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

Author

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

Abstract

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

Published
2024

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

Author

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

Abstract

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

Published
2024

3. 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

4. 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

5. 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

6. 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

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

Author

Dimou, N, Kim, AE, Flanagan, O, Murphy, N, Diez-Obrero, V, Shcherbina, A, Aglago, EK, Bouras, E, Campbell, PT, Casey, G, Gallinger, S, Gruber, SB, Jenkins, MA, Lin, Y, Moreno, V, Ruiz-Narvaez, E, Stern, MC, Tian, Y, Tsilidis, KK, Arndt, V, Barry, EL, Baurley, JW, Berndt, SI, Bezieau, S, Bien, SA, Bishop, DT, Brenner, H, Budiarto, A, Carreras-Torres, R, Cenggoro, TW, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, X, Conti, DV, Dampier, CH, Devall, M, Drew, DA, Figueiredo, JC, Giles, GG, Gsur, A, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jordahl, K, Kawaguchi, E, Keku, TO, Larsson, SC, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, J, Newcomb, PA, Newton, CC, Obon-Santacana, M, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Scacheri, PC, Schoen, RE, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Ulrich, CM, Um, CY, van Duijnhoven, FJB, Visvanathan, K, Vodicka, P, Vodickova, L, White, E, Wolk, A, Woods, MO, Qu, C, Kundaje, A, Hsu, L, Gauderman, WJ, Gunter, MJ, Peters, U, Dimou, N, Kim, AE, Flanagan, O, Murphy, N, Diez-Obrero, V, Shcherbina, A, Aglago, EK, Bouras, E, Campbell, PT, Casey, G, Gallinger, S, Gruber, SB, Jenkins, MA, Lin, Y, Moreno, V, Ruiz-Narvaez, E, Stern, MC, Tian, Y, Tsilidis, KK, Arndt, V, Barry, EL, Baurley, JW, Berndt, SI, Bezieau, S, Bien, SA, Bishop, DT, Brenner, H, Budiarto, A, Carreras-Torres, R, Cenggoro, TW, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, X, Conti, DV, Dampier, CH, Devall, M, Drew, DA, Figueiredo, JC, Giles, GG, Gsur, A, Harrison, TA, Hidaka, A, Hoffmeister, M, Huyghe, JR, Jordahl, K, Kawaguchi, E, Keku, TO, Larsson, SC, Le Marchand, L, Lewinger, JP, Li, L, Mahesworo, B, Morrison, J, Newcomb, PA, Newton, CC, Obon-Santacana, M, Ose, J, Pai, RK, Palmer, JR, Papadimitriou, N, Pardamean, B, Peoples, AR, Pharoah, PDP, Platz, EA, Potter, JD, Rennert, G, Scacheri, PC, Schoen, RE, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Ulrich, CM, Um, CY, van Duijnhoven, FJB, Visvanathan, K, Vodicka, P, Vodickova, L, White, E, Wolk, A, Woods, MO, Qu, C, Kundaje, A, Hsu, L, Gauderman, WJ, Gunter, MJ, and Peters, U

Abstract

BACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10-11) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10-09). DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.

Published
2023

8. 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

9. 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

10. Dietary intake of acrylamide and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Author

Obón-Santacana, M., Slimani, N., Lujan-Barroso, L., Travier, N., Hallmans, G., Freisling, H., Ferrari, P., Boutron-Ruault, M.C., Racine, A., Clavel, F., Saieva, C., Pala, V., Tumino, R., Mattiello, A., Vineis, P., Argüelles, M., Ardanaz, E., Amiano, P., Navarro, C., Sánchez, M.J., Molina Montes, E., Key, T., Khaw, K.-T., Wareham, N., Peeters, P.H., Trichopoulou, A., Bamia, C., Trichopoulos, D., Boeing, H., Kaaks, R., Katzke, V., Ye, W., Sund, M., Ericson, U., Wirfält, E., Overvad, K., Tjønneland, A., Olsen, A., Skeie, G., Åsli, L.A., Weiderpass, E., Riboli, E., Bueno-de-Mesquita, H.B., and Duell, E.J.

Published
2013
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11. 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

12. Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

Author

Georgeson, P, Harrison, TA, Pope, BJ, Zaidi, SH, Qu, C, Steinfelder, RS, Lin, Y, Joo, JE, Mahmood, K, Clendenning, M, Walker, R, Amitay, EL, Berndt, S, Brenner, H, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Doheny, KF, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gsur, A, Gunter, MJ, Hoffmeister, M, Hsu, L, Huang, W-Y, Limburg, P, Manson, JE, Moreno, V, Nassir, R, Nowak, JA, Obon-Santacana, M, Ogino, S, Phipps, A, Potter, JD, Schoen, RE, Sun, W, Toland, AE, Trinh, QM, Ugai, T, Macrae, FA, Rosty, C, Hudson, TJ, Jenkins, MA, Thibodeau, SN, Winship, IM, Peters, U, Buchanan, DD, Georgeson, P, Harrison, TA, Pope, BJ, Zaidi, SH, Qu, C, Steinfelder, RS, Lin, Y, Joo, JE, Mahmood, K, Clendenning, M, Walker, R, Amitay, EL, Berndt, S, Brenner, H, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Doheny, KF, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gsur, A, Gunter, MJ, Hoffmeister, M, Hsu, L, Huang, W-Y, Limburg, P, Manson, JE, Moreno, V, Nassir, R, Nowak, JA, Obon-Santacana, M, Ogino, S, Phipps, A, Potter, JD, Schoen, RE, Sun, W, Toland, AE, Trinh, QM, Ugai, T, Macrae, FA, Rosty, C, Hudson, TJ, Jenkins, MA, Thibodeau, SN, Winship, IM, Peters, U, and Buchanan, DD

Abstract

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.

Published
2022

13. 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

14. Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations

Author

van Duijnhoven, F. J. B., Jenab, M., Hveem, K., Siersema, P. D., Fedirko, V., Duell, E. J., Kampman, E., Halfweeg, A., van Kranen, H. J., van den Ouweland, J. M. W., Weiderpass, E., Langhammer, A., Ness-Jensen, E., Olsen, A., Tjonneland, A., Overvad, K., Cadeau, C., Kvaskoff, M., Boutron-Ruault, M. C., Katzke, V. A., Kuhn, T., Boeing, H., Trichopoulou, A., Kotanidou, A., Kritikou, M., Palli, D., Agnoli, C., Tumino, R., Panico, S., Matullo, G., Peeters, P., Brustad, M., Olsen, K. S., Lasheras, C., Obon-Santacana, M., Sanchez, M. J., Dorronsoro, M., Chirlaque, M. D., Barricarte, A., Manjer, J., Almquist, M., Renstrom, F., Ye, W., Wareham, N., Khaw, K. T., Bradbury, K. E., Freisling, H., Aune, D., Norat, T., Riboli, E., and Bueno-de-Mesquita, H. B. A.

Subjects
SDG 3 - Good Health and Well-being
Abstract

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre‐diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case‐control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord‐Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow‐up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope‐dilution liquid chromatography‐tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42–1.20); 0.94 (0.72–1.22); 1.12 (0.82–1.53) and 1.26 (0.79–2.01) for clinically pre‐defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season‐standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre‐diagnostic concentrations of vitamin D, they are not statistically significant.

Published
2018
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15. GCAT vertical bar Genomes for life: a prospective cohort study of the genomes of Catalonia

Author

Obon-Santacana, M, Vilardell, M, Carreras, A, Duran, X, Velasco, J, Galvan-Femenia, I, Alonso, T, Puig, L, Sumoy, L, Duell, EJ, Perucho, M, Moreno, V, and de Cid, R

Abstract

Purpose The prevalence of chronic non-communicable diseases (NCDs) is increasing worldwide. NCDs are the leading cause of both morbidity and mortality, and it is estimated that by 2030, they will be responsible for 80% of deaths across the world. The Genomes for Life (GCAT) project is a long-term prospective cohort study that was designed to integrate and assess the role of epidemiological, genomic and epigenomic factors in the development of major chronic diseases in Catalonia, a north-east region of Spain. Participants At the end of 2017, the GCAT Study will have recruited 20 000 participants aged 40-65 years. Participants who agreed to take part in the study completed a self-administered computer-driven questionnaire, and underwent blood pressure, cardiac frequency and anthropometry measurements. For each participant, blood plasma, blood serum and white blood cells are collected at baseline. The GCAT Study has access to the electronic health records of the Catalan Public Healthcare System. Participants will he followed biannually at least 20 years after recruitment. Findings to date Among all GCAT participants, 59.2% are women arid 83.3% of the cohort identified themselves as Caucasian/white. More than half of the participants have higher education levels, 72.2% are current workers and 42.1 % are classified as overweight (body mass index >= 25 and

Published
2018

16. Flavonoid and lignan intake and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Author

Molina-Montes, E, Sánchez, MJ, Zamora-Ros, R, Bueno-de-Mesquita, HB, Wark, PA, Obon-Santacana, M, Kühn, T, Katzke, V, Travis, RC, Ye, W, Sund, M, Naccarati, A, Mattiello, A, Krogh, V, Martorana, C, Masala, G, Amiano, P, Huerta, JM, Barricarte, A, Quirós, JR, Weiderpass, E, Åsli, LA, Skeie, G, Ericson, U, Sonestedt, E, Peeters, PH, Romieu, I, Scalbert, A, Overvad, K, Clemens, M, Boeing, H, Trichopoulou, A, Peppa, E, Vidalis, P, Khaw, KT, Wareham, N, Olsen, A, Tjønneland, A, Boutroun-Rualt, MC, Clavel-Chapelon, F, Cross, AJ, Lu, Y, Riboli, E, Duell, EJ, and Imperial College Trust

Subjects
flavonoids, pancreatic cancer, lignans, cohort, Oncology & Carcinogenesis, diet, 1112 Oncology And Carcinogenesis
Abstract

© 2016 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICCDespite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow-up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the US Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center-stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status. Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk (multivariable-adjusted HR for a doubling of intake = 1.03, 95% CI: 0.95–1.11 and 1.02; 95% CI: 0.89–1.17, respectively). Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases (HR for a doubling of intake = 0.96, 95% CI: 0.91–1.00). In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort.

Published
2016

17. Flavonoid and lignan intake and pancreatic cancer risk in the European prospective investigation into cancer and nutrition cohort

Author

Molina-Montes, E., Sanchez, M. J., Zamora-Ros, R., Bueno-de-Mesquita, H. B., Wark, P. A., Obon-Santacana, M., Kuhn, T., Katzke, V., Travis, R. C., Ye, W., Sund, M., Naccarati, A., Mattiello, A., Krogh, V., Martorana, C., Masala, G., Amiano, P., Huerta, J. M., Barricarte, A., Quiros, J. R., Weiderpass, E., Angell Asli, L., Skeie, G., Ericson, U., Sonestedt, E., Peeters, P. H., Romieu, I., Scalbert, A., Overvad, K., Clemens, M., Boeing, H., Trichopoulou, A., Peppa, E., Vidalis, P., Khaw, K. T., Wareham, N., Olsen, A., Tjonneland, A., Boutroun-Rualt, M. C., Clavel-Chapelon, F., Cross, A. J., Riboli, E., and Duell, E. J.

Subjects
SDG 3 - Good Health and Well-being
Abstract

Despite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow-up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the US Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center-stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status. Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk (multivariable-adjusted HR for a doubling of intake 5 1.03, 95% CI: 0.95–1.11 and 1.02; 95% CI: 0.89– 1.17, respectively). Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases (HR for a doubling of intake 5 0.96, 95% CI: 0.91–1.00). In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort.

Published
2016
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18. Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort

Author

Ose, J. Fortner, R. T. Schock, H. Peeters, P. H. and Onland-Moret, N. C. Bueno-de-Mesquita, H. B. Weiderpass, E. and Gram, I. T. Overvad, K. Tjonneland, A. Dossus, L. and Fournier, A. Baglietto, L. Trichopoulou, A. Benetou, V. and Trichopoulos, D. Boeing, H. Masala, G. Krogh, V. and Matiello, A. Tumino, R. Popovic, M. Obon-Santacana, M. and Larranaga, N. Ardanaz, E. Sanchez, M-J Menendez, V. and Chirlaque, M-D Travis, R. C. Khaw, K-T Braendstedt, J. and Idahl, A. Lundin, E. Rinaldi, S. Kuhn, E. Romieu, I. and Gunter, M. J. Merritt, M. A. Riboli, E. Kaaks, R.

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

Background: Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics. Methods: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n = 565 cases). Multivariable conditional logistic regression models were used to estimate associations. Results: We observed no association between IGF-I and EOC overall or by tumour characteristics. Conclusions: In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk.

Published
2015

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

Author

Obon-Santacana, M. Kaaks, R. Slimani, N. Lujan-Barroso, L. and Freisling, H. Ferrari, P. Dossus, L. Chabbert-Buffet, N. and Baglietto, L. Fortner, R. T. Boeing, H. Tjonneland, A. and Olsen, A. Overvad, K. Menendez, V. Molina-Montes, E. and Larranaga, N. Chirlaque, M-D Ardanaz, E. Khaw, K-T and Wareham, N. Travis, R. C. Lu, Y. Merritt, M. A. and Trichopoulou, A. Benetou, V. Trichopoulos, D. Saieva, C. and Sieri, S. Tumino, R. Sacerdote, C. Galasso, R. and Bueno-de-Mesquita, H. B. Wirfalt, E. Ericson, U. Idahl, A. and Ohlson, N. Skeie, G. Gram, I. T. Weiderpass, E. and Onland-Moret, N. C. Riboli, E. Duell, E. J.

Abstract

Background: Three prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The objective of this study was to evaluate the association between acrylamide intake and EC risk: for overall EC, for type-I EC, and in never smokers and never users of oral contraceptives (OCs). Smoking is a source of acrylamide, and OC use is a protective factor for EC risk. Methods: Cox regression was used to estimate hazard ratios (HRs) for the association between acrylamide intake and EC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Acrylamide intake was estimated from the EU acrylamide monitoring database, which was matched with EPIC questionnaire-based food consumption data. Acrylamide intake was energy adjusted using the residual method. Results: No associations were observed between acrylamide intake and overall EC (n = 1382) or type-I EC risk (n = 627). We observed increasing relative risks for type-I EC with increasing acrylamide intake among women who both never smoked and were non-users of OCs (HRQ5vsQ1: 1.97, 95% CI: 1.08-3.62; likelihood ratio test (LRT) P-value: 0.01, n = 203). Conclusions: Dietary intake of acrylamide was not associated with overall or type-I EC risk; however, positive associations with type I were observed in women who were both non-users of OCs and never smokers.

Published
2014

20. Dietary intake of acrylamide and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Author

Obon-Santacana, M. Slimani, N. Lujan-Barroso, L. Travier, N. and Hallmans, G. Freisling, H. Ferrari, P. Boutron-Ruault, M. C. Racine, A. Clavel, F. Saieva, C. Pala, V. and Tumino, R. Mattiello, A. Vineis, P. Argueelles, M. and Ardanaz, E. Amiano, P. Navarro, C. Sanchez, M. J. and Montes, E. Molina Key, T. Khaw, K. -T. Wareham, N. and Peeters, P. H. Trichopoulou, A. Bamia, C. Trichopoulos, D. and Boeing, H. Kaaks, R. Katzke, V. Ye, W. Sund, M. and Ericson, U. Wirfalt, E. Overvad, K. Tjonneland, A. and Olsen, A. Skeie, G. Asli, L. A. Weiderpass, E. Riboli, E. Bueno-De-Mesquita, H. B. Duell, E. J.

Abstract

In 1994, acrylamide (AA) was classified as a probable human carcinogen by the International Agency for Research on Cancer. In 2002, AA was discovered at relatively high concentrations in some starchy, plant-based foods cooked at high temperatures. A prospective analysis was conducted to evaluate the association between the dietary intake of AA and ductal adenocarcinoma of the exocrine pancreatic cancer (PC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort using Cox regression modeling. EPIC includes > 500 000 men and women aged 35-75 at enrollment from 10 European countries. AA intake was estimated for each participant by combining questionnaire-based food consumption data with a harmonized AA database derived from the EU monitoring database of AA levels in foods, and evaluated in quintiles and continuously. After a mean follow-up of 11 years, 865 first incident adenocarcinomas of the exocrine pancreas were observed and included in the present analysis. At baseline, the mean dietary AA intake in EPIC was 26.22 mu g/day. No overall association was found between continuous or quintiles of dietary AA intake and PC risk in EPIC (HR:0.95, 95%CI:0.89-1.01 per 10 mu g/day). There was no effect measure modification by smoking status, sex, diabetes, alcohol intake or geographic region. However, there was an inverse association (HR: 0.73, 95% CI: 0.61-0.88 per 10 mu g/day) between AA intake and PC risk in obese persons as defined using the body mass index (BMI, >= 30 kg/m(2)), but not when body fatness was defined using waist and hip circumference or their ratio. Dietary intake of AA was not associated with an increased risk of PC in the EPIC cohort.

Published
2013

21. Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics : results from the EPIC cohort

Author

Ose, J., Fortner, R. T., Schock, H., Peeters, P. H., Onland-Moret, N. C., Bueno-de-Mesquita, H. B., Weiderpass, E., Gram, I. T., Overvad, K., Tjonneland, A., Dossus, L., Fournier, A., Baglietto, L., Trichopoulou, A., Benetou, V., Trichopoulos, D., Boeing, H., Masala, G., Krogh, V., Matiello, A., Tumino, R., Popovic, M., Obon-Santacana, M., Larranaga, N., Ardanaz, E., Sanchez, M-J, Menendez, V., Chirlaque, M-D, Travis, R. C., Khaw, K-T, Braendstedt, J., Idahl, Annika, Lundin, Eva, Rinaldi, S., Kuhn, E., Romieu, I., Gunter, M. J., Merritt, M. A., Riboli, E., Kaaks, R., Ose, J., Fortner, R. T., Schock, H., Peeters, P. H., Onland-Moret, N. C., Bueno-de-Mesquita, H. B., Weiderpass, E., Gram, I. T., Overvad, K., Tjonneland, A., Dossus, L., Fournier, A., Baglietto, L., Trichopoulou, A., Benetou, V., Trichopoulos, D., Boeing, H., Masala, G., Krogh, V., Matiello, A., Tumino, R., Popovic, M., Obon-Santacana, M., Larranaga, N., Ardanaz, E., Sanchez, M-J, Menendez, V., Chirlaque, M-D, Travis, R. C., Khaw, K-T, Braendstedt, J., Idahl, Annika, Lundin, Eva, Rinaldi, S., Kuhn, E., Romieu, I., Gunter, M. J., Merritt, M. A., Riboli, E., and Kaaks, R.

Abstract

Background: Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics. Methods: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n = 565 cases). Multivariable conditional logistic regression models were used to estimate associations. Results: We observed no association between IGF-I and EOC overall or by tumour characteristics. Conclusions: In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk.

Published
2015
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22. Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort

Author

Ose, J, Fortner, RT, Schock, H, Peeters, PH, Onland-Moret, NC, Bueno-de-Mesquita, HB, Weiderpass, E, Gram, IT, Overvad, K, Tjonneland, A, Dossus, L, Fournier, A, Baglietto, L, Trichopoulou, A, Benetou, V, Trichopoulos, D, Boeing, H, Masala, G, Krogh, V, Matiello, A, Tumino, R, Popovic, M, Obon-Santacana, M, Larranaga, N, Ardanaz, E, Sanchez, M-J, Menendez, V, Chirlaque, M-D, Travis, RC, Khaw, K-T, Braendstedt, J, Idahl, A, Lundin, E, Rinaldi, S, Kuhn, E, Romieu, I, Gunter, MJ, Merritt, MA, Riboli, E, Kaaks, R, Ose, J, Fortner, RT, Schock, H, Peeters, PH, Onland-Moret, NC, Bueno-de-Mesquita, HB, Weiderpass, E, Gram, IT, Overvad, K, Tjonneland, A, Dossus, L, Fournier, A, Baglietto, L, Trichopoulou, A, Benetou, V, Trichopoulos, D, Boeing, H, Masala, G, Krogh, V, Matiello, A, Tumino, R, Popovic, M, Obon-Santacana, M, Larranaga, N, Ardanaz, E, Sanchez, M-J, Menendez, V, Chirlaque, M-D, Travis, RC, Khaw, K-T, Braendstedt, J, Idahl, A, Lundin, E, Rinaldi, S, Kuhn, E, Romieu, I, Gunter, MJ, Merritt, MA, Riboli, E, and Kaaks, R

Abstract

BACKGROUND: Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics. METHODS: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n=565 cases). Multivariable conditional logistic regression models were used to estimate associations. RESULTS: We observed no association between IGF-I and EOC overall or by tumour characteristics. CONCLUSIONS: In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk.

Published
2015

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

Author

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

Abstract

BACKGROUND: Three prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The objective of this study was to evaluate the association between acrylamide intake and EC risk: for overall EC, for type-I EC, and in never smokers and never users of oral contraceptives (OCs). Smoking is a source of acrylamide, and OC use is a protective factor for EC risk. METHODS: Cox regression was used to estimate hazard ratios (HRs) for the association between acrylamide intake and EC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Acrylamide intake was estimated from the EU acrylamide monitoring database, which was matched with EPIC questionnaire-based food consumption data. Acrylamide intake was energy adjusted using the residual method. RESULTS: No associations were observed between acrylamide intake and overall EC (n=1382) or type-I EC risk (n=627). We observed increasing relative risks for type-I EC with increasing acrylamide intake among women who both never smoked and were non-users of OCs (HRQ5vsQ1: 1.97, 95% CI: 1.08-3.62; likelihood ratio test (LRT) P-value: 0.01, n=203). CONCLUSIONS: Dietary intake of acrylamide was not associated with overall or type-I EC risk; however, positive associations with type I were observed in women who were both non-users of OCs and never smokers.

Published
2014

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

Author

Dimou N, Kim AE, Flanagan O, Murphy N, Diez-Obrero V, Shcherbina A, Aglago EK, Bouras E, Campbell PT, Casey G, Gallinger S, Gruber SB, Jenkins MA, Lin Y, Moreno V, Ruiz-Narvaez E, Stern MC, Tian Y, Tsilidis KK, Arndt V, Barry EL, Baurley JW, Berndt SI, Bézieau S, Bien SA, Bishop DT, Brenner H, Budiarto A, Carreras-Torres R, Cenggoro TW, Chan AT, Chang-Claude J, Chanock SJ, Chen X, Conti DV, Dampier CH, Devall M, Drew DA, Figueiredo JC, Giles GG, Gsur A, Harrison TA, Hidaka A, Hoffmeister M, Huyghe JR, Jordahl K, Kawaguchi E, Keku TO, Larsson SC, Le Marchand L, Lewinger JP, Li L, Mahesworo B, Morrison J, Newcomb PA, Newton CC, Obon-Santacana M, Ose J, Pai RK, Palmer JR, Papadimitriou N, Pardamean B, Peoples AR, Pharoah PDP, Platz EA, Potter JD, Rennert G, Scacheri PC, Schoen RE, Su YR, Tangen CM, Thibodeau SN, Thomas DC, Ulrich CM, Um CY, van Duijnhoven FJB, Visvanathan K, Vodicka P, Vodickova L, White E, Wolk A, Woods MO, Qu C, Kundaje A, Hsu L, Gauderman WJ, Gunter MJ, and Peters U

Subjects
Humans, Gene-Environment Interaction, Genetic Predisposition to Disease, Risk Factors, Polymorphism, Single Nucleotide, Genome-Wide Association Study methods, Microfilament Proteins genetics, Diabetes Mellitus genetics, Colorectal Neoplasms genetics
Abstract

Background: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis., Methods: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test)., Results: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - OR AA : 1.62, 95% CI: 1.34-1.96; OR AG : 1.41, 95% CI: 1.30-1.54; OR GG : 1.22, 95% CI: 1.13-1.31; p-value 3-d.f. : 5.46 × 10 -11 ) and 13q14.13 (rs9526201, LRCH1 - OR GG : 2.11, 95% CI: 1.56-2.83; OR GA : 1.52, 95% CI: 1.38-1.68; OR AA : 1.13, 95% CI: 1.06-1.21; p-value 2-d.f. : 7.84 × 10 -09 )., Discussion: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship., (© 2023. The Author(s).)

Published
2023
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25. 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 SI, 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 AI, and Ogino S

Subjects
Humans, Prognosis, Proto-Oncogene Proteins B-raf genetics, DNA Methylation, Mutation, Phenotype, Microsatellite Instability, CpG Islands genetics, Colorectal Neoplasms pathology, Colonic Neoplasms pathology
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 (P trend  = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (P interaction  = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [P trend  < 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 (P trend  = 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 (P interaction  = 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., (© 2023. Japanese Society of Gastroenterology.)

Published
2023
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26. Evaluating the Potential of Polygenic Risk Score to Improve Colorectal Cancer Screening.

Author

Arnau-Collell C, Díez-Villanueva A, Bellosillo B, Augé JM, Muñoz J, Guinó E, Moreira L, Serradesanferm A, Pozo À, Torà-Rocamora I, Bonjoch L, Ibañez-Sanz G, Obon-Santacana M, Moratalla-Navarro F, Sanz-Pamplona R, Márquez Márquez C, Rueda Miret R, Pérez Berbegal R, Piquer Velasco G, Hernández Rodríguez C, Grau J, Castells A, Borràs JM, Bessa X, Moreno V, and Castellví-Bel S

Subjects
Colonoscopy, Female, Humans, Male, Mass Screening, Multifactorial Inheritance, Occult Blood, Risk Factors, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Early Detection of Cancer
Abstract

Background: Colorectal cancer has high incidence and associated mortality worldwide. Screening programs are recommended for men and women over 50. Intermediate screens such as fecal immunochemical testing (FIT) select patients for colonoscopy with suboptimal sensitivity. Additional biomarkers could improve the current scenario., Methods: We included 2,893 individuals with a positive FIT test. They were classified as cases when a high-risk lesion for colorectal cancer was detected after colonoscopy, whereas the control group comprised individuals with low-risk or no lesions. 65 colorectal cancer risk genetic variants were genotyped. Polygenic risk score (PRS) and additive models for risk prediction incorporating sex, age, FIT value, and PRS were generated., Results: Risk score was higher in cases compared with controls [per allele OR = 1.04; 95% confidence interval (CI), 1.02-1.06; P < 0.0001]. A 2-fold increase in colorectal cancer risk was observed for subjects in the highest decile of risk alleles (≥65), compared with those in the first decile (≤54; OR = 2.22; 95% CI, 1.59-3.12; P < 0.0001). The model combining sex, age, FIT value, and PRS reached the highest accuracy for identifying patients with a high-risk lesion [cross-validated area under the ROC curve (AUROC): 0.64; 95% CI, 0.62-0.66]., Conclusions: This is the first investigation analyzing PRS in a two-step colorectal cancer screening program. PRS could improve current colorectal cancer screening, most likely for higher at-risk subgroups. However, its capacity is limited to predict colorectal cancer risk status and should be complemented by additional biomarkers., Impact: PRS has capacity for risk stratification of colorectal cancer suggesting its potential for optimizing screening strategies alongside with other biomarkers., (©2022 The Authors; Published by the American Association for Cancer Research.)

Published
2022
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27. Dietary Constituents: Relationship with Breast Cancer Prognostic (MCC-SPAIN Follow-Up).

Author

Dierssen-Sotos T, Gómez-Acebo I, Gutiérrez-Ruiz N, Aragonés N, Amiano P, Molina de la Torre AJ, Guevara M, Alonso-Molero J, Obon-Santacana M, Fernández-Tardón G, Molina-Barceló A, Alguacil J, Marcos-Gragera R, Rodríguez-Cundín P, Castaño-Vinyals G, Canseco Fernandez R, Castilla J, Molinuevo A, Pérez-Gómez B, Kogevinas M, Pollán M, and Llorca J

Subjects
Female, Follow-Up Studies, Humans, Prognosis, Risk Factors, Spain epidemiology, Breast Neoplasms diagnosis, Breast Neoplasms epidemiology, Diet
Abstract

The aim of this study was to characterize the relationship between the intake of the major nutrients and prognosis in breast cancer. A cohort based on 1350 women with invasive (stage I-IV) breast cancer (BC) was followed up. Information about their dietary habits before diagnosis was collected using a semi-quantitative Food Frequency Questionnaire. Participants without FFQ or with implausible energy intake were excluded. The total amount consumed of each nutrient (Kcal/day) was divided into tertiles, considering as "high intakes" those above third tertile. The main effect studied was overall survival. Cox regression was used to assess the association between death and nutrient intake. During a median follow-up of 6.5 years, 171 deaths were observed. None of the nutrients analysed was associated with mortality in the whole sample. However, in normal-weight women (BMI 18.5-25 kg/m 2 ) a high intake of carbohydrates (≥809 Kcal/day), specifically monosaccharides (≥468 Kcal/day), worsened prognostic compared to lowest (≤352 Kcal/day). Hazard Ratios (HRs) for increasing tertiles of intake were HR:2.22 95% CI (1.04 to 4.72) and HR:2.59 95% CI (1.04 to 6.48), respectively ( p trend = 0.04)). Conversely, high intakes of polyunsaturated fats (≥135 Kcal/day) improved global survival (HR: 0.39 95% CI (0.15 to 1.02) p -trend = 0.05) compared to the lowest (≤92.8 kcal/day). In addition, a protective effect was found substituting 100 kcal of carbohydrates with 100 kcal of fats in normal-weight women (HR: 0.76 95% CI (0.59 to 0.98)). Likewise, in premenopausal women a high intake of fats (≥811 Kcal/day) showed a protective effect (HR:0.20 95% CI (0.04 to 0.98) p trend = 0.06). Finally, in Estrogen Receptors (ER) negative tumors, we found a protective effect of high intake of animal proteins (≥238 Kcal/day, HR: 0.24 95% CI (0.06 to 0.98). According to our results, menopausal status, BMI and ER status could play a role in the relationship between diet and BC survival and must be taken into account when studying the influence of different nutrients.

Published
2020
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28. Inflammatory Markers and Risk of Epithelial Ovarian Cancer by Tumor Subtypes: The EPIC Cohort.

Author

Ose J, Schock H, Tjønneland A, Hansen L, Overvad K, Dossus L, Clavel-Chapelon F, Baglietto L, Boeing H, Trichopolou A, Benetou V, Lagiou P, Masala G, Tagliabue G, Tumino R, Sacerdote C, Mattiello A, Bueno-de-Mesquita HB, Peeters PH, Onland-Moret NC, Weiderpass E, Gram IT, Sánchez S, Obon-Santacana M, Sànchez-Pérez MJ, Larrañaga N, Castaño JM, Ardanaz E, Brändstedt J, Lundin E, Idahl A, Travis RC, Khaw KT, Rinaldi S, Romieu I, Merritt MA, Gunter MJ, Riboli E, Kaaks R, and Fortner RT

Subjects
Adenocarcinoma, Clear Cell blood, Adenocarcinoma, Clear Cell etiology, Adenocarcinoma, Mucinous blood, Adenocarcinoma, Mucinous etiology, Adult, Aged, Case-Control Studies, Cystadenocarcinoma, Serous blood, Cystadenocarcinoma, Serous etiology, Endometrial Neoplasms blood, Endometrial Neoplasms etiology, Female, Follow-Up Studies, Humans, Inflammation blood, Inflammation complications, Inflammation pathology, Middle Aged, Neoplasm Grading, Neoplasm Invasiveness, Neoplasm Staging, Ovarian Neoplasms blood, Ovarian Neoplasms etiology, Prognosis, Prospective Studies, Adenocarcinoma, Clear Cell pathology, Adenocarcinoma, Mucinous pathology, Biomarkers, Tumor blood, Cystadenocarcinoma, Serous pathology, Endometrial Neoplasms pathology, Inflammation Mediators blood, Ovarian Neoplasms pathology
Abstract

Background: Evidence suggests an etiologic role for inflammation in ovarian carcinogenesis and heterogeneity between tumor subtypes and anthropometric indices. Prospective studies on circulating inflammatory markers and epithelial invasive ovarian cancer (EOC) have predominantly investigated overall risk; data characterizing risk by tumor characteristics (histology, grade, stage, dualistic model of ovarian carcinogenesis) and anthropometric indices are sparse., Methods: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate C-reactive protein (CRP), IL6, and EOC risk by tumor characteristics. A total of 754 eligible EOC cases were identified; two controls (n = 1,497) were matched per case. We used multivariable conditional logistic regression to assess associations., Results: CRP and IL6 were not associated with overall EOC risk. However, consistent with prior research, CRP >10 versus CRP ≤1 mg/L was associated with higher overall EOC risk [OR, 1.67 (1.03-2.70)]. We did not observe significant associations or heterogeneity in analyses by tumor characteristics. In analyses stratified by waist circumference, inflammatory markers were associated with higher risk among women with higher waist circumference; no association was observed for women with normal waist circumference [e.g., IL6: waist ≤80: ORlog2, 0.97 (0.81-1.16); waist >88: ORlog2, 1.78 (1.28-2.48), Pheterogeneity ≤ 0.01]., Conclusions: Our data suggest that high CRP is associated with increased risk of overall EOC, and that IL6 and CRP may be associated with EOC risk among women with higher adiposity., Impact: Our data add to global evidence that ovarian carcinogenesis may be promoted by an inflammatory milieu., (©2015 American Association for Cancer Research.)

Published
2015
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