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1. Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses

Author

Papadimitriou, N, Qu, C, Harrison, TA, Bever, AM, Martin, RM, Tsilidis, KK, Newcomb, PA, Thibadeau, SN, Newton, CC, Um, CY, Obon-Santacana, M, Moreno, V, Brenner, H, Mandic, M, Chang-Claude, J, Hoffmeister, M, Pellatt, AJ, Schoen, RE, Harlid, S, Ogino, S, Ugai, T, Buchanan, DD, Lynch, BM, Gruber, SB, Cao, Y, Hsu, L, Huyghe, JR, Lin, Y, Steinfelder, RS, Sun, W, Van Guelpen, B, Zaidi, SH, Toland, AE, Berndt, SI, Huang, W-Y, Aglago, EK, Drew, DA, French, AJ, Georgeson, P, Giannakis, M, Hullar, M, Nowak, JA, Thomas, CE, LeMarchand, L, Cheng, I, Gallinger, S, Jenkins, MA, Gunter, MJ, Campbell, PT, Peters, U, Song, M, Phipps, AI, Murphya, N, Papadimitriou, N, Qu, C, Harrison, TA, Bever, AM, Martin, RM, Tsilidis, KK, Newcomb, PA, Thibadeau, SN, Newton, CC, Um, CY, Obon-Santacana, M, Moreno, V, Brenner, H, Mandic, M, Chang-Claude, J, Hoffmeister, M, Pellatt, AJ, Schoen, RE, Harlid, S, Ogino, S, Ugai, T, Buchanan, DD, Lynch, BM, Gruber, SB, Cao, Y, Hsu, L, Huyghe, JR, Lin, Y, Steinfelder, RS, Sun, W, Van Guelpen, B, Zaidi, SH, Toland, AE, Berndt, SI, Huang, W-Y, Aglago, EK, Drew, DA, French, AJ, Georgeson, P, Giannakis, M, Hullar, M, Nowak, JA, Thomas, CE, LeMarchand, L, Cheng, I, Gallinger, S, Jenkins, MA, Gunter, MJ, Campbell, PT, Peters, U, Song, M, Phipps, AI, and Murphya, N

Abstract

BACKGROUND: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. METHODS: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). FINDINGS: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10-5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10-5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). INTERPRETATION: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). FUNDING: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, Americ

Published
2024

2. Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk

Author

Tian, Y, Lin, Y, Qu, C, Arndt, V, Baurley, JW, Berndt, SI, Bien, SA, Bishop, DT, Brenner, H, Buchanan, DD, Budiarto, A, Campbell, PT, Carreras-Torres, R, Casey, G, Chan, AT, Chen, R, Chen, X, Conti, DV, Diez-Obrero, V, Dimou, N, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gunter, MJ, Harlid, S, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Joshi, AD, Keku, TO, Kawaguchi, E, Kim, AE, Kundaje, A, Larsson, SC, Marchand, LL, Lewinger, JP, Li, L, Moreno, V, Morrison, J, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pardamean, B, Pellatt, AJ, Peoples, AR, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Ruiz-Narvaez, EA, Sakoda, LC, Schoen, RE, Shcherbina, A, Stern, MC, Su, Y-R, Thibodeau, SN, Thomas, DC, Tsilidis, KK, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Peters, U, Gauderman, WJ, Hsu, L, Chang-Claude, J, Tian, Y, Lin, Y, Qu, C, Arndt, V, Baurley, JW, Berndt, SI, Bien, SA, Bishop, DT, Brenner, H, Buchanan, DD, Budiarto, A, Campbell, PT, Carreras-Torres, R, Casey, G, Chan, AT, Chen, R, Chen, X, Conti, DV, Diez-Obrero, V, Dimou, N, Drew, DA, Figueiredo, JC, Gallinger, S, Giles, GG, Gruber, SB, Gunter, MJ, Harlid, S, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jenkins, MA, Jordahl, KM, Joshi, AD, Keku, TO, Kawaguchi, E, Kim, AE, Kundaje, A, Larsson, SC, Marchand, LL, Lewinger, JP, Li, L, Moreno, V, Morrison, J, Murphy, N, Nan, H, Nassir, R, Newcomb, PA, Obon-Santacana, M, Ogino, S, Ose, J, Pardamean, B, Pellatt, AJ, Peoples, AR, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Ruiz-Narvaez, EA, Sakoda, LC, Schoen, RE, Shcherbina, A, Stern, MC, Su, Y-R, Thibodeau, SN, Thomas, DC, Tsilidis, KK, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Peters, U, Gauderman, WJ, Hsu, L, and Chang-Claude, J

Abstract

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Published
2024

3. 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

4. Body mass index and molecular subtypes of colorectal cancer.

Author

Murphy, N, Newton, CC, Song, M, Papadimitriou, N, Hoffmeister, M, Phipps, AI, Harrison, TA, Newcomb, PA, Aglago, EK, Berndt, SI, Brenner, H, Buchanan, DD, Cao, Y, Chan, AT, Chen, X, Cheng, I, Chang-Claude, J, Dimou, N, Drew, D, Farris, AB, French, AJ, Gallinger, S, Georgeson, P, Giannakis, M, Giles, GG, Gruber, SB, Harlid, S, Hsu, L, Huang, W-Y, Jenkins, MA, Laskar, RS, Le Marchand, L, Limburg, P, Lin, Y, Mandic, M, Nowak, JA, Obón-Santacana, M, Ogino, S, Qu, C, Sakoda, LC, Schoen, RE, Southey, MC, Stadler, ZK, Steinfelder, RS, Sun, W, Thibodeau, SN, Toland, AE, Trinh, QM, Tsilidis, KK, Ugai, T, Van Guelpen, B, Wang, X, Woods, MO, Zaidi, SH, Gunter, MJ, Peters, U, Campbell, PT, Murphy, N, Newton, CC, Song, M, Papadimitriou, N, Hoffmeister, M, Phipps, AI, Harrison, TA, Newcomb, PA, Aglago, EK, Berndt, SI, Brenner, H, Buchanan, DD, Cao, Y, Chan, AT, Chen, X, Cheng, I, Chang-Claude, J, Dimou, N, Drew, D, Farris, AB, French, AJ, Gallinger, S, Georgeson, P, Giannakis, M, Giles, GG, Gruber, SB, Harlid, S, Hsu, L, Huang, W-Y, Jenkins, MA, Laskar, RS, Le Marchand, L, Limburg, P, Lin, Y, Mandic, M, Nowak, JA, Obón-Santacana, M, Ogino, S, Qu, C, Sakoda, LC, Schoen, RE, Southey, MC, Stadler, ZK, Steinfelder, RS, Sun, W, Thibodeau, SN, Toland, AE, Trinh, QM, Tsilidis, KK, Ugai, T, Van Guelpen, B, Wang, X, Woods, MO, Zaidi, SH, Gunter, MJ, Peters, U, and Campbell, PT

Abstract

BACKGROUND: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. METHODS: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. RESULTS: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control). CONCLUSIONS: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.

Published
2023

5. 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

7. Diabetes mellitus in relation to colorectal tumor molecular subtypes: A pooled analysis of more than 9000 cases

Author

Harlid, S, Van Guelpen, B, Qu, C, Gylling, B, Aglago, EK, Amitay, EL, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gunter, MJ, Hoffmeister, M, Hsu, L, Jenkins, MA, Lin, Y, Moreno, V, Murphy, N, Newcomb, PA, Newton, CC, Nowak, JA, Obon-Santacana, M, Ogino, S, Potter, JD, Song, M, Steinfelder, RS, Sun, W, Thibodeau, SN, Toland, AE, Ugai, T, Um, CY, Woods, MO, Phipps, A, Harrison, T, Peters, U, Harlid, S, Van Guelpen, B, Qu, C, Gylling, B, Aglago, EK, Amitay, EL, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gunter, MJ, Hoffmeister, M, Hsu, L, Jenkins, MA, Lin, Y, Moreno, V, Murphy, N, Newcomb, PA, Newton, CC, Nowak, JA, Obon-Santacana, M, Ogino, S, Potter, JD, Song, M, Steinfelder, RS, Sun, W, Thibodeau, SN, Toland, AE, Ugai, T, Um, CY, Woods, MO, Phipps, A, Harrison, T, and Peters, U

Abstract

Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj : 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj : 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.

Published
2022

8. 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

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

Author

Tian, Y, Kim, AE, Bien, SA, Lin, Y, Qu, C, Harrison, TA, Carreras-Torres, R, Diez-Obrero, V, Dimou, N, Drew, DA, Hidaka, A, Huyghe, JR, Jordahl, KM, Morrison, J, Murphy, N, Obon-Santacana, M, Ulrich, CM, Ose, J, Peoples, AR, Ruiz-Narvaez, EA, Shcherbina, A, Stern, MC, Su, Y-R, van Duijnhoven, FJB, Arndt, V, Baurley, JW, Berndt, S, Bishop, DT, Brenner, H, Buchanan, DD, Chan, AT, Figueiredo, JC, Gallinger, S, Gruber, SB, Harlid, S, Hoffmeister, M, Jenkins, MA, Joshi, AD, Keku, TO, Larsson, SC, Le Marchand, L, Li, L, Giles, GG, Milne, RL, Nan, H, Nassir, R, Ogino, S, Budiarto, A, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Sakoda, LC, Schoen, RE, Slattery, ML, Thibodeau, SN, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Casey, G, Conti, D, Gunter, MJ, Kundaje, A, Lewinger, JP, Moreno, V, Newcomb, PA, Pardamean, B, Thomas, DC, Tsilidis, KK, Peters, U, Gauderman, WJ, Hsu, L, Chang-Claude, J, Tian, Y, Kim, AE, Bien, SA, Lin, Y, Qu, C, Harrison, TA, Carreras-Torres, R, Diez-Obrero, V, Dimou, N, Drew, DA, Hidaka, A, Huyghe, JR, Jordahl, KM, Morrison, J, Murphy, N, Obon-Santacana, M, Ulrich, CM, Ose, J, Peoples, AR, Ruiz-Narvaez, EA, Shcherbina, A, Stern, MC, Su, Y-R, van Duijnhoven, FJB, Arndt, V, Baurley, JW, Berndt, S, Bishop, DT, Brenner, H, Buchanan, DD, Chan, AT, Figueiredo, JC, Gallinger, S, Gruber, SB, Harlid, S, Hoffmeister, M, Jenkins, MA, Joshi, AD, Keku, TO, Larsson, SC, Le Marchand, L, Li, L, Giles, GG, Milne, RL, Nan, H, Nassir, R, Ogino, S, Budiarto, A, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Sakoda, LC, Schoen, RE, Slattery, ML, Thibodeau, SN, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Casey, G, Conti, D, Gunter, MJ, Kundaje, A, Lewinger, JP, Moreno, V, Newcomb, PA, Pardamean, B, Thomas, DC, Tsilidis, KK, Peters, U, Gauderman, WJ, Hsu, L, and Chang-Claude, J

Abstract

BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

Published
2022

10. A longitudinal evaluation of alcohol intake throughout adulthood and colorectal cancer risk

Author

Mayen, A, Viallon, V, Botteri, E, Proust-Lima, C, Bagnardi, V, Batista, V, Cross, A, Laouali, N, Macdonald, C, Severi, G, Katzke, V, Bergmann, M, Schulze, M, Tjonneland, A, Eriksen, A, Dahm, C, Antoniussen, C, Jakszyn, P, Sanchez, M, Amiano, P, Colorado-Yohar, S, Ardanaz, E, Travis, R, Palli, D, Sabina, S, Tumino, R, Ricceri, F, Panico, S, Bueno-de-Mesquita, B, Derksen, J, Sonestedt, E, Winkvist, A, Harlid, S, Braaten, T, Gram, I, Lukic, M, Jenab, M, Riboli, E, Freisling, H, Weiderpass, E, Gunter, M, Ferrari, P, Mayen, A, Viallon, V, Botteri, E, Proust-Lima, C, Bagnardi, V, Batista, V, Cross, A, Laouali, N, Macdonald, C, Severi, G, Katzke, V, Bergmann, M, Schulze, M, Tjonneland, A, Eriksen, A, Dahm, C, Antoniussen, C, Jakszyn, P, Sanchez, M, Amiano, P, Colorado-Yohar, S, Ardanaz, E, Travis, R, Palli, D, Sabina, S, Tumino, R, Ricceri, F, Panico, S, Bueno-de-Mesquita, B, Derksen, J, Sonestedt, E, Winkvist, A, Harlid, S, Braaten, T, Gram, I, Lukic, M, Jenab, M, Riboli, E, Freisling, H, Weiderpass, E, Gunter, M, and Ferrari, P

Abstract

Background: Alcohol intake is an established risk factor for colorectal cancer (CRC); however, there is limited knowledge on whether changing alcohol drinking habits during adulthood modifies CRC risk. Objective: Leveraging longitudinal exposure assessments on alcohol intake at different ages, we examined the relationship between change in alcohol intake and subsequent CRC risk. Methods: Within the European Prospective Investigation into Cancer and Nutrition, changes in alcohol intake comparing follow-up with baseline assessments were investigated in relation to CRC risk. The analysis included 191,180, participants and 1530 incident CRC cases, with exclusion of the first three years of follow-up to minimize reverse causation. Trajectory profiles of alcohol intake, assessed at ages 20, 30, 40, 50 years, at baseline and during follow-up, were estimated using latent class mixed models and related to CRC risk, including 407,605 participants and 5,008 incident CRC cases. Results: Mean age at baseline was 50.2 years and the follow-up assessment occurred on average 7.1 years later. Compared to stable intake, a 12 g/day increase in alcohol intake during follow-up was positively associated with CRC risk (HR = 1.15, 95%CI 1.04, 1.25), while a 12 g/day reduction was inversely associated with CRC risk (HR = 0.86, 95%CI 0.78, 0.95). Trajectory analysis showed that compared to low alcohol intake, men who increased their alcohol intake from early- to mid- and late-adulthood by up to 30 g/day on average had significantly increased CRC risk (HR = 1.24; 95%CI 1.08, 1.42), while no associations were observed in women. Results were consistent by anatomical subsite. Conclusions: Increasing alcohol intake during mid-to-late adulthood raised CRC risk, while reduction lowered risk.

Published
2022

11. Associations between dietary amino acid intakes and blood concentration levels

Author

Iguacel, I., Perez-Cornago, A., Van Puyvelde, H., Travis, R., Stepien, M., Scalbert, A., Casagrande, C., Weiderpass, E., Riboli, E., Schulze, M.B., Skeie, G., Bodén, S., Boeing, H., Cross, A.J., Harlid, S., Jensen, T.E., Huerta, J.M., Katzke, V., Kühn, T., Lujan-Barroso, L., Masala, G., Rodriguez-Barranco, M., Rostgaard-Hansen, A.L., van der Schouw, Y.T., Vermeulen, R., Tagliabue, G., Tjønneland, A., Trevisan, M., Ferrari, P., Gunter, M.J., Huybrechts, I., IRAS OH Epidemiology Chemical Agents, and dIRAS RA-2

Subjects
Dietary questionnaire, Nutrition and Dietetics, Blood levels, Dietary intake, Amino acids, Critical Care and Intensive Care Medicine, 24-H dietary recall
Abstract

Background and aims: Emerging evidence suggests a role of amino acids (AAs) in the development of various diseases including renal failure, liver cirrhosis, diabetes and cancer. However, mechanistic pathways and the effects of dietary AA intakes on circulating levels and disease outcomes are unclear. We aimed to compare protein and AA intakes, with their respective blood concentrations in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: Dietary protein and AA intakes were assessed via the EPIC dietary questionnaires (DQ) and 24-h dietary recalls (24-HDR). A subsample of 3768 EPIC participants who were free of cancer had blood AA concentrations measured. To investigate how circulating levels relate to their respective intakes, dietary AA intake was examined in quintiles and ANOVA tests were run. Pearson correlations were examined for continous associations between intakes and blood concentrations. Results: Dietary AA intakes (assessed with the DQ) and blood AA concentrations were not strongly correlated (−0.15 ≤ r ≤ 0.17) and the direction of the correlations depended on AA class: weak positive correlations were found for most essential AAs (isoleucine, leucine, lysine, methionine, threonine, tryptophan, and valine) and conditionally essential AAs (arginine and tyrosine), while negative associations were found for non-essential AAs. Similar results were found when using the 24-HDR. When conducting ANOVA tests for essential AAs, higher intake quintiles were linked to higher blood AA concentrations, except for histidine and phenylalanine. For non-essential AAs and glycine, an inverse relationship was observed. Conditionally-essential AAs showed mixed results. Conclusions: Weak positive correlations and dose responses were found between most essential and conditionally essential AA intakes, and blood concentrations, but not for the non-essential AAs. These results suggest that intake of dietary AA might be related to physiological AA status, particularly for the essential AAs. However, these results should be further evaluated and confirmed in large-scale prospective studies.

Published
2021

12. Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study

Author

Stepien, M., Keski-Rahkonen, P., Kiss, A., Robinot, N., Duarte-Salles, T., Murphy, N., Perlemuter, G., Viallon, V., Tjønneland, A., Rostgaard-Hansen, A.L., Dahm, C.C., Overvad, K., Boutron-Ruault, M.-C., Mancini, F.R., Mahamat-Saleh, Y., Aleksandrova, K., Kaaks, R., Kühn, T., Trichopoulou, A., Karakatsani, A., Panico, S., Tumino, R., Palli, D., Tagliabue, G., Naccarati, A., Vermeulen, R.C.H., Bueno-de-Mesquita, H.B., Weiderpass, E., Skeie, G., Ramón Quirós, J., Ardanaz, E., Mokoroa, O., Sala, N., Sánchez, M.-J., Huerta, J.M., Winkvist, A., Harlid, S., Ohlsson, B., Sjöberg, K., Wareham, N., Khaw, K.-T., Ferrari, P., Rothwell, J.A., Gunter, M., Riboli, E., Scalbert, A., Jenab, M., IRAS OH Epidemiology Chemical Agents, and dIRAS RA-2

Subjects
untargeted metabolomics, Cancer Research, prospective observational cohort, Oncology, hepatocellular carcinoma
Abstract

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

Published
2021

13. Development and validation of a lifestyle-based model for colorectal cancer risk prediction: the LiFeCRC score

Author

Aleksandrova, K. Reichmann, R. Kaaks, R. Jenab, M. Bueno-de-Mesquita, H.B. Dahm, C.C. Eriksen, A.K. Tjønneland, A. Artaud, F. Boutron-Ruault, M.-C. Severi, G. Hüsing, A. Trichopoulou, A. Karakatsani, A. Peppa, E. Panico, S. Masala, G. Grioni, S. Sacerdote, C. Tumino, R. Elias, S.G. May, A.M. Borch, K.B. Sandanger, T.M. Skeie, G. Sánchez, M.-J. Huerta, J.M. Sala, N. Gurrea, A.B. Quirós, J.R. Amiano, P. Berntsson, J. Drake, I. van Guelpen, B. Harlid, S. Key, T. Weiderpass, E. Aglago, E.K. Cross, A.J. Tsilidis, K.K. Riboli, E. Gunter, M.J.

Abstract

Background: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population. Methods: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992–2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed. Results: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell’s C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data led to improved model performance overall (continuous net reclassification improvement = 0.307 (95% CI 0.264–0.352)), and especially for young individuals below 45 years (continuous net reclassification improvement = 0.364 (95% CI 0.084–0.575)). Conclusions: LiFeCRC score based on age and lifestyle data accurately identifies individuals at risk for incident colorectal cancer in European populations and could contribute to improved prevention through motivating lifestyle change at an individual level. © 2020, The Author(s).

Published
2021

14. Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study

Author

Stepien, M. Keski-Rahkonen, P. Kiss, A. Robinot, N. Duarte-Salles, T. Murphy, N. Perlemuter, G. Viallon, V. Tjønneland, A. Rostgaard-Hansen, A.L. Dahm, C.C. Overvad, K. Boutron-Ruault, M.-C. Mancini, F.R. Mahamat-Saleh, Y. Aleksandrova, K. Kaaks, R. Kühn, T. Trichopoulou, A. Karakatsani, A. Panico, S. Tumino, R. Palli, D. Tagliabue, G. Naccarati, A. Vermeulen, R.C.H. Bueno-de-Mesquita, H.B. Weiderpass, E. Skeie, G. Ramón Quirós, J. Ardanaz, E. Mokoroa, O. Sala, N. Sánchez, M.-J. Huerta, J.M. Winkvist, A. Harlid, S. Ohlsson, B. Sjöberg, K. Schmidt, J.A. Wareham, N. Khaw, K.-T. Ferrari, P. Rothwell, J.A. Gunter, M. Riboli, E. Scalbert, A. Jenab, M.

Subjects
digestive system diseases
Abstract

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development. © 2020 UICC

Published
2021

15. Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Author

Hampe J., Zuber V., Cross A.J., Perez-Cornago A., Hunter D.J., van Duijnhoven F.J.B., Albanes D., Arndt V., Berndt S.I., Bezieau S., Bishop D.T., Boehm J., Brenner H., Burnett-Hartman A., Campbell P.T., Casey G., Castellvi-Bel S., Chan A.T., Chang-Claude J., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Giles G.G., Goodman P.J., Gsur A., Markozannes G., Hampel H., Hoffmeister M., Jenkins M.A., Keku T.O., Kweon S.-S., Larsson S.C., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., Milne R.L., Moreno V., Nan H., Nassir R., Newcomb P.A., Offit K., Pharoah P.D.P., Platz E.A., Potter J.D., Qi L., Rennert G., Sakoda L.C., Schafmayer C., Slattery M.L., Snetselaar L., Schenk J., Thibodeau S.N., Ulrich C.M., Van Guelpen B., Harlid S., Visvanathan K., Vodickova L., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Zheng W., Bueno-de-Mesquita B., Boutron-Ruault M.-C., Hughes D.J., Jakszyn P., Kuhn T., Palli D., Riboli E., Giovannucci E.L., Banbury B.L., Gruber S.B., Peters U., Gunter M.J., Tsilidis K.K., Papadimitriou N., Dimou N., Gill D., Lewis S.J., Martin R.M., Murphy N., Burrows K., Lopez D.S., Key T.J., Travis R.C., Hampe J., Zuber V., Cross A.J., Perez-Cornago A., Hunter D.J., van Duijnhoven F.J.B., Albanes D., Arndt V., Berndt S.I., Bezieau S., Bishop D.T., Boehm J., Brenner H., Burnett-Hartman A., Campbell P.T., Casey G., Castellvi-Bel S., Chan A.T., Chang-Claude J., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Giles G.G., Goodman P.J., Gsur A., Markozannes G., Hampel H., Hoffmeister M., Jenkins M.A., Keku T.O., Kweon S.-S., Larsson S.C., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., Milne R.L., Moreno V., Nan H., Nassir R., Newcomb P.A., Offit K., Pharoah P.D.P., Platz E.A., Potter J.D., Qi L., Rennert G., Sakoda L.C., Schafmayer C., Slattery M.L., Snetselaar L., Schenk J., Thibodeau S.N., Ulrich C.M., Van Guelpen B., Harlid S., Visvanathan K., Vodickova L., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Zheng W., Bueno-de-Mesquita B., Boutron-Ruault M.-C., Hughes D.J., Jakszyn P., Kuhn T., Palli D., Riboli E., Giovannucci E.L., Banbury B.L., Gruber S.B., Peters U., Gunter M.J., Tsilidis K.K., Papadimitriou N., Dimou N., Gill D., Lewis S.J., Martin R.M., Murphy N., Burrows K., Lopez D.S., Key T.J., and Travis R.C.

Abstract

BACKGROUND: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. OBJECTIVE(S): To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHOD(S): Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. RESULT(S): Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value=0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value=0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value=0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of beta-caroten

Published
2021

16. Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: A Mendelian randomization study.

Author

Tsilidis K.K., Papadimitriou N., Dimou N., Gill D., Lewis S.J., Martin R.M., Murphy N., Markozannes G., Zuber V., Cross A.J., Burrows K., Lopez D.S., Key T.J., Travis R.C., Perez-Cornago A., Hunter D.J., Van Duijnhoven F.J.B., Albanes D., Arndt V., Berndt S.I., Bezieau S., Bishop D.T., Boehm J., Brenner H., Burnett-Hartman A., Campbell P.T., Casey G., Castellvi-Bel S., Chan A.T., Chang-Claude J., De La Chapelle A., Figueiredo J.C., Gallinger S.J., Giles G.G., Goodman P.J., Gsur A., Hampe J., Hampel H., Hoffmeister M., Jenkins M.A., Keku T.O., Kweon S.-S., Larsson S.C., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., Milne R.L., Moreno V., Nan H., Nassir R., Newcomb P.A., Offit K., Pharoah P.D.P., Platz E.A., Potter J.D., Qi L., Rennert G., Sakoda L.C., Schafmayer C., Slattery M.L., Snetselaar L., Schenk J., Thibodeau S.N., Ulrich C.M., Van Guelpen B., Harlid S., Visvanathan K., Vodickova L., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Zheng W., Bueno-De-Mesquita B., Boutron-Ruault M.-C., Hughes D.J., Jakszyn P., Kuhn T., Palli D., Riboli E., Giovannucci E.L., Banbury B.L., Gruber S.B., Peters U., Gunter M.J., Tsilidis K.K., Papadimitriou N., Dimou N., Gill D., Lewis S.J., Martin R.M., Murphy N., Markozannes G., Zuber V., Cross A.J., Burrows K., Lopez D.S., Key T.J., Travis R.C., Perez-Cornago A., Hunter D.J., Van Duijnhoven F.J.B., Albanes D., Arndt V., Berndt S.I., Bezieau S., Bishop D.T., Boehm J., Brenner H., Burnett-Hartman A., Campbell P.T., Casey G., Castellvi-Bel S., Chan A.T., Chang-Claude J., De La Chapelle A., Figueiredo J.C., Gallinger S.J., Giles G.G., Goodman P.J., Gsur A., Hampe J., Hampel H., Hoffmeister M., Jenkins M.A., Keku T.O., Kweon S.-S., Larsson S.C., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., Milne R.L., Moreno V., Nan H., Nassir R., Newcomb P.A., Offit K., Pharoah P.D.P., Platz E.A., Potter J.D., Qi L., Rennert G., Sakoda L.C., Schafmayer C., Slattery M.L., Snetselaar L., Schenk J., Thibodeau S.N., Ulrich C.M., Van Guelpen B., Harlid S., Visvanathan K., Vodickova L., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Zheng W., Bueno-De-Mesquita B., Boutron-Ruault M.-C., Hughes D.J., Jakszyn P., Kuhn T., Palli D., Riboli E., Giovannucci E.L., Banbury B.L., Gruber S.B., Peters U., and Gunter M.J.

Abstract

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. Objective(s): To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). Method(s): Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. Result(s): Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08 95% CI: 1.00, 1.17 P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12 95% CI: 1.03, 1.21 P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98 95% CI: 0.96, 1.00 P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of beta-caroten

Published
2021

17. Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study

Author

IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Stepien, M., Keski-Rahkonen, P., Kiss, A., Robinot, N., Duarte-Salles, T., Murphy, N., Perlemuter, G., Viallon, V., Tjønneland, A., Rostgaard-Hansen, A.L., Dahm, C.C., Overvad, K., Boutron-Ruault, M.-C., Mancini, F.R., Mahamat-Saleh, Y., Aleksandrova, K., Kaaks, R., Kühn, T., Trichopoulou, A., Karakatsani, A., Panico, S., Tumino, R., Palli, D., Tagliabue, G., Naccarati, A., Vermeulen, R.C.H., Bueno-de-Mesquita, H.B., Weiderpass, E., Skeie, G., Ramón Quirós, J., Ardanaz, E., Mokoroa, O., Sala, N., Sánchez, M.-J., Huerta, J.M., Winkvist, A., Harlid, S., Ohlsson, B., Sjöberg, K., Wareham, N., Khaw, K.-T., Ferrari, P., Rothwell, J.A., Gunter, M., Riboli, E., Scalbert, A., Jenab, M., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Stepien, M., Keski-Rahkonen, P., Kiss, A., Robinot, N., Duarte-Salles, T., Murphy, N., Perlemuter, G., Viallon, V., Tjønneland, A., Rostgaard-Hansen, A.L., Dahm, C.C., Overvad, K., Boutron-Ruault, M.-C., Mancini, F.R., Mahamat-Saleh, Y., Aleksandrova, K., Kaaks, R., Kühn, T., Trichopoulou, A., Karakatsani, A., Panico, S., Tumino, R., Palli, D., Tagliabue, G., Naccarati, A., Vermeulen, R.C.H., Bueno-de-Mesquita, H.B., Weiderpass, E., Skeie, G., Ramón Quirós, J., Ardanaz, E., Mokoroa, O., Sala, N., Sánchez, M.-J., Huerta, J.M., Winkvist, A., Harlid, S., Ohlsson, B., Sjöberg, K., Wareham, N., Khaw, K.-T., Ferrari, P., Rothwell, J.A., Gunter, M., Riboli, E., Scalbert, A., and Jenab, M.

Published
2021

18. Associations between dietary amino acid intakes and blood concentration levels

Author

IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Iguacel, I., Perez-Cornago, A., Van Puyvelde, H., Travis, R., Stepien, M., Scalbert, A., Casagrande, C., Weiderpass, E., Riboli, E., Schulze, M.B., Skeie, G., Bodén, S., Boeing, H., Cross, A.J., Harlid, S., Jensen, T.E., Huerta, J.M., Katzke, V., Kühn, T., Lujan-Barroso, L., Masala, G., Rodriguez-Barranco, M., Rostgaard-Hansen, A.L., van der Schouw, Y.T., Vermeulen, R., Tagliabue, G., Tjønneland, A., Trevisan, M., Ferrari, P., Gunter, M.J., Huybrechts, I., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Iguacel, I., Perez-Cornago, A., Van Puyvelde, H., Travis, R., Stepien, M., Scalbert, A., Casagrande, C., Weiderpass, E., Riboli, E., Schulze, M.B., Skeie, G., Bodén, S., Boeing, H., Cross, A.J., Harlid, S., Jensen, T.E., Huerta, J.M., Katzke, V., Kühn, T., Lujan-Barroso, L., Masala, G., Rodriguez-Barranco, M., Rostgaard-Hansen, A.L., van der Schouw, Y.T., Vermeulen, R., Tagliabue, G., Tjønneland, A., Trevisan, M., Ferrari, P., Gunter, M.J., and Huybrechts, I.

Published
2021

19. Development and validation of a lifestyle-based model for colorectal cancer risk prediction: the LiFeCRC score

Author

Aleksandrova, K, Reichmann, R, Kaaks, R, Jenab, M, Bueno-de-Mesquita, HB, Dahm, CC, Eriksen, AK, Tjonneland, A, Artaud, F, Boutron-Ruault, M-C, Severi, G, Husing, A, Trichopoulou, A, Karakatsani, A, Peppa, E, Panico, S, Masala, G, Grioni, S, Sacerdote, C, Tumino, R, Elias, SG, May, AM, Borch, KB, Sandanger, TM, Skeie, G, Sanchez, M-J, Huerta, JM, Sala, N, Gurrea, AB, Quiros, JR, Amiano, P, Berntsson, J, Drake, I, van Guelpen, B, Harlid, S, Key, T, Weiderpass, E, Aglago, EK, Cross, AJ, Tsilidis, KK, Riboli, E, Gunter, MJ, Aleksandrova, K, Reichmann, R, Kaaks, R, Jenab, M, Bueno-de-Mesquita, HB, Dahm, CC, Eriksen, AK, Tjonneland, A, Artaud, F, Boutron-Ruault, M-C, Severi, G, Husing, A, Trichopoulou, A, Karakatsani, A, Peppa, E, Panico, S, Masala, G, Grioni, S, Sacerdote, C, Tumino, R, Elias, SG, May, AM, Borch, KB, Sandanger, TM, Skeie, G, Sanchez, M-J, Huerta, JM, Sala, N, Gurrea, AB, Quiros, JR, Amiano, P, Berntsson, J, Drake, I, van Guelpen, B, Harlid, S, Key, T, Weiderpass, E, Aglago, EK, Cross, AJ, Tsilidis, KK, Riboli, E, and Gunter, MJ

Abstract

BACKGROUND: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population. METHODS: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992-2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed. RESULTS: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell's C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data l

Published
2021

20. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author

Huyghe, JR, Harrison, TA, Bien, SA, Hampel, H, Figueiredo, JC, Schmit, SL, Conti, D, Chen, S, Qu, C, Lin, Y, Barfield, R, Baron, JA, Cross, AJ, Diergaarde, B, Duggan, D, Harlid, S, Imaz, L, Kang, HM, Levine, DM, Perduca, V, Perez-Cornago, A, Sakoda, LC, Schumacher, FR, Slattery, ML, Toland, AE, van Duijnhoven, FJB, Van Guelpen, B, Agudo, A, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Banbury, BL, Bassik, MC, Berndt, S, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Caan, BJ, Campbell, PT, Carr, PR, Castells, A, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Curtis, KR, de la Chapelle, A, Easton, DF, English, DR, Feskens, EJM, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Jenab, M, Jenkins, MA, Joshi, AD, Keku, TO, Kooperberg, C, Kuhn, T, Kury, S, Le Marchand, L, Lejbkowicz, F, Li, C, Li, L, Lieb, W, Lindblom, A, Lindor, NM, Mannisto, S, Markowitz, SD, Milne, RL, Moreno, L, Murphy, N, Nassir, R, Offit, K, Ogino, S, Panico, S, Parfrey, PS, Pearlman, R, Pharoah, PDP, Phipps, A, Platz, EA, Potter, JD, Prentice, RL, Qi, L, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Schafmayer, C, Schoen, RE, Seminara, D, Song, M, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Ulrich, CM, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Nickerson, DA, Scacheri, PC, Kundaje, A, Casey, G, Gruber, SB, Hsu, L, Moreno, V, Hayes, RB, Newcomb, PA, Peters, U, Huyghe, JR, Harrison, TA, Bien, SA, Hampel, H, Figueiredo, JC, Schmit, SL, Conti, D, Chen, S, Qu, C, Lin, Y, Barfield, R, Baron, JA, Cross, AJ, Diergaarde, B, Duggan, D, Harlid, S, Imaz, L, Kang, HM, Levine, DM, Perduca, V, Perez-Cornago, A, Sakoda, LC, Schumacher, FR, Slattery, ML, Toland, AE, van Duijnhoven, FJB, Van Guelpen, B, Agudo, A, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Banbury, BL, Bassik, MC, Berndt, S, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Caan, BJ, Campbell, PT, Carr, PR, Castells, A, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Curtis, KR, de la Chapelle, A, Easton, DF, English, DR, Feskens, EJM, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Jenab, M, Jenkins, MA, Joshi, AD, Keku, TO, Kooperberg, C, Kuhn, T, Kury, S, Le Marchand, L, Lejbkowicz, F, Li, C, Li, L, Lieb, W, Lindblom, A, Lindor, NM, Mannisto, S, Markowitz, SD, Milne, RL, Moreno, L, Murphy, N, Nassir, R, Offit, K, Ogino, S, Panico, S, Parfrey, PS, Pearlman, R, Pharoah, PDP, Phipps, A, Platz, EA, Potter, JD, Prentice, RL, Qi, L, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Schafmayer, C, Schoen, RE, Seminara, D, Song, M, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Ulrich, CM, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Nickerson, DA, Scacheri, PC, Kundaje, A, Casey, G, Gruber, SB, Hsu, L, Moreno, V, Hayes, RB, Newcomb, PA, and Peters, U

Abstract

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Published
2021

21. Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition

Author

Christakoudi, S. Kakourou, A. Markozannes, G. Tzoulaki, I. Weiderpass, E. Brennan, P. Gunter, M. Dahm, C.C. Overvad, K. Olsen, A. Tjønneland, A. Boutron-Ruault, M.-C. Madika, A.-L. Severi, G. Katzke, V. Kühn, T. Bergmann, M.M. Boeing, H. Karakatsani, A. Martimianaki, G. Thriskos, P. Masala, G. Sieri, S. Panico, S. Tumino, R. Ricceri, F. Agudo, A. Redondo-Sánchez, D. Colorado-Yohar, S.M. Mokoroa, O. Melander, O. Stocks, T. Häggström, C. Harlid, S. Bueno-de-Mesquita, B. van Gils, C.H. Vermeulen, R.C.H. Khaw, K.-T. Wareham, N.J. Tong, T.Y.N. Freisling, H. Johansson, M. Lennon, H. Aune, D. Riboli, E. Trichopoulos, D. Trichopoulou, A. Tsilidis, K.K.

Abstract

Several studies have reported associations of hypertension with cancer, but not all results were conclusive. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with the development of incident cancer at all anatomical sites in the European Prospective Investigation into Cancer and Nutrition (EPIC). Hazard ratios (HRs) (95% confidence intervals) were estimated using multivariable Cox proportional hazards models, stratified by EPIC-participating center and age at recruitment, and adjusted for sex, education, smoking, body mass index, physical activity, diabetes and dietary (in women also reproductive) factors. The study included 307,318 men and women, with an average follow-up of 13.7 (standard deviation 4.4) years and 39,298 incident cancers. We confirmed the expected positive association with renal cell carcinoma: HR = 1.12 (1.08–1.17) per 10 mm Hg higher SBP and HR = 1.23 (1.14–1.32) for DBP. We additionally found positive associations for esophageal squamous cell carcinoma (SCC): HR = 1.16 (1.07–1.26) (SBP), HR = 1.31 (1.13–1.51) (DBP), weaker for head and neck cancers: HR = 1.08 (1.04–1.12) (SBP), HR = 1.09 (1.01–1.17) (DBP) and, similarly, for skin SCC, colon cancer, postmenopausal breast cancer and uterine adenocarcinoma (AC), but not for esophageal AC, lung SCC, lung AC or uterine endometroid cancer. We observed weak inverse associations of SBP with cervical SCC: HR = 0.91 (0.82–1.00) and lymphomas: HR = 0.97 (0.93–1.00). There were no consistent associations with cancers in other locations. Our results are largely compatible with published studies and support weak associations of blood pressure with cancers in specific locations and morphologies. © 2019 UICC

Published
2020

22. Antibody responses to helicobacter pylori and risk of developing colorectal cancer in a European cohort

Author

Butt, J. Jenab, M. Pawlita, M. Tjønneland, A. Kyrø, C. Boutron-Ruault, M.-C. Carbonnel, F. Dong, C. Kaaks, R. Kuhn, T. Boeing, H. Schulze, M.B. Trichopoulou, A. Karakatsani, A. Vecchia, C.L. Palli, D. Agnoli, C. Tumino, R. Sacerdote, C. Panico, S. Bueno-De-Mesquita, B. Vermeulen, R. Gram, I.T. Weiderpass, E. Borch, K.B. Quiros, J.R. Agudo, A. Rodríguez-Barranco, M. Santiuste, C. Ardanaz, E. van Guelpen, B. Harlid, S. Imaz, L. Perez-Cornago, A. Gunter, M.J. Zouiouich, S. Park, J.Y. Riboli, E. Cross, A.J. Heath, A.K. Waterboer, T. Hughes, D.J.

Subjects
bacterial infections and mycoses
Abstract

Background: While Helicobacter pylori (H. pylori) is the major cause of gastric cancer, it has also been suggested to be involved in colorectal cancer development. However, prospective studies addressing H. pylori and colorectal cancer are sparse and inconclusive. We assessed the association of antibody responses to H. pylori proteins with colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: We applied H. pylori multiplex serology to measure antibody responses to 13 H. pylori proteins in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls nested within the EPIC study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable conditional logistic regression to estimate the association of H. pylori overall and protein-specific seropositivity with odds of developing colorectal cancer. Results: Fifty-one percent of colorectal cancer cases were H. pylori seropositive compared with 44% of controls, resulting in an OR of 1.36 (95% CI, 1.00–1.85). Among the 13 individual H. pylori proteins, the association was driven mostly by seropositivity to Helicobacter cysteine-rich protein C (HcpC; OR: 1.66; 95% CI, 1.19–2.30) and Vacuolating cytotoxin A (VacA) (OR: 1.34; 95% CI, 0.99–1.82), the latter being nonstatistically significant only in the fully adjusted model. Conclusions: In this prospective multicenter European study, antibody responses to H. pylori proteins, specifically HcpC and VacA, were associated with an increased risk of developing colorectal cancer. Impact: Biological mechanisms for a potential causal role of H. pylori in colorectal carcinogenesis need to be elucidated, and subsequently whether H. pylori eradication may decrease colorectal cancer incidence. © 2020 American Association for Cancer Research.

Published
2020

23. Antibody responses to helicobacter pylori and risk of developing colorectal cancer in a European cohort

Author

Butt, J., Jenab, M., Pawlita, M., Tjønneland, A., Kyrø, C., Boutron-Ruault, M.-C., Carbonnel, F., Dong, C., Kaaks, R., Kuhn, T., Boeing, H., Schulze, M.B., Trichopoulou, A., Karakatsani, A., Vecchia, C.L., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Panico, S., Bueno-De-Mesquita, B., Vermeulen, R., Gram, I.T., Weiderpass, E., Borch, K.B., Quiros, J.R., Agudo, A., Rodríguez-Barranco, M., Santiuste, C., Ardanaz, E., van Guelpen, B., Harlid, S., Imaz, L., Perez-Cornago, A., Gunter, M.J., Zouiouich, S., Riboli, E., Cross, A.J., Heath, A.K., Waterboer, T., Hughes, D.J., Butt, J., Jenab, M., Pawlita, M., Tjønneland, A., Kyrø, C., Boutron-Ruault, M.-C., Carbonnel, F., Dong, C., Kaaks, R., Kuhn, T., Boeing, H., Schulze, M.B., Trichopoulou, A., Karakatsani, A., Vecchia, C.L., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Panico, S., Bueno-De-Mesquita, B., Vermeulen, R., Gram, I.T., Weiderpass, E., Borch, K.B., Quiros, J.R., Agudo, A., Rodríguez-Barranco, M., Santiuste, C., Ardanaz, E., van Guelpen, B., Harlid, S., Imaz, L., Perez-Cornago, A., Gunter, M.J., Zouiouich, S., Riboli, E., Cross, A.J., Heath, A.K., Waterboer, T., and Hughes, D.J.

Abstract

Background: While Helicobacter pylori (H. pylori) is the major cause of gastric cancer, it has also been suggested to be involved in colorectal cancer development. However, prospective studies addressing H. pylori and colorectal cancer are sparse and inconclusive. We assessed the association of antibody responses to H. pylori proteins with colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: We applied H. pylori multiplex serology to measure antibody responses to 13 H. pylori proteins in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls nested within the EPIC study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable conditional logistic regression to estimate the association of H. pylori overall and protein-specific seropositivity with odds of developing colorectal cancer. Results: Fifty-one percent of colorectal cancer cases were H. pylori seropositive compared with 44% of controls, resulting in an OR of 1.36 (95% CI, 1.00–1.85). Among the 13 individual H. pylori proteins, the association was driven mostly by seropositivity to Helicobacter cysteine-rich protein C (HcpC; OR: 1.66; 95% CI, 1.19–2.30) and Vacuolating cytotoxin A (VacA) (OR: 1.34; 95% CI, 0.99–1.82), the latter being nonstatistically significant only in the fully adjusted model. Conclusions: In this prospective multicenter European study, antibody responses to H. pylori proteins, specifically HcpC and VacA, were associated with an increased risk of developing colorectal cancer. Impact: Biological mechanisms for a potential causal role of H. pylori in colorectal carcinogenesis need to be elucidated, and subsequently whether H. pylori eradication may decrease colorectal cancer incidence.

Published
2020

24. Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition

Author

Christakoudi, S., Kakourou, A., Markozannes, G., Tzoulaki, I., Weiderpass, E., Brennan, P., Gunter, M., Dahm, C.C., Overvad, K., Olsen, A., Tjønneland, A., Boutron-Ruault, M.-C., Madika, A.-L., Severi, G., Katzke, V., Kühn, T., Bergmann, M.M., Boeing, H., Karakatsani, A., Martimianaki, G., Thriskos, P., Masala, G., Sieri, S., Panico, S., Tumino, R., Ricceri, F., Agudo, A., Redondo-Sánchez, D., Colorado-Yohar, S.M., Mokoroa, O., Melander, O., Stocks, T., Häggström, C., Harlid, S., Bueno-de-Mesquita, B., van Gils, C.H., Vermeulen, R.C.H., Khaw, K.-T., Wareham, N.J., Tong, T.Y.N., Freisling, H., Johansson, M., Lennon, H., Aune, D., Riboli, E., Trichopoulos, D., Trichopoulou, A., Tsilidis, K.K., Christakoudi, S., Kakourou, A., Markozannes, G., Tzoulaki, I., Weiderpass, E., Brennan, P., Gunter, M., Dahm, C.C., Overvad, K., Olsen, A., Tjønneland, A., Boutron-Ruault, M.-C., Madika, A.-L., Severi, G., Katzke, V., Kühn, T., Bergmann, M.M., Boeing, H., Karakatsani, A., Martimianaki, G., Thriskos, P., Masala, G., Sieri, S., Panico, S., Tumino, R., Ricceri, F., Agudo, A., Redondo-Sánchez, D., Colorado-Yohar, S.M., Mokoroa, O., Melander, O., Stocks, T., Häggström, C., Harlid, S., Bueno-de-Mesquita, B., van Gils, C.H., Vermeulen, R.C.H., Khaw, K.-T., Wareham, N.J., Tong, T.Y.N., Freisling, H., Johansson, M., Lennon, H., Aune, D., Riboli, E., Trichopoulos, D., Trichopoulou, A., and Tsilidis, K.K.

Abstract

Several studies have reported associations of hypertension with cancer, but not all results were conclusive. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with the development of incident cancer at all anatomical sites in the European Prospective Investigation into Cancer and Nutrition (EPIC). Hazard ratios (HRs) (95% confidence intervals) were estimated using multivariable Cox proportional hazards models, stratified by EPIC-participating center and age at recruitment, and adjusted for sex, education, smoking, body mass index, physical activity, diabetes and dietary (in women also reproductive) factors. The study included 307,318 men and women, with an average follow-up of 13.7 (standard deviation 4.4) years and 39,298 incident cancers. We confirmed the expected positive association with renal cell carcinoma: HR = 1.12 (1.08–1.17) per 10 mm Hg higher SBP and HR = 1.23 (1.14–1.32) for DBP. We additionally found positive associations for esophageal squamous cell carcinoma (SCC): HR = 1.16 (1.07–1.26) (SBP), HR = 1.31 (1.13–1.51) (DBP), weaker for head and neck cancers: HR = 1.08 (1.04–1.12) (SBP), HR = 1.09 (1.01–1.17) (DBP) and, similarly, for skin SCC, colon cancer, postmenopausal breast cancer and uterine adenocarcinoma (AC), but not for esophageal AC, lung SCC, lung AC or uterine endometroid cancer. We observed weak inverse associations of SBP with cervical SCC: HR = 0.91 (0.82–1.00) and lymphomas: HR = 0.97 (0.93–1.00). There were no consistent associations with cancers in other locations. Our results are largely compatible with published studies and support weak associations of blood pressure with cancers in specific locations and morphologies.

Published
2020

25. Antibody responses to helicobacter pylori and risk of developing colorectal cancer in a European cohort

Author

IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Butt, J., Jenab, M., Pawlita, M., Tjønneland, A., Kyrø, C., Boutron-Ruault, M.-C., Carbonnel, F., Dong, C., Kaaks, R., Kuhn, T., Boeing, H., Schulze, M.B., Trichopoulou, A., Karakatsani, A., Vecchia, C.L., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Panico, S., Bueno-De-Mesquita, B., Vermeulen, R., Gram, I.T., Weiderpass, E., Borch, K.B., Quiros, J.R., Agudo, A., Rodríguez-Barranco, M., Santiuste, C., Ardanaz, E., van Guelpen, B., Harlid, S., Imaz, L., Perez-Cornago, A., Gunter, M.J., Zouiouich, S., Riboli, E., Cross, A.J., Heath, A.K., Waterboer, T., Hughes, D.J., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Butt, J., Jenab, M., Pawlita, M., Tjønneland, A., Kyrø, C., Boutron-Ruault, M.-C., Carbonnel, F., Dong, C., Kaaks, R., Kuhn, T., Boeing, H., Schulze, M.B., Trichopoulou, A., Karakatsani, A., Vecchia, C.L., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Panico, S., Bueno-De-Mesquita, B., Vermeulen, R., Gram, I.T., Weiderpass, E., Borch, K.B., Quiros, J.R., Agudo, A., Rodríguez-Barranco, M., Santiuste, C., Ardanaz, E., van Guelpen, B., Harlid, S., Imaz, L., Perez-Cornago, A., Gunter, M.J., Zouiouich, S., Riboli, E., Cross, A.J., Heath, A.K., Waterboer, T., and Hughes, D.J.

Published
2020

26. Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition

Author

IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Christakoudi, S., Kakourou, A., Markozannes, G., Tzoulaki, I., Weiderpass, E., Brennan, P., Gunter, M., Dahm, C.C., Overvad, K., Olsen, A., Tjønneland, A., Boutron-Ruault, M.-C., Madika, A.-L., Severi, G., Katzke, V., Kühn, T., Bergmann, M.M., Boeing, H., Karakatsani, A., Martimianaki, G., Thriskos, P., Masala, G., Sieri, S., Panico, S., Tumino, R., Ricceri, F., Agudo, A., Redondo-Sánchez, D., Colorado-Yohar, S.M., Mokoroa, O., Melander, O., Stocks, T., Häggström, C., Harlid, S., Bueno-de-Mesquita, B., van Gils, C.H., Vermeulen, R.C.H., Khaw, K.-T., Wareham, N.J., Tong, T.Y.N., Freisling, H., Johansson, M., Lennon, H., Aune, D., Riboli, E., Trichopoulos, D., Trichopoulou, A., Tsilidis, K.K., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Christakoudi, S., Kakourou, A., Markozannes, G., Tzoulaki, I., Weiderpass, E., Brennan, P., Gunter, M., Dahm, C.C., Overvad, K., Olsen, A., Tjønneland, A., Boutron-Ruault, M.-C., Madika, A.-L., Severi, G., Katzke, V., Kühn, T., Bergmann, M.M., Boeing, H., Karakatsani, A., Martimianaki, G., Thriskos, P., Masala, G., Sieri, S., Panico, S., Tumino, R., Ricceri, F., Agudo, A., Redondo-Sánchez, D., Colorado-Yohar, S.M., Mokoroa, O., Melander, O., Stocks, T., Häggström, C., Harlid, S., Bueno-de-Mesquita, B., van Gils, C.H., Vermeulen, R.C.H., Khaw, K.-T., Wareham, N.J., Tong, T.Y.N., Freisling, H., Johansson, M., Lennon, H., Aune, D., Riboli, E., Trichopoulos, D., Trichopoulou, A., and Tsilidis, K.K.

Published
2020

27. Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer

Author

Archambault, AN, Su, Y-R, Jeon, J, Thomas, M, Lin, Y, Conti, DV, Win, AK, Sakoda, LC, Lansdorp-Vogelaar, I, Peterse, EFP, Zauber, AG, Duggan, D, Holowatyj, AN, Huyghe, JR, Brenner, H, Cotterchio, M, Bezieau, S, Schmit, SL, Edlund, CK, Southey, MC, MacInnis, RJ, Campbell, PT, Chang-Claude, J, Slattery, ML, Chan, AT, Joshi, AD, Song, M, Cao, Y, Woods, MO, White, E, Weinstein, SJ, Ulrich, CM, Hoffmeister, M, Bien, SA, Harrison, TA, Hampe, J, Li, CI, Schafmayer, C, Offit, K, Pharoah, PD, Moreno, V, Lindblom, A, Wolk, A, Wu, AH, Li, L, Gunter, MJ, Gsur, A, Keku, TO, Pearlman, R, Bishop, DT, Castellvi-Bel, S, Moreira, L, Vodicka, P, Kampman, E, Giles, GG, Albanes, D, Baron, JA, Berndt, SI, Brezina, S, Buch, S, Buchanan, DD, Trichopoulou, A, Severi, G, Chirlaque, M-D, Sanchez, M-J, Palli, D, Kuhn, T, Murphy, N, Cross, AJ, Burnett-Hartman, AN, Chanock, SJ, de la Chapelle, A, Easton, DF, Elliott, F, English, DR, Feskens, EJM, FitzGerald, LM, Goodman, PJ, Hopper, JL, Hudson, TJ, Hunter, DJ, Jacobs, EJ, Joshu, CE, Kury, S, Markowitz, SD, Milne, RL, Platz, EA, Rennert, G, Rennert, HS, Schumacher, FR, Sandler, RS, Seminara, D, Tangen, CM, Thibodeau, SN, Toland, AE, van Duijnhoven, FJB, Visvanathan, K, Vodickova, L, Potter, JD, Mannisto, S, Weigl, K, Figueiredo, J, Martin, V, Larsson, SC, Parfrey, PS, Huang, W-Y, Lenz, H-J, Castelao, JE, Gago-Dominguez, M, Munoz-Garzon, V, Mancao, C, Haiman, CA, Wilkens, LR, Siegel, E, Barry, E, Younghusband, B, Van Guelpen, B, Harlid, S, Zeleniuch-Jacquotte, A, Liang, PS, Du, M, Casey, G, Lindor, NM, Le Marchand, L, Gallinger, SJ, Jenkins, MA, Newcomb, PA, Gruber, SB, Schoen, RE, Hampel, H, Corley, DA, Hsu, L, Peters, U, Hayes, RB, Archambault, AN, Su, Y-R, Jeon, J, Thomas, M, Lin, Y, Conti, DV, Win, AK, Sakoda, LC, Lansdorp-Vogelaar, I, Peterse, EFP, Zauber, AG, Duggan, D, Holowatyj, AN, Huyghe, JR, Brenner, H, Cotterchio, M, Bezieau, S, Schmit, SL, Edlund, CK, Southey, MC, MacInnis, RJ, Campbell, PT, Chang-Claude, J, Slattery, ML, Chan, AT, Joshi, AD, Song, M, Cao, Y, Woods, MO, White, E, Weinstein, SJ, Ulrich, CM, Hoffmeister, M, Bien, SA, Harrison, TA, Hampe, J, Li, CI, Schafmayer, C, Offit, K, Pharoah, PD, Moreno, V, Lindblom, A, Wolk, A, Wu, AH, Li, L, Gunter, MJ, Gsur, A, Keku, TO, Pearlman, R, Bishop, DT, Castellvi-Bel, S, Moreira, L, Vodicka, P, Kampman, E, Giles, GG, Albanes, D, Baron, JA, Berndt, SI, Brezina, S, Buch, S, Buchanan, DD, Trichopoulou, A, Severi, G, Chirlaque, M-D, Sanchez, M-J, Palli, D, Kuhn, T, Murphy, N, Cross, AJ, Burnett-Hartman, AN, Chanock, SJ, de la Chapelle, A, Easton, DF, Elliott, F, English, DR, Feskens, EJM, FitzGerald, LM, Goodman, PJ, Hopper, JL, Hudson, TJ, Hunter, DJ, Jacobs, EJ, Joshu, CE, Kury, S, Markowitz, SD, Milne, RL, Platz, EA, Rennert, G, Rennert, HS, Schumacher, FR, Sandler, RS, Seminara, D, Tangen, CM, Thibodeau, SN, Toland, AE, van Duijnhoven, FJB, Visvanathan, K, Vodickova, L, Potter, JD, Mannisto, S, Weigl, K, Figueiredo, J, Martin, V, Larsson, SC, Parfrey, PS, Huang, W-Y, Lenz, H-J, Castelao, JE, Gago-Dominguez, M, Munoz-Garzon, V, Mancao, C, Haiman, CA, Wilkens, LR, Siegel, E, Barry, E, Younghusband, B, Van Guelpen, B, Harlid, S, Zeleniuch-Jacquotte, A, Liang, PS, Du, M, Casey, G, Lindor, NM, Le Marchand, L, Gallinger, SJ, Jenkins, MA, Newcomb, PA, Gruber, SB, Schoen, RE, Hampel, H, Corley, DA, Hsu, L, Peters, U, and Hayes, RB

Abstract

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be mo

Published
2020

28. Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival

Author

Zaidi, SH, Harrison, TA, Phipps, A, Steinfelder, R, Trinh, QM, Qu, C, Banbury, BL, Georgeson, P, Grasso, CS, Giannakis, M, Adams, JB, Alwers, E, Amitay, EL, Barfield, RT, Berndt, S, Borozan, I, Brenner, H, Brezina, S, Buchanan, DD, Cao, Y, Chan, AT, Chang-Claude, J, Connolly, CM, Drew, DA, Farris, AB, Figueiredo, JC, French, AJ, Fuchs, CS, Garraway, LA, Gruber, S, Guinter, MA, Hamilton, SR, Harlid, S, Heisler, LE, Hidaka, A, Hopper, JL, Huang, W-Y, Huyghe, JR, Jenkins, MA, Krzyzanowski, PM, Lemire, M, Lin, Y, Luo, X, Mardis, ER, McPherson, JD, Miller, JK, Moreno, V, Mu, XJ, Nishihara, R, Papadopoulos, N, Pasternack, D, Quist, MJ, Rafikova, A, Reid, EEG, Shinbrot, E, Shirts, BH, Stein, LD, Teney, CD, Timms, L, Um, CY, Van Guelpen, B, Van Tassel, M, Wang, X, Wheeler, DA, Yung, CK, Hsu, L, Ogino, S, Gsur, A, Newcomb, PA, Gallinger, S, Hoffmeister, M, Campbell, PT, Thibodeau, SN, Sun, W, Hudson, TJ, Peters, U, Zaidi, SH, Harrison, TA, Phipps, A, Steinfelder, R, Trinh, QM, Qu, C, Banbury, BL, Georgeson, P, Grasso, CS, Giannakis, M, Adams, JB, Alwers, E, Amitay, EL, Barfield, RT, Berndt, S, Borozan, I, Brenner, H, Brezina, S, Buchanan, DD, Cao, Y, Chan, AT, Chang-Claude, J, Connolly, CM, Drew, DA, Farris, AB, Figueiredo, JC, French, AJ, Fuchs, CS, Garraway, LA, Gruber, S, Guinter, MA, Hamilton, SR, Harlid, S, Heisler, LE, Hidaka, A, Hopper, JL, Huang, W-Y, Huyghe, JR, Jenkins, MA, Krzyzanowski, PM, Lemire, M, Lin, Y, Luo, X, Mardis, ER, McPherson, JD, Miller, JK, Moreno, V, Mu, XJ, Nishihara, R, Papadopoulos, N, Pasternack, D, Quist, MJ, Rafikova, A, Reid, EEG, Shinbrot, E, Shirts, BH, Stein, LD, Teney, CD, Timms, L, Um, CY, Van Guelpen, B, Van Tassel, M, Wang, X, Wheeler, DA, Yung, CK, Hsu, L, Ogino, S, Gsur, A, Newcomb, PA, Gallinger, S, Hoffmeister, M, Campbell, PT, Thibodeau, SN, Sun, W, Hudson, TJ, and Peters, U

Abstract

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.

Published
2020

29. Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis

Author

Papadimitriou, N, Dimou, N, Tsilidis, KK, Banbury, B, Martin, RM, Lewis, SJ, Kazmi, N, Robinson, TM, Albanes, D, Aleksandrova, K, Berndt, SI, Bishop, DT, Brenner, H, Buchanan, DD, Bueno-de-Mesquita, B, Campbell, PT, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Ellingjord-Dale, M, Figueiredo, JC, Gallinger, SJ, Giles, GG, Giovannucci, E, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harlid, S, Harrison, TA, Hoffmeister, M, Hopper, JL, Hsu, L, Maria Huerta, J, Huyghe, JR, Jenkins, MA, Keku, TO, Kuehn, T, La Vecchia, C, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Lindor, NM, Lynch, B, Markowitz, SD, Masala, G, May, AM, Milne, R, Monninkhof, E, Moreno, L, Moreno, V, Newcomb, PA, Offit, K, Perduca, V, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Riboli, E, Sanchez, M-J, Schmit, SL, Schoen, RE, Severi, G, Sieri, S, Slattery, ML, Song, M, Tangen, CM, Thibodeau, SN, Travis, RC, Trichopoulou, A, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Vodicka, P, White, E, Wolk, A, Woods, MO, Wu, AH, Peters, U, Gunter, MJ, Murphy, N, Papadimitriou, N, Dimou, N, Tsilidis, KK, Banbury, B, Martin, RM, Lewis, SJ, Kazmi, N, Robinson, TM, Albanes, D, Aleksandrova, K, Berndt, SI, Bishop, DT, Brenner, H, Buchanan, DD, Bueno-de-Mesquita, B, Campbell, PT, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Ellingjord-Dale, M, Figueiredo, JC, Gallinger, SJ, Giles, GG, Giovannucci, E, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harlid, S, Harrison, TA, Hoffmeister, M, Hopper, JL, Hsu, L, Maria Huerta, J, Huyghe, JR, Jenkins, MA, Keku, TO, Kuehn, T, La Vecchia, C, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Lindor, NM, Lynch, B, Markowitz, SD, Masala, G, May, AM, Milne, R, Monninkhof, E, Moreno, L, Moreno, V, Newcomb, PA, Offit, K, Perduca, V, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Riboli, E, Sanchez, M-J, Schmit, SL, Schoen, RE, Severi, G, Sieri, S, Slattery, ML, Song, M, Tangen, CM, Thibodeau, SN, Travis, RC, Trichopoulou, A, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Vodicka, P, White, E, Wolk, A, Woods, MO, Wu, AH, Peters, U, Gunter, MJ, and Murphy, N

Abstract

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

Published
2020

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

Author

Christakoudi, S, Pagoni, P, Ferrari, P, Cross, AJ, Tzoulaki, I, Muller, DC, Weiderpass, E, Freisling, H, Murphy, N, Dossus, L, Turzanski Fortner, R, Agudo, A, Overvad, K, Perez-Cornago, A, Key, TJ, Brennan, P, Johansson, M, Tjonneland, A, Halkjaer, J, Boutron-Ruault, M-C, Artaud, F, Severi, G, Kaaks, R, Schulze, MB, Bergmann, MM, Masala, G, Grioni, S, Simeon, V, Tumino, R, Sacerdote, C, Skeie, G, Rylander, C, Borch, KB, Quiros, JR, Rodriguez-Barranco, M, Chirlaque, M-D, Ardanaz, E, Amiano, P, Drake, I, Stocks, T, Haggstrom, C, Harlid, S, Ellingjord-Dale, M, Riboli, E, Tsilidis, KK, Christakoudi, S, Pagoni, P, Ferrari, P, Cross, AJ, Tzoulaki, I, Muller, DC, Weiderpass, E, Freisling, H, Murphy, N, Dossus, L, Turzanski Fortner, R, Agudo, A, Overvad, K, Perez-Cornago, A, Key, TJ, Brennan, P, Johansson, M, Tjonneland, A, Halkjaer, J, Boutron-Ruault, M-C, Artaud, F, Severi, G, Kaaks, R, Schulze, MB, Bergmann, MM, Masala, G, Grioni, S, Simeon, V, Tumino, R, Sacerdote, C, Skeie, G, Rylander, C, Borch, KB, Quiros, JR, Rodriguez-Barranco, M, Chirlaque, M-D, Ardanaz, E, Amiano, P, Drake, I, Stocks, T, Haggstrom, C, Harlid, S, Ellingjord-Dale, M, Riboli, E, and Tsilidis, KK

Abstract

Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.

Published
2020

31. Antibody responses to Fusobacterium nucleatum Proteins in prediagnostic blood samples are not associated with risk of developing colorectal cancer

Author

Butt, J. Jenab, M. Pawlita, M. Overvad, K. Tjonneland, A. Olsen, A. Boutron-Ruault, M.-C. Carbonnel, F. Mancini, F.R. Kaaks, R. Kuhn, T. Boeing, H. Trichopoulou, A. Karakatsani, A. Palli, D. Pala, V.M. Tumino, R. Sacerdote, C. Panico, S. Bueno-De-Mesquita, B. Van Gils, C.H. Vermeulen, R.C.H. Weiderpass, E. Quiros, J.R. Duell, E.J. Sanchez, M.-J. Dorronsoro, M. Huerta, J.M. Ardanaz, E. Van Guelpen, B. Harlid, S. Perez-Cornago, A. Gunter, M.J. Murphy, N. Freisling, H. Aune, D. Waterboer, T. Hughes, D.J.

Subjects
stomatognathic diseases, stomatognathic system
Abstract

Background: There is a lack of prospective data on the potential association of Fusobacterium nucleatum (F. nucleatum) and colorectal cancer risk. In this study, we assessed whether antibody responses to F. nucleatum are associated with colorectal cancer risk in prediagnostic serum samples in the European Prospective Investigation into Nutrition and Cancer (EPIC) cohort. Methods: We applied a multiplex serology assay to simultaneously measure antibody responses to 11 F. nucleatum antigens in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI). Results: We observed neither a statistically significant colorectal cancer risk association for antibodies to individual F. nucleatum proteins nor for combined positivity to any of the 11 proteins (OR, 0.81; 95% CI, 0.62–1.06). Conclusions: Antibody responses to F. nucleatum proteins in prediagnostic serum samples from a subset of colorectal cancer cases and matched controls within the EPIC study were not associated with colorectal cancer risk. Impact: Our findings in prospectively ascertained serum samples contradict the existing literature on the association of F. nucleatum with colorectal cancer risk. Future prospective studies, specifically detecting F. nucleatum in stool or tissue biopsies, are needed to complement our findings. © 2019 American Association for Cancer Research.

Published
2019

32. Reproductive Factors, Exogenous Hormone Use, and Risk of B-Cell Non-Hodgkin Lymphoma in a Cohort of Women from the European Prospective Investigation into Cancer and Nutrition

Author

Costas, L. Lujan-Barroso, L. Benavente, Y. Allen, N.E. Amiano, P. Ardanaz, E. Besson, C. Boeing, H. Bueno-De-Mesquita, B. Cervenka, I. Fortner, R.T. Fournier, A. Gunter, M. Harlid, S. Huerta, J.M. Jerkeman, M. Jirström, K. Kaaks, R. Karakatsani, A. Khaw, K.-T. Kotanidou, A. Lund, E. Masala, G. Mattiello, A. Melin, B. Menéndez, V. Murphy, N. Nieters, A. Overvad, K. Riboli, E. Sacerdote, C. Sánchez, M.-J. Schmidt, J.A. Sieri, S. Tjønneland, A. Trichopoulou, A. Tumino, R. Vermeulen, R. Weiderpass, E. De Sanjosé, S. Agudo, A. Casabonne, D.

Abstract

The role of hormonal factors in the etiology of lymphoid neoplasms remains unclear. Previous studies have yielded conflicting results, have lacked sufficient statistical power to assess many lymphoma subtypes, or have lacked detailed information on relevant exposures. Within the European Prospective Investigation Into Cancer and Nutrition cohort, we analyzed comprehensive data on reproductive factors and exogenous hormone use collected at baseline (1992-2000) among 343,458 women, including data on 1,427 incident cases of B-cell non-Hodgkin lymphoma (NHL) and its major subtypes identified after a mean follow-up period of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use, or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had undergone surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) than women with natural menopause (hazard ratio = 1.51, 95% confidence interval: 1.17, 1.94). Given that this result may have been due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis. © The Author(s) 2018.

Published
2019

33. Association of selenoprotein and selenium pathway genotypes with risk of colorectal cancer and interaction with selenium status

Author

Fedirko, V. Jenab, M. Méplan, C. Jones, J.S. Zhu, W. Schomburg, L. Siddiq, A. Hybsier, S. Overvad, K. Tjønneland, A. Omichessan, H. Perduca, V. Boutron-Ruault, M.-C. Kühn, T. Katzke, V. Aleksandrova, K. Trichopoulou, A. Karakatsani, A. Kotanidou, A. Tumino, R. Panico, S. Masala, G. Agnoli, C. Naccarati, A. Bueno-De-Mesquita, B. Vermeulen, R.C.H. Weiderpass, E. Skeie, G. Nøst, T.H. Lujan-Barroso, L. Quirós, J.R. Huerta, J.M. Rodríguez-Barranco, M. Barricarte, A. Gylling, B. Harlid, S. Bradbury, K.E. Wareham, N. Khaw, K.-T. Gunter, M. Murphy, N. Freisling, H. Tsilidis, K. Aune, D. Riboli, E. Hesketh, J.E. Hughes, D.J.

Abstract

Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengate assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10; PACT significance threshold was P < 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Published
2019

34. Discovery of common and rare genetic risk variants for colorectal cancer

Author

Huyghe, J.R. Bien, S.A. Harrison, T.A. Kang, H.M. Chen, S. Schmit, S.L. Conti, D.V. Qu, C. Jeon, J. Edlund, C.K. Greenside, P. Wainberg, M. Schumacher, F.R. Smith, J.D. Levine, D.M. Nelson, S.C. Sinnott-Armstrong, N.A. Albanes, D. Alonso, M.H. Anderson, K. Arnau-Collell, C. Arndt, V. Bamia, C. Banbury, B.L. Baron, J.A. Berndt, S.I. Bézieau, S. Bishop, D.T. Boehm, J. Boeing, H. Brenner, H. Brezina, S. Buch, S. Buchanan, D.D. Burnett-Hartman, A. Butterbach, K. Caan, B.J. Campbell, P.T. Carlson, C.S. Castellví-Bel, S. Chan, A.T. Chang-Claude, J. Chanock, S.J. Chirlaque, M.-D. Cho, S.H. Connolly, C.M. Cross, A.J. Cuk, K. Curtis, K.R. de la Chapelle, A. Doheny, K.F. Duggan, D. Easton, D.F. Elias, S.G. Elliott, F. English, D.R. Feskens, E.J.M. Figueiredo, J.C. Fischer, R. FitzGerald, L.M. Forman, D. Gala, M. Gallinger, S. Gauderman, W.J. Giles, G.G. Gillanders, E. Gong, J. Goodman, P.J. Grady, W.M. Grove, J.S. Gsur, A. Gunter, M.J. Haile, R.W. Hampe, J. Hampel, H. Harlid, S. Hayes, R.B. Hofer, P. Hoffmeister, M. Hopper, J.L. Hsu, W.-L. Huang, W.-Y. Hudson, T.J. Hunter, D.J. Ibañez-Sanz, G. Idos, G.E. Ingersoll, R. Jackson, R.D. Jacobs, E.J. Jenkins, M.A. Joshi, A.D. Joshu, C.E. Keku, T.O. Key, T.J. Kim, H.R. Kobayashi, E. Kolonel, L.N. Kooperberg, C. Kühn, T. Küry, S. Kweon, S.-S. Larsson, S.C. Laurie, C.A. Le Marchand, L. Leal, S.M. Lee, S.C. Lejbkowicz, F. Lemire, M. Li, C.I. Li, L. Lieb, W. Lin, Y. Lindblom, A. Lindor, N.M. Ling, H. Louie, T.L. Männistö, S. Markowitz, S.D. Martín, V. Masala, G. McNeil, C.E. Melas, M. Milne, R.L. Moreno, L. Murphy, N. Myte, R. Naccarati, A. Newcomb, P.A. Offit, K. Ogino, S. Onland-Moret, N.C. Pardini, B. Parfrey, P.S. Pearlman, R. Perduca, V. Pharoah, P.D.P. Pinchev, M. Platz, E.A. Prentice, R.L. Pugh, E. Raskin, L. Rennert, G. Rennert, H.S. Riboli, E. Rodríguez-Barranco, M. Romm, J. Sakoda, L.C. Schafmayer, C. Schoen, R.E. Seminara, D. Shah, M. Shelford, T. Shin, M.-H. Shulman, K. Sieri, S. Slattery, M.L. Southey, M.C. Stadler, Z.K. Stegmaier, C. Su, Y.-R. Tangen, C.M. Thibodeau, S.N. Thomas, D.C. Thomas, S.S. Toland, A.E. Trichopoulou, A. Ulrich, C.M. Van Den Berg, D.J. van Duijnhoven, F.J.B. Van Guelpen, B. van Kranen, H. Vijai, J. Visvanathan, K. Vodicka, P. Vodickova, L. Vymetalkova, V. Weigl, K. Weinstein, S.J. White, E. Win, A.K. Wolf, C.R. Wolk, A. Woods, M.O. Wu, A.H. Zaidi, S.H. Zanke, B.W. Zhang, Q. Zheng, W. Scacheri, P.C. Potter, J.D. Bassik, M.C. Kundaje, A. Casey, G. Moreno, V. Abecasis, G.R. Nickerson, D.A. Gruber, S.B. Hsu, L. Peters, U.

Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10 −8 , bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development. © 2018, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2019

35. Antibody responses to Fusobacterium nucleatum Proteins in prediagnostic blood samples are not associated with risk of developing colorectal cancer

Author

Butt, J., Jenab, M., Pawlita, M., Overvad, K., Tjonneland, A., Olsen, A., Boutron-Ruault, M.-C., Carbonnel, F., Mancini, F.R., Kaaks, R., Kuhn, T., Boeing, H., Trichopoulou, A., Karakatsani, A., Palli, D., Pala, V.M., Tumino, R., Sacerdote, C., Panico, S., Bueno-De-Mesquita, B., Van Gils, C.H., Vermeulen, R.C.H., Weiderpass, E., Quiros, J.R., Duell, E.J., Sanchez, M.-J., Dorronsoro, M., Huerta, J.M., Ardanaz, E., Van Guelpen, B., Harlid, S., Perez-Cornago, A., Gunter, M.J., Murphy, N., Freisling, H., Aune, D., Waterboer, T., Hughes, D.J., Butt, J., Jenab, M., Pawlita, M., Overvad, K., Tjonneland, A., Olsen, A., Boutron-Ruault, M.-C., Carbonnel, F., Mancini, F.R., Kaaks, R., Kuhn, T., Boeing, H., Trichopoulou, A., Karakatsani, A., Palli, D., Pala, V.M., Tumino, R., Sacerdote, C., Panico, S., Bueno-De-Mesquita, B., Van Gils, C.H., Vermeulen, R.C.H., Weiderpass, E., Quiros, J.R., Duell, E.J., Sanchez, M.-J., Dorronsoro, M., Huerta, J.M., Ardanaz, E., Van Guelpen, B., Harlid, S., Perez-Cornago, A., Gunter, M.J., Murphy, N., Freisling, H., Aune, D., Waterboer, T., and Hughes, D.J.

Published
2019

36. Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations

Author

Fedirko, V., Mandle, H.B., Zhu, W., Hughes, D.J., Siddiq, A., Ferrari, P., Romieu, I., Riboli, E., Bueno-de-Mesquita, B., Duijnhoven, F. J. B. van, Siersema, P.D., Tjonneland, A., Olsen, A., Perduca, V., Carbonnel, F., Boutron-Ruault, M.C., Kuhn, T., Johnson, T., Krasimira, A., Trichopoulou, A., Makrythanasis, P., Thanos, D., Panico, S., Krogh, V., Sacerdote, C., Skeie, G., Weiderpass, E., Colorado-Yohar, S., Sala, N., Barricarte, A., Sanchez, M.J., Quiros, R., Amiano, P., Gylling, B., Harlid, S., Perez-Cornago, A., Heath, A.K., Tsilidis, K.K., Aune, D., Freisling, H., Murphy, N., Gunter, M.J., Jenab, M., Fedirko, V., Mandle, H.B., Zhu, W., Hughes, D.J., Siddiq, A., Ferrari, P., Romieu, I., Riboli, E., Bueno-de-Mesquita, B., Duijnhoven, F. J. B. van, Siersema, P.D., Tjonneland, A., Olsen, A., Perduca, V., Carbonnel, F., Boutron-Ruault, M.C., Kuhn, T., Johnson, T., Krasimira, A., Trichopoulou, A., Makrythanasis, P., Thanos, D., Panico, S., Krogh, V., Sacerdote, C., Skeie, G., Weiderpass, E., Colorado-Yohar, S., Sala, N., Barricarte, A., Sanchez, M.J., Quiros, R., Amiano, P., Gylling, B., Harlid, S., Perez-Cornago, A., Heath, A.K., Tsilidis, K.K., Aune, D., Freisling, H., Murphy, N., Gunter, M.J., and Jenab, M.

Abstract

Contains fulltext : 215343.pdf (publisher's version ) (Open Access), Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor beta (TGFbeta) signaling was associated with CRC risk (P

Published
2019

37. Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Author

Schmit, SL, Edlund, CK, Schumacher, FR, Gong, J, Harrison, TA, Huyghe, JR, Qu, C, Melas, M, Van den Berg, DJ, Wang, H, Tring, S, Plummer, SJ, Albanes, D, Alonso, MH, Amos, CI, Anton, K, Aragaki, AK, Arndt, V, Barry, EL, Berndt, SI, Bezieau, S, Bien, S, Bloomer, A, Boehm, J, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castelao, JE, Chan, AT, Chang-Claude, J, Chanock, SJ, Cheng, I, Cheng, Y-W, Chin, LS, Church, JM, Church, T, Coetzee, GA, Cotterchio, M, Correa, MC, Curtis, KR, Duggan, D, Easton, DF, English, D, Feskens, EJM, Fischer, R, FitzGerald, LM, Fortini, BK, Fritsche, LG, Fuchs, CS, Gago-Dominguez, M, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Giovannucci, EL, Gogarten, SM, Gonzalez-Villalpando, C, Gonzalez-Villalpando, EM, Grady, WM, Greenson, JK, Gsur, A, Gunter, M, Haiman, CA, Hampe, J, Harlid, S, Harju, JF, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Huang, S-C, Huerta, JM, Hudson, TJ, Hunter, DJ, Idos, GE, Iwasaki, M, Jackson, RD, Jacobs, EJ, Jee, SH, Jenkins, MA, Jia, W-H, Jiao, S, Joshi, AD, Kolonel, LN, Kono, S, Kooperberg, C, Krogh, V, Kuehn, T, Kury, S, LaCroix, A, Laurie, CA, Lejbkowicz, F, Lemire, M, Lenz, H-J, Levine, D, Li, CI, Li, L, Lieb, W, Lin, Y, Lindor, NM, Liu, Y-R, Loupakis, F, Lu, Y, Luh, F, Ma, J, Mancao, C, Manion, FJ, Markowitz, SD, Martin, V, Matsuda, K, Matsuo, K, McDonnell, KJ, McNeil, CE, Milne, R, Molina, AJ, Mukherjee, B, Murphy, N, Newcomb, PA, Offit, K, Omichessan, H, Palli, D, Cotore, JPP, Perez-Mayoral, J, Pharoah, PD, Potter, JD, Raskin, L, Rennert, G, Rennert, HS, Riggs, BM, Schafmayer, C, Schoen, RE, Sellers, TA, Seminara, D, Severi, G, Shi, W, Shibata, D, Shu, X-O, Siegel, EM, Slattery, ML, Southey, M, Stadler, ZK, Stern, MC, Stintzing, S, Taverna, D, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Tsugane, S, Ulrich, CM, van Duijnhoven, FJB, van Guelpan, B, Vijai, J, Virtamo, J, Weinstein, SJ, White, E, Win, AK, Wolk, A, Woods, M, Wu, AH, Wu, K, Xiang, Y-B, Yen, Y, Zanke, BW, Zeng, Y-X, Zhang, B, Zubair, N, Kweon, S-S, Figueiredo, JC, Zheng, W, Le Marchand, L, Lindblom, A, Moreno, V, Peters, U, Casey, G, Hsu, L, Conti, DV, Gruber, SB, Schmit, SL, Edlund, CK, Schumacher, FR, Gong, J, Harrison, TA, Huyghe, JR, Qu, C, Melas, M, Van den Berg, DJ, Wang, H, Tring, S, Plummer, SJ, Albanes, D, Alonso, MH, Amos, CI, Anton, K, Aragaki, AK, Arndt, V, Barry, EL, Berndt, SI, Bezieau, S, Bien, S, Bloomer, A, Boehm, J, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castelao, JE, Chan, AT, Chang-Claude, J, Chanock, SJ, Cheng, I, Cheng, Y-W, Chin, LS, Church, JM, Church, T, Coetzee, GA, Cotterchio, M, Correa, MC, Curtis, KR, Duggan, D, Easton, DF, English, D, Feskens, EJM, Fischer, R, FitzGerald, LM, Fortini, BK, Fritsche, LG, Fuchs, CS, Gago-Dominguez, M, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Giovannucci, EL, Gogarten, SM, Gonzalez-Villalpando, C, Gonzalez-Villalpando, EM, Grady, WM, Greenson, JK, Gsur, A, Gunter, M, Haiman, CA, Hampe, J, Harlid, S, Harju, JF, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Huang, S-C, Huerta, JM, Hudson, TJ, Hunter, DJ, Idos, GE, Iwasaki, M, Jackson, RD, Jacobs, EJ, Jee, SH, Jenkins, MA, Jia, W-H, Jiao, S, Joshi, AD, Kolonel, LN, Kono, S, Kooperberg, C, Krogh, V, Kuehn, T, Kury, S, LaCroix, A, Laurie, CA, Lejbkowicz, F, Lemire, M, Lenz, H-J, Levine, D, Li, CI, Li, L, Lieb, W, Lin, Y, Lindor, NM, Liu, Y-R, Loupakis, F, Lu, Y, Luh, F, Ma, J, Mancao, C, Manion, FJ, Markowitz, SD, Martin, V, Matsuda, K, Matsuo, K, McDonnell, KJ, McNeil, CE, Milne, R, Molina, AJ, Mukherjee, B, Murphy, N, Newcomb, PA, Offit, K, Omichessan, H, Palli, D, Cotore, JPP, Perez-Mayoral, J, Pharoah, PD, Potter, JD, Raskin, L, Rennert, G, Rennert, HS, Riggs, BM, Schafmayer, C, Schoen, RE, Sellers, TA, Seminara, D, Severi, G, Shi, W, Shibata, D, Shu, X-O, Siegel, EM, Slattery, ML, Southey, M, Stadler, ZK, Stern, MC, Stintzing, S, Taverna, D, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Tsugane, S, Ulrich, CM, van Duijnhoven, FJB, van Guelpan, B, Vijai, J, Virtamo, J, Weinstein, SJ, White, E, Win, AK, Wolk, A, Woods, M, Wu, AH, Wu, K, Xiang, Y-B, Yen, Y, Zanke, BW, Zeng, Y-X, Zhang, B, Zubair, N, Kweon, S-S, Figueiredo, JC, Zheng, W, Le Marchand, L, Lindblom, A, Moreno, V, Peters, U, Casey, G, Hsu, L, Conti, DV, and Gruber, SB

Abstract

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: T

Published
2019

38. Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies

Author

Smith, T, Muller, DC, Moons, KGM, Cross, AJ, Johansson, M, Ferrari, P, Fagherazzi, G, Peeters, PHM, Severi, G, Huesing, A, Kaaks, R, Tjonneland, A, Olsen, A, Overvad, K, Bonet, C, Rodriguez-Barranco, M, Huerta, JM, Gurrea, AB, Bradbury, KE, Trichopoulou, A, Bamia, C, Orfanos, P, Palli, D, Pala, V, Vineis, P, Bueno-de-Mesquita, B, Ohlsson, B, Harlid, S, Van Guelpen, B, Skeie, G, Weiderpass, E, Jenab, M, Murphy, N, Riboli, E, Gunter, MJ, Aleksandrova, KJ, Tzoulaki, I, Smith, T, Muller, DC, Moons, KGM, Cross, AJ, Johansson, M, Ferrari, P, Fagherazzi, G, Peeters, PHM, Severi, G, Huesing, A, Kaaks, R, Tjonneland, A, Olsen, A, Overvad, K, Bonet, C, Rodriguez-Barranco, M, Huerta, JM, Gurrea, AB, Bradbury, KE, Trichopoulou, A, Bamia, C, Orfanos, P, Palli, D, Pala, V, Vineis, P, Bueno-de-Mesquita, B, Ohlsson, B, Harlid, S, Van Guelpen, B, Skeie, G, Weiderpass, E, Jenab, M, Murphy, N, Riboli, E, Gunter, MJ, Aleksandrova, KJ, and Tzoulaki, I

Abstract

OBJECTIVE: To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts. DESIGN: Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability). RESULTS: The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC. CONCLUSION: Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.

Published
2019

39. Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition

Author

Christakoudi, S, Kakourou, A, Markozannes, G, Tzoulaki, I, Weiderpass, E, Brennan, P, Gunter, M, Dahm, CC, Overvad, K, Olsen, A, Tjonneland, A, Boutron-Ruault, M-C, Madika, A-L, Severi, G, Katzke, V, Kuehn, T, Bergmann, MM, Boeing, H, Karakatsani, A, Martimianaki, G, Thriskos, P, Masala, G, Sieri, S, Panico, S, Tumino, R, Ricceri, F, Agudo, A, Redondo-Sanchez, D, Colorado-Yohar, SM, Mokoroa, O, Melander, O, Stocks, T, Haggstrom, C, Harlid, S, Bueno-de-Mesquita, B, van Gils, CH, Vermeulen, RC, Khaw, K-T, Wareham, NJ, Tong, TYN, Freisling, H, Johansson, M, Lennon, H, AUne, D, Ribolil, E, Trichopoulos, D, Trichopoulou, A, Tsilidis, KK, Christakoudi, S, Kakourou, A, Markozannes, G, Tzoulaki, I, Weiderpass, E, Brennan, P, Gunter, M, Dahm, CC, Overvad, K, Olsen, A, Tjonneland, A, Boutron-Ruault, M-C, Madika, A-L, Severi, G, Katzke, V, Kuehn, T, Bergmann, MM, Boeing, H, Karakatsani, A, Martimianaki, G, Thriskos, P, Masala, G, Sieri, S, Panico, S, Tumino, R, Ricceri, F, Agudo, A, Redondo-Sanchez, D, Colorado-Yohar, SM, Mokoroa, O, Melander, O, Stocks, T, Haggstrom, C, Harlid, S, Bueno-de-Mesquita, B, van Gils, CH, Vermeulen, RC, Khaw, K-T, Wareham, NJ, Tong, TYN, Freisling, H, Johansson, M, Lennon, H, AUne, D, Ribolil, E, Trichopoulos, D, Trichopoulou, A, and Tsilidis, KK

Abstract

Several studies have reported associations of hypertension with cancer, but not all results were conclusive. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with the development of incident cancer at all anatomical sites in the European Prospective Investigation into Cancer and Nutrition (EPIC). Hazard ratios (HRs) (95% confidence intervals) were estimated using multivariable Cox proportional hazards models, stratified by EPIC-participating center and age at recruitment, and adjusted for sex, education, smoking, body mass index, physical activity, diabetes and dietary (in women also reproductive) factors. The study included 307,318 men and women, with an average follow-up of 13.7 (standard deviation 4.4) years and 39,298 incident cancers. We confirmed the expected positive association with renal cell carcinoma: HR = 1.12 (1.08-1.17) per 10 mm Hg higher SBP and HR = 1.23 (1.14-1.32) for DBP. We additionally found positive associations for esophageal squamous cell carcinoma (SCC): HR = 1.16 (1.07-1.26) (SBP), HR = 1.31 (1.13-1.51) (DBP), weaker for head and neck cancers: HR = 1.08 (1.04-1.12) (SBP), HR = 1.09 (1.01-1.17) (DBP) and, similarly, for skin SCC, colon cancer, postmenopausal breast cancer and uterine adenocarcinoma (AC), but not for esophageal AC, lung SCC, lung AC or uterine endometroid cancer. We observed weak inverse associations of SBP with cervical SCC: HR = 0.91 (0.82-1.00) and lymphomas: HR = 0.97 (0.93-1.00). There were no consistent associations with cancers in other locations. Our results are largely compatible with published studies and support weak associations of blood pressure with cancers in specific locations and morphologies.

Published
2019

40. Discovery of common and rare genetic risk variants for colorectal cancer

Author

Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibanez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kuehn, T, Kury, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Mannisto, S, Markowitz, SD, Martin, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodriguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L, Peters, U, Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibanez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kuehn, T, Kury, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Mannisto, S, Markowitz, SD, Martin, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodriguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L, and Peters, U

Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Published
2019

41. Identifying and correcting epigenetics measurements for systematic sources of variation

Author

Perrier, F. Novoloaca, A. Ambatipudi, S. Baglietto, L. Ghantous, A. Perduca, V. Barrdahl, M. Harlid, S. Ong, K.K. Cardona, A. Polidoro, S. Nøst, T.H. Overvad, K. Omichessan, H. Dollé, M. Bamia, C. Huerta, J.M. Vineis, P. Herceg, Z. Romieu, I. Ferrari, P.

Abstract

Background: Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features. In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis. Results: A sizeable proportion of systematic variability due to variables expressing 'batch' and 'sample position' within 'chip' was identified, with values of the partial R2 statistics equal to 9.5 and 11.4% of total variation, respectively. After application of ComBat or the residuals' methods, the contribution was 1.3 and 0.2%, respectively. The SVA technique resulted in a reduced variability due to 'batch' (1.3%) and 'sample position' (0.6%), and in a diminished variability attributable to 'chip' within a batch (0.9%). After ComBat or the residuals' corrections, a larger number of significant sites (k = 600 and k = 427, respectively) were associated to smoking status than the SVA correction (k = 96). Conclusions: The three correction methods removed systematic variation in DNA methylation data, as assessed by the PC-PR2, which lent itself as a useful tool to explore variability in large dimension data. SVA produced more conservative findings than ComBat in the association between smoking and DNA methylation. © 2018 The Author(s).

Published
2018

42. Identifying and correcting epigenetics measurements for systematic sources of variation

Author

Perrier, F, Novoloaca, A, Ambatipudi, S, Baglietto, L, Ghantous, A, Perduca, V, Barrdahl, M, Harlid, S, Ong, KK, Cardona, A, Polidoro, S, Nost, TH, Overvad, K, Omichessan, H, Dolle, M, Bamia, C, Maria Huerta, J, Vineis, P, Herceg, Z, Romieu, I, Ferrari, P, Perrier, F, Novoloaca, A, Ambatipudi, S, Baglietto, L, Ghantous, A, Perduca, V, Barrdahl, M, Harlid, S, Ong, KK, Cardona, A, Polidoro, S, Nost, TH, Overvad, K, Omichessan, H, Dolle, M, Bamia, C, Maria Huerta, J, Vineis, P, Herceg, Z, Romieu, I, and Ferrari, P

Abstract

BACKGROUND: Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features.In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis. RESULTS: A sizeable proportion of systematic variability due to variables expressing 'batch' and 'sample position' within 'chip' was identified, with values of the partial R2 statistics equal to 9.5 and 11.4% of total variation, respectively. After application of ComBat or the residuals' methods, the contribution was 1.3 and 0.2%, respectively. The SVA technique resulted in a reduced variability due to 'batch' (1.3%) and 'sample position' (0.6%), and in a diminished variability attributable to 'chip' within a batch (0.9%). After ComBat or the residuals' corrections, a larger number of significant sites (k = 600 and k = 427, respectively) were associ

Published
2018

45. Combined effect of low-penetrant SNPs on breast cancer risk

Author

Harlid, S, primary, Ivarsson, M I L, additional, Butt, S, additional, Grzybowska, E, additional, Eyfjörd, J E, additional, Lenner, P, additional, Försti, A, additional, Hemminki, K, additional, Manjer, J, additional, Dillner, J, additional, and Carlson, J, additional

Published
2011
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46. Combined effect of low-penetrant SNPs on breast cancer risk.

Author

Harlid, S, Ivarsson, M I L, Butt, S, Grzybowska, E, Eyfjörd, J E, Lenner, P, Försti, A, Hemminki, K, Manjer, J, Dillner, J, and Carlson, J

Subjects
*GENETICS of breast cancer, *GENE frequency, *SINGLE nucleotide polymorphisms, *CONTROL groups, *MATRIX-assisted laser desorption-ionization
Abstract

Background:Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status.Methods:Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression.Results:Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 × 10−20 and 1.5 × 10−25, respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 × 10−4).Conclusion:The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer. [ABSTRACT FROM AUTHOR]

Published
2012
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48. Genetic predisposition, parity, age at first childbirth and risk for breast cancer

Author

Butt Salma, Harlid Sophia, Borgquist Signe, Ivarsson Malin, Landberg Göran, Dillner Joakim, Carlson Joyce, and Manjer Jonas

Subjects
Medicine, Biology (General), QH301-705.5, Science (General), Q1-390
Abstract

Abstract Background Recent studies have identified several single-nucleotide polymorphisms (SNPs) associated with the risk of breast cancer and parity and age at first childbirth are well established and important risk factors for breast cancer. The aim of the present study was to examine the interaction between these environmental factors and genetic variants on breast cancer risk. Methods The Malmö Diet and Cancer Study (MDCS) included 17 035 female participants, from which 728 incident breast cancer cases were matched to 1448 controls. The associations between 14 SNPs and breast cancer risk were investigated in different strata of parity and age at first childbirth. A logistic regression analysis for the per allele risk, adjusted for potential confounders yielded odds ratios (OR) with 95% confidence intervals (CI). Results Six of the previously identified SNPs showed a statistically significant association with breast cancer risk: rs2981582 (FGFR2), rs3803662 (TNRC9), rs12443621 (TNRC9), rs889312 (MAP3K1), rs3817198 (LSP1) and rs2107425 (H19). We could not find any statistically significant interaction between the effects of tested SNPs and parity/age at first childbirth on breast cancer risk after adjusting for multiple comparisons. Conclusions The results of this study are in agreement with previous studies of null interactions between tested SNPs and parity/age at first childbirth with regard to breast cancer risk.

Published
2012
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49. Interactive effect of genetic susceptibility with height, body mass index, and hormone replacement therapy on the risk of breast cancer

Author

Harlid Sophia, Butt Salma, Ivarsson Malin IL, Eyfjörd Jorunn, Lenner Per, Manjer Jonas, Dillner Joakim, and Carlson Joyce

Subjects
Gynecology and obstetrics, RG1-991, Public aspects of medicine, RA1-1270
Abstract

Abstract Background Breast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs) and height, body mass index (BMI) and hormone replacement therapy (HRT). Methods We analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case–control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry-Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model. Results One SNP (rs851987 in ESR1) tended to interact with height, with an increasingly protective effect of the major allele in taller women (p = 0.007) and rs13281615 (on 8q24) tended to confer risk only in non users of HRT (p-for interaction = 0.03). There were no significant interactions after correction for multiple testing. Conclusions We conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene-environment interactions in independent materials.

Published
2012
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50. Changes in lifestyle and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition

Author

Edoardo Botteri, Giulia Peveri, Paula Berstad, Vincenzo Bagnardi, Sairah L.F. Chen, Torkjel M. Sandanger, Geir Hoff, Christina C. Dahm, Christian S. Antoniussen, Anne Tjønneland, Anne Kirstine Eriksen, Guri Skeie, Aurora Perez-Cornago, José María Huerta, Paula Jakszyn, Sophia Harlid, Björn Sundström, Aurelio Barricarte, Evelyn M. Monninkhof, Jeroen W.G. Derksen, Matthias B. Schulze, Bas Bueno-de-Mesquita, Maria-Jose Sánchez, Amanda J. Cross, Konstantinos K. Tsilidis, Maria Santucci De Magistris, Rudolf Kaaks, Verena Katzke, Joseph A. Rothwell, Nasser Laouali, Gianluca Severi, Pilar Amiano, Paolo Contiero, Carlotta Sacerdote, Marcel Goldberg, Mathilde Touvier, Heinz Freisling, Vivian Viallon, Elisabete Weiderpass, Elio Riboli, Marc J. Gunter, Mazda Jenab, Pietro Ferrari, 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, and Ferrari, P

Subjects
lifestyle, Hepatology, alcohol, Gastroenterology, Nutritional Status, colorectal cancer, smoking, Settore MED/01 - Statistica Medica, nutrition, Risk Factors, Humans, Prospective Studies, Life Style, Colorectal Neoplasms/epidemiology
Abstract

Introduction: We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multi-country European cohort. Methods: We used baseline and follow-up questionnaire data from the EPIC 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 two timepoints. HLI ranged from 0 (most unfavourable) to 16 (most favourable). 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. 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
2022

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