S, Gagnon, DR, Tsao, PS, Muralidhar, S, Edwards, TL, Damrauer, SM, Joseph, J, Pennells, L, Wilson, PWF, Harrison, S, Gaziano, TA, Inouye, M, Baigent, C, Casas, JP, Langenberg, C, Wareham, N, Riboli, E, Gaziano, JM, Danesh, J, Hung, AM, Butterworth, AS, Wood, AM, Di Angelantonio, E, Gaziano, L, Sun, L, Arnold, M, Bell, S, Cho, K, Kaptoge, SK, Song, RJ, Burgess, S, Posner, DC, Mosconi, K, Cohen, CR, Mason, AM, Bolton, TR, Tao, R, Allara, E, Schubert, P, Chen, L, Staley, JR, Staplin, N, Altay, S, Amiano, P, Arndt, PV, Arnlov, J, Barr, ELM, Bjorkelund, C, Boer, JMA, Brenner, H, Casiglia, E, Chiodini, P, Cooper, JA, Coresh, J, Cushman, M, Dankner, R, Davidson, KW, de Jongh, RT, Donfrancesco, C, Engstrom, G, Freisling, H, de la Camara, AG, Gudnason, V, Hankey, GJ, Hansson, P, Heath, AK, Hoorn, EJ, Imano, H, Jassal, SK, Kaaks, R, Katzke, V, Kauhanen, J, Kiechl, S, Koenig, W, Kronmal, RA, Kyro, C, Lawlor, DA, Ljungberg, B, MacDonald, C, Masala, G, Meisinger, C, Melander, O, Iribas, CM, Ninomiya, T, Nitsch, D, Nordestgaard, BG, OnlandMoret, C, Palmieri, L, Petrova, D, Garcia, JRQ, Rosengren, A, Sacerdote, C, Sakurai, M, Santiuste, C, Schulze, MB, Sieri, S, Sundstrom, J, Tikhonoff, V, Tjonneland, A, Tong, T, Tumino, R, Tzoulaki, I, van der Schouw, YT, Verschuren, WMM, Volzke, H, Wallace, RB, Wannamethee, SG, Weiderpass, E, Willeit, P, Woodward, M, Yamagishi, K, ZamoraRos, R, Akwo, EA, Pyarajan, S, Gagnon, DR, Tsao, PS, Muralidhar, S, Edwards, TL, Damrauer, SM, Joseph, J, Pennells, L, Wilson, PWF, Harrison, S, Gaziano, TA, Inouye, M, Baigent, C, Casas, JP, Langenberg, C, Wareham, N, Riboli, E, Gaziano, JM, Danesh, J, Hung, AM, Butterworth, AS, Wood, AM, and Di Angelantonio, E

Abstract

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches th

Published
2022

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

Author

Jung, AY, Ahearn, TU, Behrens, S, Middha, P, Bolla, MK, Wang, Q, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Becher, H, Brenner, H, Canzian, F, Carey, LA, Consortium, C, Czene, K, Eliassen, AH, Eriksson, M, Evans, DG, Figueroa, JD, Fritschi, L, Gabrielson, M, Giles, GG, Guenel, P, Hadjisavvas, A, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Huesing, A, Kaaks, R, Kosma, V-M, Koutros, S, Kraft, P, Lacey, J, Le Marchand, L, Lissowska, J, Loizidou, MA, Mannermaa, A, Maurer, T, Murphy, RA, Olshan, AF, Olsson, H, Patel, A, Perou, CM, Rennert, G, Shibli, R, Shu, X-O, Southey, MC, Stone, J, Tamimi, RM, Teras, LR, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Wolk, A, Wu, AH, Yang, XR, Zheng, W, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Chatterjee, N, Schmidt, MK, Garcia-Closas, M, Chang-Claude, J, Jung, AY, Ahearn, TU, Behrens, S, Middha, P, Bolla, MK, Wang, Q, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Becher, H, Brenner, H, Canzian, F, Carey, LA, Consortium, C, Czene, K, Eliassen, AH, Eriksson, M, Evans, DG, Figueroa, JD, Fritschi, L, Gabrielson, M, Giles, GG, Guenel, P, Hadjisavvas, A, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Huesing, A, Kaaks, R, Kosma, V-M, Koutros, S, Kraft, P, Lacey, J, Le Marchand, L, Lissowska, J, Loizidou, MA, Mannermaa, A, Maurer, T, Murphy, RA, Olshan, AF, Olsson, H, Patel, A, Perou, CM, Rennert, G, Shibli, R, Shu, X-O, Southey, MC, Stone, J, Tamimi, RM, Teras, LR, Troester, MA, Truong, T, Vachon, CM, Wang, SS, Wolk, A, Wu, AH, Yang, XR, Zheng, W, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Chatterjee, N, Schmidt, MK, Garcia-Closas, M, and Chang-Claude, J

Abstract

BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all

Published
2022

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

Author

Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Lynch, BM, Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, and Lynch, BM

Abstract

OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer r

Published
2022

50. 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

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