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1. Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer

Author: Laskar, R.S., Qu, C., Huyghe, J.R., Harrison, T., Hayes, R.B., Cao, Y., Campbell, P.T., Steinfelder, R., Talukdar, F.R., Brenner, H., Ogino, S., Brendt, S., Bishop, D.T., Buchanan, D.D., Chan, A.T., Cotterchio, M., Gruber, S.B., Gsur, A., van Guelpen, B., Jenkins, M.A., Keku, T.O., Lynch, B.M., Le Marchand, L., Martin, R.M., McCarthy, K., Moreno, V., Pearlman, R., Song, M., Tsilidis, K.K., Vodička, P., Woods, M.O., Wu, K., Hsu, L., Gunter, M.J., Peters, U., and Murphy, N.
Published: 2024
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2. Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition

Author: Yammine, S. G., Huybrechts, I., Biessy, C., Dossus, L., Panico, S., Sánchez, M. J., Benetou, V., Turzanski-Fortner, R., Katzke, V., Idahl, A., Skeie, G., Olsen, K. Standahl, Tjønneland, A., Halkjaer, J., Colorado-Yohar, S., Heath, A. K., Sonestedt, E., Sartor, H., Schulze, M. B., Palli, D., Crous-Bou, M., Dorronsoro, A., Overvad, K., Gurrea, A. Barricarte, Severi, G., Vermeulen, R. C.H., Sandanger, T. M., Travis, R. C., Key, T., Amiano, P., Van Guelpen, B., Johansson, M., Sund, M., Tumino, R., Wareham, N., Sacerdote, C., Krogh, V., Brennan, P., Riboli, E., Weiderpass, E., Gunter, M. J., and Chajès, V.
Published: 2023
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3. 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

4. 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

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

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

6. Prognostic role of detailed colorectal location and tumor molecular features: analyses of 13,101 colorectal cancer patients including 2994 early-onset cases

Author: Ugai, T, Akimoto, N, Haruki, K, Harrison, TA, Cao, Y, Qu, C, Chan, AT, Campbell, PT, Berndt, S, Buchanan, DD, Cross, AJ, Diergaarde, B, Gallinger, SJ, Gunter, MJ, Harlid, S, Hidaka, A, Hoffmeister, M, Brenner, H, Chang-Claude, J, Hsu, L, Jenkins, MA, Lin, Y, Milne, RL, Moreno, V, Newcomb, PA, Nishihara, R, Obon-Santacana, M, Pai, RK, Sakoda, LC, Schoen, RE, Slattery, ML, Sun, W, Amitay, EL, Alwers, E, Thibodeau, SN, Toland, AE, Van Guelpen, B, Zaidi, SH, Potter, JD, Meyerhardt, JA, Giannakis, M, Song, M, Nowak, JA, Peters, U, Phipps, A, Ogino, S, Ugai, T, Akimoto, N, Haruki, K, Harrison, TA, Cao, Y, Qu, C, Chan, AT, Campbell, PT, Berndt, S, Buchanan, DD, Cross, AJ, Diergaarde, B, Gallinger, SJ, Gunter, MJ, Harlid, S, Hidaka, A, Hoffmeister, M, Brenner, H, Chang-Claude, J, Hsu, L, Jenkins, MA, Lin, Y, Milne, RL, Moreno, V, Newcomb, PA, Nishihara, R, Obon-Santacana, M, Pai, RK, Sakoda, LC, Schoen, RE, Slattery, ML, Sun, W, Amitay, EL, Alwers, E, Thibodeau, SN, Toland, AE, Van Guelpen, B, Zaidi, SH, Potter, JD, Meyerhardt, JA, Giannakis, M, Song, M, Nowak, JA, Peters, U, Phipps, A, and Ogino, S
Abstract: BACKGROUND: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics. METHODS: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation. RESULTS: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (Ptrend = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (Pinteraction = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [Ptrend < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70-0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI 1.15-3.92). The prognostic association of colon tumor location also differed by CIMP status (Pinteraction = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages. CONCLUSIONS: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research.
Published: 2023

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

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

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

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

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

Author: Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Bien, S, Diez-Obrero, V, Li, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Harris, S, Svinti, V, McDonnell, K, Farrington, S, Studd, J, Vaughan-Shaw, P, Shu, X-O, Long, J, Cai, Q, Guo, X, Lu, Y, Scacheri, P, Huyghe, J, Harrison, T, Shibata, D, Haiman, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obon-Santacana, M, Martin-Sanchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, S-S, Shin, M-H, Shin, A, Ahn, Y-O, Kim, D-H, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, Y-T, Jia, W-H, Potter, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Boehm, J, Mecklin, L-P, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hanninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Mannisto, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellvi-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, Y-R, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, H-J, White, E, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Joshi, A, Schafmayer, C, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Toland, A, Markowitz, S, Kim, A, Gruber, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bezieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Le Marchand, L, Wu, A, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R, Peters, U, Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Bien, S, Diez-Obrero, V, Li, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Harris, S, Svinti, V, McDonnell, K, Farrington, S, Studd, J, Vaughan-Shaw, P, Shu, X-O, Long, J, Cai, Q, Guo, X, Lu, Y, Scacheri, P, Huyghe, J, Harrison, T, Shibata, D, Haiman, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obon-Santacana, M, Martin-Sanchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, S-S, Shin, M-H, Shin, A, Ahn, Y-O, Kim, D-H, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, Y-T, Jia, W-H, Potter, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Boehm, J, Mecklin, L-P, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hanninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Mannisto, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellvi-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, Y-R, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, H-J, White, E, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Joshi, A, Schafmayer, C, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Toland, A, Markowitz, S, Kim, A, Gruber, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bezieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Le Marchand, L, Wu, A, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R, and Peters, U
Abstract: Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
Published: 2023

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

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

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

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

12. Body mass index and molecular subtypes of colorectal cancer

Author: Murphy, N, Newton, CC, Song, M, Papadimitriou, N, Hoffmeister, M, Phipps, A, Harrison, TA, Newcomb, PA, Aglago, EK, Berndt, S, 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, Obon-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, A, Harrison, TA, Newcomb, PA, Aglago, EK, Berndt, S, 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, Obon-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

13. Prevalent diabetes and risk of total, colorectal, prostate and breast cancers in an ageing population: meta-analysis of individual participant data from cohorts of the CHANCES consortium

Author: Amadou, A., Freisling, H., Jenab, M., Tsilidis, K.K., Trichopoulou, A., Boffetta, P., Van Guelpen, B., Mokoroa, O., Wilsgaard, T., Kee, F., Schöttker, B., Ordóñez-Mena, J.M., Männistö, S., Söderberg, S., Vermeulen, R.C.H., Quirós, J.R., Liao, L.M., Sinha, R., Kuulasmaa, K., Brenner, H., Romieu, I., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Sub Algemeen Theoretical Physics, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Sub Algemeen Theoretical Physics, Amadou A., Freisling H., Jenab M., Tsilidis K.K., Trichopoulou A., Boffetta P., Van Guelpen B., Mokoroa O., Wilsgaard T., Kee F., Schottker B., Ordonez-Mena J.M., Mannisto S., Soderberg S., Vermeulen R.C.H., Quiros J.R., Liao L.M., Sinha R., Kuulasmaa K., Brenner H., and Romieu I.
Subjects: Male, Aging, Cancer Research, medicine.medical_specialty, Colorectal cancer, Breast Neoplasms, Colorectal Neoplasm, Overweight, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Neoplasms, Internal medicine, Diabetes Mellitus, Prevalence, medicine, Humans, Prospective cohort study, Aged, Aged, 80 and over, business.industry, Risk Factor, Hazard ratio, Prostatic Neoplasms, Cancer, Diabetes Mellitu, Middle Aged, medicine.disease, Obesity, United States, Confidence interval, Europe, Oncology, 030220 oncology & carcinogenesis, Prostatic Neoplasm, Neoplasm, Female, Cohort Studie, medicine.symptom, Colorectal Neoplasms, business, Breast Neoplasm, Human
Abstract: BACKGROUND: We investigated whether associations between prevalent diabetes and cancer risk are pertinent to older adults and whether associations differ across subgroups of age, body weight status or levels of physical activity. METHODS: We harmonised data from seven prospective cohort studies of older individuals in Europe and the United States participating in the CHANCES consortium. Cox proportional hazard regression was used to estimate the associations of prevalent diabetes with cancer risk (all cancers combined, and for colorectum, prostate and breast). We calculated summary risk estimates across cohorts using pooled analysis and random-effects meta-analysis. RESULTS: A total of 667,916 individuals were included with an overall median (P25–P75) age at recruitment of 62.3 (57–67) years. During a median follow-up time of 10.5 years, 114,404 total cancer cases were ascertained. Diabetes was not associated with the risk of all cancers combined (hazard ratio (HR) = 0.94; 95% confidence interval (CI): 0.86–1.04; I(2) = 63.3%). Diabetes was positively associated with colorectal cancer risk in men (HR = 1.17; 95% CI: 1.08–1.26; I(2) = 0%) and a similar HR in women (1.13; 95% CI: 0.82–1.56; I(2) = 46%), but with a confidence interval including the null. Diabetes was inversely associated with prostate cancer risk (HR = 0.81; 95% CI: 0.77–0.85; I(2) = 0%), but not with postmenopausal breast cancer (HR = 0.96; 95% CI: 0.89–1.03; I(2) = 0%). In exploratory subgroup analyses, diabetes was inversely associated with prostate cancer risk only in men with overweight or obesity. CONCLUSIONS: Prevalent diabetes was positively associated with colorectal cancer risk and inversely associated with prostate cancer risk in older Europeans and Americans.
Published: 2021

14. 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

15. Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival

Author: Labadie, JD, Savas, S, Harrison, TA, Banbury, B, Huang, Y, Buchanan, DD, Campbell, PT, Gallinger, SJ, Giles, GG, Gunter, MJ, Hoffmeister, M, Hsu, L, Jenkins, MA, Lin, Y, Ogino, S, Phipps, A, Slattery, ML, Steinfelder, RS, Sun, W, Van Guelpen, B, Hua, X, Figuieredo, JC, Pai, RK, Nassir, R, Qi, L, Chan, AT, Peters, U, Newcomb, PA, Labadie, JD, Savas, S, Harrison, TA, Banbury, B, Huang, Y, Buchanan, DD, Campbell, PT, Gallinger, SJ, Giles, GG, Gunter, MJ, Hoffmeister, M, Hsu, L, Jenkins, MA, Lin, Y, Ogino, S, Phipps, A, Slattery, ML, Steinfelder, RS, Sun, W, Van Guelpen, B, Hua, X, Figuieredo, JC, Pai, RK, Nassir, R, Qi, L, Chan, AT, Peters, U, and Newcomb, PA
Abstract: Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10-8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30-1.69, p = 8.47 × 10-9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65-2.77, p = 9.19 × 10-9 and rs144717887, HR = 2.01, 95% CI 1.57-2.58, p = 3.14 × 10-8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.
Published: 2022

16. Metabolic Signatures of Healthy Lifestyle Patterns and Colorectal Cancer Risk in a European Cohort.

Author: Rothwell, JA, Murphy, N, Bešević, J, Kliemann, N, Jenab, M, Ferrari, P, Achaintre, D, Gicquiau, A, Vozar, B, Scalbert, A, Huybrechts, I, Freisling, H, Prehn, C, Adamski, J, Cross, AJ, Pala, VM, Boutron-Ruault, M-C, Dahm, CC, Overvad, K, Gram, IT, Sandanger, TM, Skeie, G, Jakszyn, P, Tsilidis, KK, Aleksandrova, K, Schulze, MB, Hughes, DJ, van Guelpen, B, Bodén, S, Sánchez, M-J, Schmidt, JA, Katzke, V, Kühn, T, Colorado-Yohar, S, Tumino, R, Bueno-de-Mesquita, B, Vineis, P, Masala, G, Panico, S, Eriksen, AK, Tjønneland, A, Aune, D, Weiderpass, E, Severi, G, Chajès, V, Gunter, MJ, Rothwell, JA, Murphy, N, Bešević, J, Kliemann, N, Jenab, M, Ferrari, P, Achaintre, D, Gicquiau, A, Vozar, B, Scalbert, A, Huybrechts, I, Freisling, H, Prehn, C, Adamski, J, Cross, AJ, Pala, VM, Boutron-Ruault, M-C, Dahm, CC, Overvad, K, Gram, IT, Sandanger, TM, Skeie, G, Jakszyn, P, Tsilidis, KK, Aleksandrova, K, Schulze, MB, Hughes, DJ, van Guelpen, B, Bodén, S, Sánchez, M-J, Schmidt, JA, Katzke, V, Kühn, T, Colorado-Yohar, S, Tumino, R, Bueno-de-Mesquita, B, Vineis, P, Masala, G, Panico, S, Eriksen, AK, Tjønneland, A, Aune, D, Weiderpass, E, Severi, G, Chajès, V, and Gunter, MJ
Abstract: BACKGROUND & AIMS: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort. METHODS: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression. RESULTS: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29-0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50-0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86-1.00) overall. Signature associations were stronger in male compared with female participants. CONCLUSIONS: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.
Published: 2022

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

Author: Nimptsch, K, Aleksandrova, K, Fedirko, V, Jenab, M, Gunter, MJ, Siersema, PD, Wu, K, Katzke, V, Kaaks, R, Panico, S, Palli, D, May, AM, Sieri, S, Bueno-de-Mesquita, B, Standahl, K, Sánchez, M-J, Perez-Cornago, A, Olsen, A, Tjønneland, A, Bonet, CB, Dahm, CC, Chirlaque, M-D, Fiano, V, Tumino, R, Gurrea, AB, Boutron-Ruault, M-C, Menegaux, F, Severi, G, van Guelpen, B, Lee, Y-A, Pischon, T, Nimptsch, K, Aleksandrova, K, Fedirko, V, Jenab, M, Gunter, MJ, Siersema, PD, Wu, K, Katzke, V, Kaaks, R, Panico, S, Palli, D, May, AM, Sieri, S, Bueno-de-Mesquita, B, Standahl, K, Sánchez, M-J, Perez-Cornago, A, Olsen, A, Tjønneland, A, Bonet, CB, Dahm, CC, Chirlaque, M-D, Fiano, V, Tumino, R, Gurrea, AB, Boutron-Ruault, M-C, Menegaux, F, Severi, G, van Guelpen, B, Lee, Y-A, and Pischon, T
Abstract: BACKGROUND: The role of elevated pre-diagnostic C-reactive protein (CRP) concentrations on mortality in individuals with colorectal cancer (CRC) remains unclear. METHODS: We investigated the association between pre-diagnostic high-sensitivity CRP concentrations and CRP genetic variation associated with circulating CRP and CRC-specific and all-cause mortality based on data from 1,235 individuals with CRC within the European Prospective Investigation into Cancer and Nutrition cohort using multivariable-adjusted Cox proportional hazards regression. RESULTS: During a median follow-up of 9.3 years, 455 CRC-specific deaths were recorded, out of 590 deaths from all causes. Pre-diagnostic CRP concentrations were not associated with CRC-specific (hazard ratio, HR highest versus lowest quintile 0.92, 95% confidence interval, CI 0.66, 1.28) or all-cause mortality (HR 0.91, 95% CI 0.68, 1.21). Genetic predisposition to higher CRP (weighted score based on alleles of four CRP SNPs associated with higher circulating CRP) was not significantly associated with CRC-specific mortality (HR per CRP-score unit 0.95, 95% CI 0.86, 1.05) or all-cause mortality (HR 0.98, 95% CI 0.90, 1.07). Among four investigated CRP genetic variants, only SNP rs1205 was significantly associated with CRC-specific (comparing the CT and CC genotypes with TT genotype, HR 0.54, 95% CI 0.35, 0.83 and HR 0.58, 95% CI 0.38, 0.88, respectively) and all-cause mortality (HR 0.58, 95% CI 0.40, 0.85 and 0.64, 95% CI 0.44, 0.92, respectively). CONCLUSIONS: The results of this prospective cohort study do not support a role of pre-diagnostic CRP concentrations on mortality in individuals with CRC. The observed associations with rs1205 deserve further scientific attention.
Published: 2022

18. 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

19. Dietary Folate Intake and Breast Cancer Risk: European Prospective Investigation Into Cancer and Nutrition

Author: de Batlle, J., Ferrari, P., Chajes, V., Park, J. Y., Slimani, N., McKenzie, F., Overvad, K., Roswall, N., Tjønneland, A., Boutron-Ruault, M. C., Clavel-Chapelon, F., Fagherazzi, G., Katzke, V., Kaaks, R., Bergmann, M. M., Trichopoulou, A., Lagiou, P., Trichopoulos, D., Palli, D., Sieri, S., Panico, S., Tumino, R., Vineis, P., Bueno-de-Mesquita, H. B., Peeters, P. H., Hjartåker, A., Engeset, D., Weiderpass, E., Sánchez, S., Travier, N., Sánchez, M. J., Amiano, P., Chirlaque, M. D., Barricarte Gurrea, A., Khaw, K. T., Key, T. J., Bradbury, K. E., Ericson, U., Sonestedt, E., Van Guelpen, B., Schneede, J., Riboli, E., and Romieu, I.
Published: 2015
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20. Modified Mediterranean diet and survival after myocardial infarction: the EPIC-Elderly study

Author: Trichopoulou, A., Bamia, C., Norat, T., Overvad, K., Schmidt, E. B., Tjønneland, A., Halkjær, J., Clavel-Chapelon, F., Vercambre, M. -N., Boutron-Ruault, M. -C., Linseisen, J., Rohrmann, S., Boeing, H., Weikert, C., Benetou, V., Psaltopoulou, T., Orfanos, P., Boffetta, P., Masala, G., Pala, V., Panico, S., Tumino, R., Sacerdote, C., Bueno-de-Mesquita, H. B., Ocke, M. C., Peeters, P. H., Van der Schouw, Y. T., González, C., Sanchez, M. J., Chirlaque, M. D., Moreno, C., Larrañaga, N., Van Guelpen, B., Jansson, J. -H., Bingham, S., Khaw, K. -T., Spencer, E. A., Key, T., Riboli, E., and Trichopoulos, D.
Published: 2007

21. 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

22. Response to Li and Hopper.

Author: Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Huyghe J.R., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., Hsu L., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Huyghe J.R., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., and Hsu L.
Published: 2021

23. 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

24. Salicylic acid and risk of colorectal cancer: A two-sample mendelian randomization study.

Author: Nounu A., Richmond R.C., Stewart I.D., Surendran P., Wareham N.J., Butterworth A., Weinstein S.J., Albanes D., Baron J.A., Hopper J.L., Figueiredo J.C., Newcomb P.A., Lindor N.M., Casey G., Platz E.A., Marchand L.L., Ulrich C.M., Li C.I., van Dujinhoven F.J.B., Gsur A., Campbell P.T., Moreno V., Vodicka P., Vodickova L., Amitay E., Alwers E., Chang-Claude J., Sakoda L.C., Slattery M.L., Schoen R.E., Gunter M.J., Castellvi-Bel S., Kim H.-R., Kweon S.-S., Chan A.T., Li L., Zheng W., Bishop D.T., Buchanan D.D., Giles G.G., Gruber S.B., Rennert G., Stadler Z.K., Harrison T.A., Lin Y., Keku T.O., Woods M.O., Schafmayer C., Van Guelpen B., Gallinger S., Hampel H., Berndt S.I., Pharoah P.D.P., Lindblom A., Wolk A., Wu A.H., White E., Peters U., Drew D.A., Scherer D., Bermejo J.L., Brenner H., Hoffmeister M., Williams A.C., Relton C.L., Nounu A., Richmond R.C., Stewart I.D., Surendran P., Wareham N.J., Butterworth A., Weinstein S.J., Albanes D., Baron J.A., Hopper J.L., Figueiredo J.C., Newcomb P.A., Lindor N.M., Casey G., Platz E.A., Marchand L.L., Ulrich C.M., Li C.I., van Dujinhoven F.J.B., Gsur A., Campbell P.T., Moreno V., Vodicka P., Vodickova L., Amitay E., Alwers E., Chang-Claude J., Sakoda L.C., Slattery M.L., Schoen R.E., Gunter M.J., Castellvi-Bel S., Kim H.-R., Kweon S.-S., Chan A.T., Li L., Zheng W., Bishop D.T., Buchanan D.D., Giles G.G., Gruber S.B., Rennert G., Stadler Z.K., Harrison T.A., Lin Y., Keku T.O., Woods M.O., Schafmayer C., Van Guelpen B., Gallinger S., Hampel H., Berndt S.I., Pharoah P.D.P., Lindblom A., Wolk A., Wu A.H., White E., Peters U., Drew D.A., Scherer D., Bermejo J.L., Brenner H., Hoffmeister M., Williams A.C., and Relton C.L.
Abstract: Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR:1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI:0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.Copyright © 2021 by the authors. Li-censee MDPI, Basel, Switzerland.
Published: 2021

25. 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

26. Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes and tumor location.

Author: Labadie J.D., Harrison T.A., Banbury B., Amtay E.L., Bernd S., Brenner H., Buchanan D.D., Campbell P.T., Cao Y., Chan A.T., Chang-Claude J., Englishc D., Figueiredo J.C., Gallingerc S.J., Gilesc G.G., Gunter M.J., Hoffmeisterc M., Hsu L., Jenkins M.A., Lin Y., Milnec R.L., Moreno V., Murphyc N., Ogino S., Phipps A.I., Sakoda L.C., Slattery M.L., Southey M.C., Sun W., Thibodeau S.N., Van Guelpen B., Zaidi S.H., Peters U., Newcomb P.A., Labadie J.D., Harrison T.A., Banbury B., Amtay E.L., Bernd S., Brenner H., Buchanan D.D., Campbell P.T., Cao Y., Chan A.T., Chang-Claude J., Englishc D., Figueiredo J.C., Gallingerc S.J., Gilesc G.G., Gunter M.J., Hoffmeisterc M., Hsu L., Jenkins M.A., Lin Y., Milnec R.L., Moreno V., Murphyc N., Ogino S., Phipps A.I., Sakoda L.C., Slattery M.L., Southey M.C., Sun W., Thibodeau S.N., Van Guelpen B., Zaidi S.H., Peters U., and Newcomb P.A.
Abstract: Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. Method(s): We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: Adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2- sided. Result(s): Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; Phet =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; Phet =.01) tumors. Conclusion(s): We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.Copy
Published: 2021

27. A combined proteomics and mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer.

Author: Pharoah P.D.P., Nounu A., Greenhough A., Heesom K.J., Richmond R.C., Zheng J., Weinstein S.J., Albanes D., Gallinger S., Hampel H., Berndt S.I., Lindblom A., Wolk A., Wu A.H., White E., Peters U., Drew D.A., Scherer D., Bermejo J.L., Williams A.C., Relton C.L., Baron J.A., Hopper J.L., Figueiredo J.C., Newcomb P.A., Lindor N.M., Casey G., Platz E.A., Le Marchand L., Ulrich C.M., Li C.I., van Duijnhoven F.J.B., Gsur A., Campbell P.T., Moreno V., Vodicka P., Vodickova L., Brenner H., Chang-Claude J., Hoffmeister M., Sakoda L.C., Slattery M.L., Schoen R.E., Gunter M.J., Castellvi-Bel S., Kim H.R., Kweon S.-S., Chan A.T., Li L., Zheng W., Bishop D.T., Buchanan D.D., Giles G.G., Gruber S.B., Rennert G., Stadler Z.K., Harrison T.A., Lin Y., Keku T.O., Woods M.O., Schafmayer C., van Guelpen B., Pharoah P.D.P., Nounu A., Greenhough A., Heesom K.J., Richmond R.C., Zheng J., Weinstein S.J., Albanes D., Gallinger S., Hampel H., Berndt S.I., Lindblom A., Wolk A., Wu A.H., White E., Peters U., Drew D.A., Scherer D., Bermejo J.L., Williams A.C., Relton C.L., Baron J.A., Hopper J.L., Figueiredo J.C., Newcomb P.A., Lindor N.M., Casey G., Platz E.A., Le Marchand L., Ulrich C.M., Li C.I., van Duijnhoven F.J.B., Gsur A., Campbell P.T., Moreno V., Vodicka P., Vodickova L., Brenner H., Chang-Claude J., Hoffmeister M., Sakoda L.C., Slattery M.L., Schoen R.E., Gunter M.J., Castellvi-Bel S., Kim H.R., Kweon S.-S., Chan A.T., Li L., Zheng W., Bishop D.T., Buchanan D.D., Giles G.G., Gruber S.B., Rennert G., Stadler Z.K., Harrison T.A., Lin Y., Keku T.O., Woods M.O., Schafmayer C., and van Guelpen B.
Abstract: Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. Method(s): Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N 1/4 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N 1/4 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). Result(s): Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively). Conclusion(s): MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.Copyright ©2020 American Association for Cancer Research.
Published: 2021

28. Prevalent diabetes and risk of total, colorectal, prostate and breast cancers in an ageing population: meta-analysis of individual participant data from cohorts of the CHANCES consortium

Author: IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Sub Algemeen Theoretical Physics, Amadou, A., Freisling, H., Jenab, M., Tsilidis, K.K., Trichopoulou, A., Boffetta, P., Van Guelpen, B., Mokoroa, O., Wilsgaard, T., Kee, F., Schöttker, B., Ordóñez-Mena, J.M., Männistö, S., Söderberg, S., Vermeulen, R.C.H., Quirós, J.R., Liao, L.M., Sinha, R., Kuulasmaa, K., Brenner, H., Romieu, I., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Sub Algemeen Theoretical Physics, Amadou, A., Freisling, H., Jenab, M., Tsilidis, K.K., Trichopoulou, A., Boffetta, P., Van Guelpen, B., Mokoroa, O., Wilsgaard, T., Kee, F., Schöttker, B., Ordóñez-Mena, J.M., Männistö, S., Söderberg, S., Vermeulen, R.C.H., Quirós, J.R., Liao, L.M., Sinha, R., Kuulasmaa, K., Brenner, H., and Romieu, I.
Published: 2021

29. Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study

Author: Nounu, A, Richmond, RC, Stewart, ID, Surendran, P, Wareham, NJ, Butterworth, A, Weinstein, SJ, Albanes, D, Baron, JA, Hopper, JL, Figueiredo, JC, Newcomb, PA, Lindor, NM, Casey, G, Platz, EA, Marchand, LL, Ulrich, CM, Li, CI, van Dujinhoven, FJB, Gsur, A, Campbell, PT, Moreno, V, Vodicka, P, Vodickova, L, Amitay, E, Alwers, E, Chang-Claude, J, Sakoda, LC, Slattery, ML, Schoen, RE, Gunter, MJ, Castellvi-Bel, S, Kim, H-R, Kweon, S-S, Chan, AT, Li, L, Zheng, W, Bishop, DT, Buchanan, DD, Giles, GG, Gruber, SB, Rennert, G, Stadler, ZK, Harrison, TA, Lin, Y, Keku, TO, Woods, MO, Schafmayer, C, Van Guelpen, B, Gallinger, S, Hampel, H, Berndt, SI, Pharoah, PDP, Lindblom, A, Wolk, A, Wu, AH, White, E, Peters, U, Drew, DA, Scherer, D, Bermejo, JL, Brenner, H, Hoffmeister, M, Williams, AC, Relton, CL, Nounu, A, Richmond, RC, Stewart, ID, Surendran, P, Wareham, NJ, Butterworth, A, Weinstein, SJ, Albanes, D, Baron, JA, Hopper, JL, Figueiredo, JC, Newcomb, PA, Lindor, NM, Casey, G, Platz, EA, Marchand, LL, Ulrich, CM, Li, CI, van Dujinhoven, FJB, Gsur, A, Campbell, PT, Moreno, V, Vodicka, P, Vodickova, L, Amitay, E, Alwers, E, Chang-Claude, J, Sakoda, LC, Slattery, ML, Schoen, RE, Gunter, MJ, Castellvi-Bel, S, Kim, H-R, Kweon, S-S, Chan, AT, Li, L, Zheng, W, Bishop, DT, Buchanan, DD, Giles, GG, Gruber, SB, Rennert, G, Stadler, ZK, Harrison, TA, Lin, Y, Keku, TO, Woods, MO, Schafmayer, C, Van Guelpen, B, Gallinger, S, Hampel, H, Berndt, SI, Pharoah, PDP, Lindblom, A, Wolk, A, Wu, AH, White, E, Peters, U, Drew, DA, Scherer, D, Bermejo, JL, Brenner, H, Hoffmeister, M, Williams, AC, and Relton, CL
Abstract: Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.
Published: 2021

30. 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

31. Association Between Smoking and Molecular Subtypes of Colorectal Cancer

Author: Wang, X, Amitay, E, Harrison, TA, Banbury, BL, Berndt, S, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Gallinger, SJ, Giannakis, M, Giles, GG, Gunter, MJ, Hopper, JL, Jenkins, MA, Lin, Y, Moreno, V, Nishihara, R, Newcomb, PA, Ogino, S, Phipps, A, Sakoda, LC, Schoen, RE, Slattery, ML, Song, M, Sun, W, Thibodeau, SN, Toland, AE, Van Guelpen, B, Woods, MO, Hsu, L, Hoffmeister, M, Peters, U, Wang, X, Amitay, E, Harrison, TA, Banbury, BL, Berndt, S, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Gallinger, SJ, Giannakis, M, Giles, GG, Gunter, MJ, Hopper, JL, Jenkins, MA, Lin, Y, Moreno, V, Nishihara, R, Newcomb, PA, Ogino, S, Phipps, A, Sakoda, LC, Schoen, RE, Slattery, ML, Song, M, Sun, W, Thibodeau, SN, Toland, AE, Van Guelpen, B, Woods, MO, Hsu, L, Hoffmeister, M, and Peters, U
Abstract: BACKGROUND: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. METHODS: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. RESULTS: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P trend < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; P difference = 2.1 x 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (P difference < .001). CONCLUSION: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.
Published: 2021

32. Prediagnostic Blood Selenium Status and Mortality among Patients with Colorectal Cancer in Western European Populations

Author: Baker, JR, Umesh, S, Jenab, M, Schomburg, L, Tjonneland, A, Olsen, A, Boutron-Ruault, M-C, Rothwell, JA, Severi, G, Katzke, V, Johnson, T, Schulze, MB, Masala, G, Agnoli, C, Simeon, V, Tumino, R, Bueno-de-Mesquita, HB, Gram, IT, Skeie, G, Bonet, C, Rodriguez-Barranco, M, Houerta, JM, Gylling, B, Van Guelpen, B, Perez-Cornago, A, Aglago, E, Freisling, H, Weiderpass, E, Cross, AJ, Heath, AK, Hughes, DJ, Fedirko, V, Baker, JR, Umesh, S, Jenab, M, Schomburg, L, Tjonneland, A, Olsen, A, Boutron-Ruault, M-C, Rothwell, JA, Severi, G, Katzke, V, Johnson, T, Schulze, MB, Masala, G, Agnoli, C, Simeon, V, Tumino, R, Bueno-de-Mesquita, HB, Gram, IT, Skeie, G, Bonet, C, Rodriguez-Barranco, M, Houerta, JM, Gylling, B, Van Guelpen, B, Perez-Cornago, A, Aglago, E, Freisling, H, Weiderpass, E, Cross, AJ, Heath, AK, Hughes, DJ, and Fedirko, V
Abstract: A higher selenium (Se) status has been shown to be associated with lower risk for colorectal cancer (CRC), but the importance of Se in survival after CRC diagnosis is not well studied. The associations of prediagnostic circulating Se status (as indicated by serum Se and selenoprotein P (SELENOP) measurements) with overall and CRC-specific mortality were estimated using multivariable Cox proportional hazards regression among 995 CRC cases (515 deaths, 396 from CRC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Se and SELENOP serum concentrations were measured on average 46 months before CRC diagnosis. Median follow-up time was 113 months. Participants with Se concentrations in the highest quintile (≥100 µg/L) had a multivariable-adjusted hazard ratio (HR) of 0.73 (95% CI: 0.52-1.02; Ptrend = 0.06) for CRC-specific mortality and 0.77 (95% CI: 0.57-1.03; Ptrend = 0.04) for overall mortality, compared with the lowest quintile (≤67.5 µg/L). Similarly, participants with SELENOP concentrations in the highest (≥5.07 mg/L) compared with the lowest quintile (≤3.53 mg/L) had HRs of 0.89 (95% CI: 0.64-1.24; Ptrend = 0.39) for CRC-specific mortality and 0.83 (95% CI: 0.62-1.11; Ptrend = 0.17) for overall mortality. Higher prediagnostic exposure to Se within an optimal concentration (100-150 µg/L) might be associated with improved survival among CRC patients, although our results were not statistically significant and additional studies are needed to confirm this potential association. Our findings may stimulate further research on selenium's role in survival among CRC patients especially among those residing in geographic regions with suboptimal Se availability.
Published: 2021

33. 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

34. Low-carbohydrate, high-protein score and mortality in a northern Swedish population-based cohort

Author: Nilsson, L M, Winkvist, A, Eliasson, M, Jansson, J-H, Hallmans, G, Johansson, I, Lindahl, B, Lenner, P, and Van Guelpen, B
Published: 2012
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35. Validity of food frequency questionnaire estimated intakes of folate and other B vitamins in a region without folic acid fortification

Author: Johansson, I, Van Guelpen, B, Hultdin, J, Johansson, M, Hallmans, G, and Stattin, P
Published: 2010
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36. Eating out of home: energy, macro- and micronutrient intakes in 10 European countries. The European Prospective Investigation into Cancer and Nutrition

Author: Orfanos, P., Naska, A., Trichopoulou, A., Grioni, S., Boer, J.M.A., van Bakel, M.M.E., Ericson, U., Rohrmann, S., Boeing, H., Rodriguez, L., Ardanaz, E., Sacerdote, C., Giurdanella, M.C., Niekerk, E.M., Peeters, P.H.M., Manjer, J., van Guelpen, B., Deharveng, G., Skeie, G., Engeset, D., Halkjaer, J., Jensen, A.M., McTaggart, A., Crowe, F., Stratigakou, V., Oikonomou, E., Touvier, M., Niravong, M., Riboli, E., Bingham, S., and Slimani, N.
Subjects: Beverages -- Investigations -- Health aspects -- Nutritional aspects -- Research, Life style -- Health aspects -- Nutritional aspects -- Investigations -- Research, Cancer -- Risk factors, Convenience foods -- Nutritional aspects -- Research -- Investigations -- Health aspects, Diet -- Health aspects -- Investigations -- Research -- Nutritional aspects, Company legal issue, Food/cooking/nutrition, Health
Abstract: Objectives: To assess the contribution of out-of-home (OH) energy and nutrient intake to total dietary intake, and to compare out- versus in-home nutrient patterns among 27 centres in 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods: Between 1995 and 2000, 36 034 participants aged between 35-74 years completed a standardized 24-h dietary recall using a software programme (EPIC-Soft) that recorded the place of food/drink consumption. Eating OH was defined as the consumption of foods and beverages anywhere other than in household premises, irrespective of the place of purchase/preparation. Nutrient intakes were estimated using a standardized nutrient database. Mean intakes were adjusted for age and weighted by season and day of recall. Results: Among women, OH eating contributed more to total fat intake than to intakes of protein and carbohydrates. Among both genders, and particularly in southern Europe, OH eating contributed more to sugar and starch intakes and less to total fibre intake. The contribution of OH eating was also lower for calcium and vitamin C intakes. The composition of diet at home was different from that consumed out of home in southern countries, but was relatively similar in the north. Conclusions: In northern Europe, OH and in-home eating are homogeneous, whereas southern Europeans consider OH eating as a distinctive occasion. In most centres, women selected more fat-rich items when eating out. doi: 10.1038/ejcn.2009.84 Keywords: eating out of home; 24-h dietary recall; EPIC; EPIC-Soft; nutrients; standardization, Introduction Modern living has led to an increase in the frequency and variety of meals and snacks consumed away from home. This trend shows no signs of future decline, which, [...]
Published: 2009
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37. Dietary intake of the water-soluble vitamins B1, B2, B6, B12 and C in 10 countries in the European Prospective Investigation into Cancer and Nutrition

Author: Olsen, A., Halkjaer, J., van Gils, C.H., Buijsse, B., Verhagen, H., Jenab, M., Boutron-Ruault, M.C., Ericson, U., Ocke, M.C., Peeters, P.H.M., Touvier, M., Niravong, M., Waaseth, M., Skeie, G., Khaw, K.T., Travis, R., Ferrari, P., Sanchez, M.J., Agudo, A., Overvad, K., Linseisen, J., Weikert, C., Sacerdote, C., Evangelista, A., Zylis, D., Tsiotas, K., Manjer, J., van Guelpen, B., Riboli, E., Slimani, N., and Bingham, S.
Subjects: Oncology, Experimental -- Health aspects, Vitamin C -- Health aspects -- Research, Vitamin B -- Health aspects -- Research, Cancer -- Research, Vitamin B in human nutrition -- Research -- Health aspects, Vitamin B complex -- Health aspects -- Research, Recommended daily allowances -- Research -- Health aspects, Food/cooking/nutrition, Health
Abstract: Objectives: To describe the intake of vitamins thiamine (B1), riboflavin (B2), B6 (pyridoxine), B12 (cobalamine) and C (ascorbic acid) and their food sources among 27 centres in 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods: Between 1995 and 2000, 36 034 persons aged between 35 and 74 years were administered a standardized 24-h dietary recall using a computerized interview software programme (EPIC-SOFT). Intakes of the four B vitamins and vitamin C were estimated using the standardized EPIC Nutrient Database (ENDB). Mean intakes were adjusted for age and weighted by season and day of recall. Results: Intake of B vitamins did not vary considerably between centres, except in the UK health-conscious cohort, in which substantially higher intakes of thiamine and lower intakes of vitamin B12 were reported compared with other centres. Overall, meat was the most important contributor to the B vitamins in all centres except in the UK health-conscious group. Vitamin C showed a clear geographical gradient, with higher intakes in the southern centres as compared with the northern ones; this was more pronounced in men than in women. Vegetables and fruits were major contributors to vitamin C in all centres, but juices and potatoes were also important sources in the northern centres. Conclusions: This study showed no major differences across centres in the mean intakes of B vitamins (thiamine, riboflavin, B6, B12), whereas a tendency towards a north-south gradient was observed for vitamin C. doi: 10.1038/ejcn.2009.78 Keywords: water-soluble vitamins; 24-h dietary recall; standardization; ENDB; EPIC; Europe, Introduction The B vitamins, together with vitamin C, constitute the water-soluble group of vitamins. Classic syndromes caused by a deficiency of water-soluble vitamins, such as scurvy (vitamin C) and beriberi [...]
Published: 2009
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38. Consumption of Fish and Long-chain n-3 Polyunsaturated Fatty Acids Is Associated With Reduced Risk of Colorectal Cancer in a Large European Cohort

Author: Aglago, E.K. Huybrechts, I. Murphy, N. Casagrande, C. Nicolas, G. Pischon, T. Fedirko, V. Severi, G. Boutron-Ruault, M.-C. Fournier, A. Katzke, V. Kühn, T. Olsen, A. Tjønneland, A. Dahm, C.C. Overvad, K. Lasheras, C. Agudo, A. Sánchez, M.-J. Amiano, P. Huerta, J.M. Ardanaz, E. Perez-Cornago, A. Trichopoulou, A. Karakatsani, A. Martimianaki, G. Palli, D. Pala, V. Tumino, R. Naccarati, A. Panico, S. Bueno-de-Mesquita, B. May, A. Derksen, J.W.G. Hellstrand, S. Ohlsson, B. Wennberg, M. Van Guelpen, B. Skeie, G. Brustad, M. Weiderpass, E. Cross, A.J. Ward, H. Riboli, E. Norat, T. Chajes, V. Gunter, M.J.
Abstract: Background & Aims: There is an unclear association between intake of fish and long-chain n-3 polyunsaturated fatty acids (n-3 LC-PUFAs) and colorectal cancer (CRC). We examined the association between fish consumption, dietary and circulating levels of n-3 LC-PUFAs, and ratio of n-6:n-3 LC-PUFA with CRC using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: Dietary intake of fish (total, fatty/oily, lean/white) and n-3 LC-PUFA were estimated by food frequency questionnaires given to 521,324 participants in the EPIC study; among these, 6291 individuals developed CRC (median follow up, 14.9 years). Levels of phospholipid LC-PUFA were measured by gas chromatography in plasma samples from a sub-group of 461 CRC cases and 461 matched individuals without CRC (controls). Multivariable Cox proportional hazards and conditional logistic regression models were used to calculate hazard ratios (HRs) and odds ratios (ORs), respectively, with 95% CIs. Results: Total intake of fish (HR for quintile 5 vs 1, 0.88; 95% CI, 0.80–0.96; Ptrend = .005), fatty fish (HR for quintile 5 vs 1, 0.90; 95% CI, 0.82–0.98; Ptrend = .009), and lean fish (HR for quintile 5 vs 1, 0.91; 95% CI, 0.83–1.00; Ptrend = .016) were inversely associated with CRC incidence. Intake of total n-3 LC-PUFA (HR for quintile 5 vs 1, 0.86; 95% CI, 0.78–0.95; Ptrend = .010) was also associated with reduced risk of CRC, whereas dietary ratio of n-6:n-3 LC-PUFA was associated with increased risk of CRC (HR for quintile 5 vs 1, 1.31; 95% CI, 1.18–1.45; Ptrend < .001). Plasma levels of phospholipid n-3 LC-PUFA was not associated with overall CRC risk, but an inverse trend was observed for proximal compared with distal colon cancer (Pheterogeneity = .026). Conclusions: In an analysis of dietary patterns of participants in the EPIC study, we found regular consumption of fish, at recommended levels, to be associated with a lower risk of CRC, possibly through exposure to n-3 LC-PUFA. Levels of n-3 LC-PUFA in plasma were not associated with CRC risk, but there may be differences in risk at different regions of the colon. © 2020 AGA Institute
Published: 2020

39. 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

40. 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

41. Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Author: Huyghe J.R., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., Hsu L., Huyghe J.R., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., and Hsu L.
Abstract: Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might be
Published: 2020

42. Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses.

Author: English D., Van Guelpen B., Visvanathan K., Vodicka P., Vodickova L., Vymetalkova V., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Zheng W., Peters U., Gunter M.J., Murphy N., Carreras-Torres R., Song M., Chan A.T., Martin R.M., Papadimitriou N., Dimou N., Tsilidis K.K., Banbury B., Bradbury K.E., Besevic J., Rinaldi S., Riboli E., Cross A.J., Travis R.C., Agnoli C., Albanes D., Berndt S.I., Bezieau S., Bishop D.T., Brenner H., Buchanan D.D., Onland-Moret N.C., Burnett-Hartman A., Campbell P.T., Casey G., Castellvi-Bel S., Chang-Claude J., Chirlaque M.-D., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Giles G.G., Gruber S.B., Gsur A., Hampe J., Hampel H., Harrison T.A., Hoffmeister M., Hsu L., Huang W.-Y., Huyghe J.R., Jenkins M.A., Keku T.O., Kuhn T., Kweon S.-S., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., Milne R.L., Moreno V., Newcomb P.A., Offit K., Ogino S., Ose J., Perduca V., Phipps A.I., Platz E.A., Potter J.D., Qu C., Rennert G., Sakoda L.C., Schafmayer C., Schoen R.E., Slattery M.L., Tangen C.M., Ulrich C.M., van Duijnhoven F.J.B., English D., Van Guelpen B., Visvanathan K., Vodicka P., Vodickova L., Vymetalkova V., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Zheng W., Peters U., Gunter M.J., Murphy N., Carreras-Torres R., Song M., Chan A.T., Martin R.M., Papadimitriou N., Dimou N., Tsilidis K.K., Banbury B., Bradbury K.E., Besevic J., Rinaldi S., Riboli E., Cross A.J., Travis R.C., Agnoli C., Albanes D., Berndt S.I., Bezieau S., Bishop D.T., Brenner H., Buchanan D.D., Onland-Moret N.C., Burnett-Hartman A., Campbell P.T., Casey G., Castellvi-Bel S., Chang-Claude J., Chirlaque M.-D., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Giles G.G., Gruber S.B., Gsur A., Hampe J., Hampel H., Harrison T.A., Hoffmeister M., Hsu L., Huang W.-Y., Huyghe J.R., Jenkins M.A., Keku T.O., Kuhn T., Kweon S.-S., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., Milne R.L., Moreno V., Newcomb P.A., Offit K., Ogino S., Ose J., Perduca V., Phipps A.I., Platz E.A., Potter J.D., Qu C., Rennert G., Sakoda L.C., Schafmayer C., Schoen R.E., Slattery M.L., Tangen C.M., Ulrich C.M., and van Duijnhoven F.J.B.
Abstract: Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. Method(s): Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) Results: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 x 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 x 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene re
Published: 2020

43. 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

44. Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.

Author: Hsu L., Berndt S.I., Bezieau S., Bishop D.T., Brenner H., Buchanan D.D., Burnett-Hartman A., Casey G., Castellvi-Bel S., Chan A.T., Chang-Claude J., Cross A.J., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Gapstur S.M., Giles G.G., Gruber S.B., Gsur A., Hampe J., Hampel H., Harrison T.A., Hoffmeister M., Huang W.-Y., Huyghe J.R., Jenkins M.A., Joshu C.E., Keku T.O., Kuhn T., Kweon S.-S., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., May A.M., Milne R.L., Moreno V., Newcomb P.A., Offit K., Ogino S., Phipps A.I., Platz E.A., Potter J.D., Qu C., Quiros J.R., Rennert G., Riboli E., Sakoda L.C., Schafmayer C., Schoen R.E., Slattery M.L., Tangen C.M., Tsilidis K.K., Ulrich C.M., van Duijnhoven F.J.B., van Guelpen B., Visvanathan K., Vodicka P., Vodickova L., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Campbell P.T., Zheng W., Peters U., Vincent E.E., Gunter M.J., Bull C.J., Bell J.A., Murphy N., Sanderson E., Davey Smith G., Timpson N.J., Banbury B.L., Albanes D., Hsu L., Berndt S.I., Bezieau S., Bishop D.T., Brenner H., Buchanan D.D., Burnett-Hartman A., Casey G., Castellvi-Bel S., Chan A.T., Chang-Claude J., Cross A.J., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Gapstur S.M., Giles G.G., Gruber S.B., Gsur A., Hampe J., Hampel H., Harrison T.A., Hoffmeister M., Huang W.-Y., Huyghe J.R., Jenkins M.A., Joshu C.E., Keku T.O., Kuhn T., Kweon S.-S., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., May A.M., Milne R.L., Moreno V., Newcomb P.A., Offit K., Ogino S., Phipps A.I., Platz E.A., Potter J.D., Qu C., Quiros J.R., Rennert G., Riboli E., Sakoda L.C., Schafmayer C., Schoen R.E., Slattery M.L., Tangen C.M., Tsilidis K.K., Ulrich C.M., van Duijnhoven F.J.B., van Guelpen B., Visvanathan K., Vodicka P., Vodickova L., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Campbell P.T., Zheng W., Peters U., Vincent E.E., Gunter M.J., Bull C.J., Bell J.A., Murphy N., Sanderson E., Davey Smith G., Timpson N.J., Banbury B.L., and Albanes D.
Abstract: Background: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Method(s): We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Result(s): In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P <= 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative
Published: 2020

45. 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

46. Hemochromatosis risk genotype is not associated with colorectal cancer or age at its diagnosis

Author: Jarvik, GP, Wang, X, Fontanillas, P, Kim, E, Chanprasert, S, Gordon, AS, Bastarache, L, Kowdley, KV, Harrison, T, Rosenthal, EA, Stanaway, IB, Bézieau, S, Weinstein, SJ, Newcomb, PA, Casey, G, Platz, EA, Visvanathan, K, Le Marchand, L, Ulrich, CM, Hardikar, S, Li, CI, van Duijnhoven, FJB, Gsur, A, Campbell, PT, Moreno, V, Vodička, P, Brenner, H, Chang-Claude, J, Hoffmeister, M, Slattery, ML, Gunter, MJ, Aglago, EK, Castellví-Bel, S, Kweon, S-S, Chan, AT, Li, L, Zheng, W, Bishop, DT, Giles, GG, Rennert, G, Offit, K, Keku, TO, Woods, MO, Hampe, J, Van Guelpen, B, Gallinger, SJ, de la Chapelle, A, Hampel, H, Berndt, SI, Tangen, CM, Lindblom, A, Wolk, A, Burnett-Hartman, A, Wu, AH, White, E, Gruber, SB, Jenkins, MA, Mountain, J, Peters, U, Crosslin, DR, Jarvik, GP, Wang, X, Fontanillas, P, Kim, E, Chanprasert, S, Gordon, AS, Bastarache, L, Kowdley, KV, Harrison, T, Rosenthal, EA, Stanaway, IB, Bézieau, S, Weinstein, SJ, Newcomb, PA, Casey, G, Platz, EA, Visvanathan, K, Le Marchand, L, Ulrich, CM, Hardikar, S, Li, CI, van Duijnhoven, FJB, Gsur, A, Campbell, PT, Moreno, V, Vodička, P, Brenner, H, Chang-Claude, J, Hoffmeister, M, Slattery, ML, Gunter, MJ, Aglago, EK, Castellví-Bel, S, Kweon, S-S, Chan, AT, Li, L, Zheng, W, Bishop, DT, Giles, GG, Rennert, G, Offit, K, Keku, TO, Woods, MO, Hampe, J, Van Guelpen, B, Gallinger, SJ, de la Chapelle, A, Hampel, H, Berndt, SI, Tangen, CM, Lindblom, A, Wolk, A, Burnett-Hartman, A, Wu, AH, White, E, Gruber, SB, Jenkins, MA, Mountain, J, Peters, U, and Crosslin, DR
Abstract: Homozygotes for the higher penetrance hemochromatosis risk allele, HFE c.845G>A (p.Cys282Tyr, or C282Y), have been reported to be at a 2- to 3-fold increased risk for colorectal cancer (CRC). These results have been reported for small sample size studies with no information about age at diagnosis for CRC. An association with age at diagnosis might alter CRC screening recommendations. We analyzed two large European ancestry datasets to assess the association of HFE genotype with CRC risk and age at CRC diagnosis. The first dataset included 59,733 CRC or advanced adenoma cases and 72,351 controls from a CRC epidemiological study consortium. The second dataset included 13,564 self-reported CRC cases and 2,880,218 controls from the personal genetics company, 23andMe. No association of the common hereditary hemochromatosis (HH) risk genotype and CRC was found in either dataset. The odds ratios (ORs) for the association of CRC and HFE C282Y homozygosity were 1.08 (95% confidence interval [CI], 0.91–1.29; p = 0.4) and 1.01 (95% CI, 0.78–1.31, p = 0.9) in the two cohorts, respectively. Age at CRC diagnosis also did not differ by HFE C282Y/C282Y genotype in either dataset. These results indicate no increased CRC risk in individuals with HH genotypes and suggest that persons with HH risk genotypes can follow population screening recommendations for CRC.
Published: 2020

47. Postmenopausal Hormone Therapy and Colorectal Cancer Risk by Molecularly Defined Subtypes and Tumor Location

Author: Labadie, JD, Harrison, TA, Banbury, B, Amtay, EL, Bernd, S, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, English, D, Figueiredo, JC, Gallinger, SJ, Giles, GG, Gunter, MJ, Hoffmeister, M, Hsu, L, Jenkins, MA, Lin, Y, Milne, RL, Moreno, V, Murphy, N, Ogino, S, Phipps, A, Sakoda, LC, Slattery, ML, Southey, MC, Sun, W, Thibodeau, SN, Van Guelpen, B, Zaidi, SH, Peters, U, Newcomb, PA, Labadie, JD, Harrison, TA, Banbury, B, Amtay, EL, Bernd, S, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, English, D, Figueiredo, JC, Gallinger, SJ, Giles, GG, Gunter, MJ, Hoffmeister, M, Hsu, L, Jenkins, MA, Lin, Y, Milne, RL, Moreno, V, Murphy, N, Ogino, S, Phipps, A, Sakoda, LC, Slattery, ML, Southey, MC, Sun, W, Thibodeau, SN, Van Guelpen, B, Zaidi, SH, Peters, U, and Newcomb, PA
Abstract: BACKGROUND: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. METHODS: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided. RESULTS: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; P het =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; P het =.01) tumors. CONCLUSIONS: We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.
Published: 2020

48. Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

Author: Bull, CJ, Bell, JA, Murphy, N, Sanderson, E, Davey Smith, G, Timpson, NJ, Banbury, BL, Albanes, D, Berndt, SI, Bezieau, S, Bishop, DT, Brenner, H, Buchanan, DD, Burnett-Hartman, A, Casey, G, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Cross, AJ, de la Chapelle, A, Figueiredo, JC, Gallinger, SJ, Gapstur, SM, Giles, GG, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hsu, L, Huang, W-Y, Huyghe, JR, Jenkins, MA, Joshu, CE, Keku, TO, Kuhn, T, Kweon, S-S, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Martin, V, May, AM, Milne, RL, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Phipps, AI, Platz, EA, Potter, JD, Qu, C, Quiros, JR, Rennert, G, Riboli, E, Sakoda, LC, Schafmayer, C, Schoen, RE, Slattery, ML, Tangen, CM, Tsilidis, KK, Ulrich, CM, van Duijnhoven, FJB, van Guelpen, B, Visvanathan, K, Vodicka, P, Vodickova, L, Wang, H, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Zheng, W, Peters, U, Vincent, EE, Gunter, MJ, Bull, CJ, Bell, JA, Murphy, N, Sanderson, E, Davey Smith, G, Timpson, NJ, Banbury, BL, Albanes, D, Berndt, SI, Bezieau, S, Bishop, DT, Brenner, H, Buchanan, DD, Burnett-Hartman, A, Casey, G, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Cross, AJ, de la Chapelle, A, Figueiredo, JC, Gallinger, SJ, Gapstur, SM, Giles, GG, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hsu, L, Huang, W-Y, Huyghe, JR, Jenkins, MA, Joshu, CE, Keku, TO, Kuhn, T, Kweon, S-S, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Martin, V, May, AM, Milne, RL, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Phipps, AI, Platz, EA, Potter, JD, Qu, C, Quiros, JR, Rennert, G, Riboli, E, Sakoda, LC, Schafmayer, C, Schoen, RE, Slattery, ML, Tangen, CM, Tsilidis, KK, Ulrich, CM, van Duijnhoven, FJB, van Guelpen, B, Visvanathan, K, Vodicka, P, Vodickova, L, Wang, H, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Zheng, W, Peters, U, Vincent, EE, and Gunter, MJ
Abstract: BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative meta
Published: 2020

49. 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

50. Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses

Author: Murphy, N, Carreras-Torres, R, Song, M, Chan, AT, Martin, RM, Papadimitriou, N, Dimou, N, Tsilidis, KK, Banbury, B, Bradbury, KE, Besevic, J, Rinaldi, S, Riboli, E, Cross, AJ, Travis, RC, Agnoli, C, Albanes, D, Berndt, SI, Bezieau, S, Bishop, DT, Brenner, H, Buchanan, DD, Onland-Moret, NC, Burnett-Hartman, A, Campbell, PT, Casey, G, Castellvi-Bel, S, Chang-Claude, J, Chirlaque, M-D, de la Chapelle, A, English, D, Figueiredo, JC, Gallinger, SJ, Giles, GG, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hsu, L, Huang, W-Y, Huyghe, JR, Jenkins, MA, Keku, TO, Kuhn, T, Kweon, S-S, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Martin, V, Milne, RL, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Ose, J, Perduca, V, Phipps, AI, Platz, EA, Potter, JD, Qu, C, Rennert, G, Sakoda, LC, Schafmayer, C, Schoen, RE, Slattery, ML, Tangen, CM, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Wang, H, White, E, Wolk, A, Woods, MO, Wu, AH, Zheng, W, Peters, U, Gunter, MJ, Murphy, N, Carreras-Torres, R, Song, M, Chan, AT, Martin, RM, Papadimitriou, N, Dimou, N, Tsilidis, KK, Banbury, B, Bradbury, KE, Besevic, J, Rinaldi, S, Riboli, E, Cross, AJ, Travis, RC, Agnoli, C, Albanes, D, Berndt, SI, Bezieau, S, Bishop, DT, Brenner, H, Buchanan, DD, Onland-Moret, NC, Burnett-Hartman, A, Campbell, PT, Casey, G, Castellvi-Bel, S, Chang-Claude, J, Chirlaque, M-D, de la Chapelle, A, English, D, Figueiredo, JC, Gallinger, SJ, Giles, GG, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hsu, L, Huang, W-Y, Huyghe, JR, Jenkins, MA, Keku, TO, Kuhn, T, Kweon, S-S, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Martin, V, Milne, RL, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Ose, J, Perduca, V, Phipps, AI, Platz, EA, Potter, JD, Qu, C, Rennert, G, Sakoda, LC, Schafmayer, C, Schoen, RE, Slattery, ML, Tangen, CM, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Wang, H, White, E, Wolk, A, Woods, MO, Wu, AH, Zheng, W, Peters, U, and Gunter, MJ
Abstract: BACKGROUND & AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene regi
Published: 2020

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