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1. Onkologie und Sport

Author

Steindorf K, Schmidt ME, Wiskemann J, and Ulrich CM

Subjects
Sports medicine, RC1200-1245
Abstract

Introduction: Epidemiologic and controlled clinical studies have shown that exercise training before, during and after a cancer therapy can have a substantial impact on therapy- and cancer-related symptoms. Further research investigated whether the benefits can be extended to cancer progression, recurrence, and cancer-specific or overall mortality. The underlying biological mechanisms are presumably complex, and may be specific for different types of training and cancer. Methods: A systematic PubMed-based literature review on the effects of exercise training on biomarkers in adult cancer patients was conducted till November 2013. Results: A total of 25 publications on 6 cancer sites were identified. Different biologic mechanisms on the effects of exercise trainings were discussed. Profound hypotheses included the modulation of metabolic factors, immune function, pro- and anti-inflammatory processes, sex hormones, and DNA repair capacities and oxidative stress. Most studies investigated breast cancer patients, endurance training, and changes in metabolic and inflammatory parameters. Results for all mechanisms are inconsistent. Discussion: Compared to the complexity of the topic and due to the paucity of studies in cancer patients the current level of evidence needs to be classified as preliminary. Future well-powered exercise intervention trials with cancer patients should, if feasible, incorporate translational and hypotheses-driven biomarker research. For clinical practice, these identified limitations of knowledge on mechanisms should not slow the increasing acceptance of physical training as safe, well-tolerated and highly effective supportive cancer therapy.Key Words: Biological mechanisms, exercise training, cancer, clinical studies

Published
2014
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2. 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

4. 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

5. International consensus-based policy recommendations to advance universal palliative care access from the American Academy of Nursing Expert Panels.

Author

Rosa, WE, Buck, HG, Squires, AP, Kozachik, SL, Huijer, HA-S, Bakitas, M, Boit, JM, Bradley, PK, Cacchione, PZ, Chan, GK, Crisp, N, Dahlin, C, Daoust, P, Davidson, PM, Davis, S, Doumit, MAA, Fink, RM, Herr, KA, Hinds, PS, Hughes, TL, Karanja, V, Kenny, DJ, King, CR, Klopper, HC, Knebel, AR, Kurth, AE, Madigan, EA, Malloy, P, Matzo, M, Mazanec, P, Meghani, SH, Monroe, TB, Moreland, PJ, Paice, JA, Phillips, JC, Rushton, CH, Shamian, J, Shattell, M, Snethen, JA, Ulrich, CM, Wholihan, D, Wocial, LD, Ferrell, BR, Rosa, WE, Buck, HG, Squires, AP, Kozachik, SL, Huijer, HA-S, Bakitas, M, Boit, JM, Bradley, PK, Cacchione, PZ, Chan, GK, Crisp, N, Dahlin, C, Daoust, P, Davidson, PM, Davis, S, Doumit, MAA, Fink, RM, Herr, KA, Hinds, PS, Hughes, TL, Karanja, V, Kenny, DJ, King, CR, Klopper, HC, Knebel, AR, Kurth, AE, Madigan, EA, Malloy, P, Matzo, M, Mazanec, P, Meghani, SH, Monroe, TB, Moreland, PJ, Paice, JA, Phillips, JC, Rushton, CH, Shamian, J, Shattell, M, Snethen, JA, Ulrich, CM, Wholihan, D, Wocial, LD, and Ferrell, BR

Abstract

The purpose of this consensus paper was to convene leaders and scholars from eight Expert Panels of the American Academy of Nursing and provide recommendations to advance nursing's roles and responsibility to ensure universal access to palliative care. On behalf of the Academy, these evidence-based recommendations will guide nurses, policy makers, government representatives, professional associations, and interdisciplinary and community partners to integrate palliative nursing services across health and social care settings. Through improved palliative nursing education, nurse-led research, nurse engagement in policy making, enhanced intersectoral partnerships with nursing, and an increased profile and visibility of palliative care nurses worldwide, nurses can assume leading roles in delivering high-quality palliative care globally, particularly for minoritized, marginalized, and other at-risk populations. Part II herein provides a summary of international responses and policy options that have sought to enhance universal palliative care and palliative nursing access to date. Additionally, we provide ten policy, education, research, and clinical practice recommendations based on the rationale and background information found in Part I. The consensus paper's 43 authors represent eight countries (Australia, Canada, England, Kenya, Lebanon, Liberia, South Africa, United States of America) and extensive international health experience, thus providing a global context for the subject matter.

Published
2022

6. 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

7. 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

8. American Academy of Nursing Expert Panel consensus statement on nursing's roles in ensuring universal palliative care access.

Author

Rosa, WE, Buck, HG, Squires, AP, Kozachik, SL, Huijer, HA-S, Bakitas, M, Boit, JM, Bradley, PK, Cacchione, PZ, Chan, GK, Crisp, N, Dahlin, C, Daoust, P, Davidson, PM, Davis, S, Doumit, MAA, Fink, RM, Herr, KA, Hinds, PS, Hughes, TL, Karanja, V, Kenny, DJ, King, CR, Klopper, HC, Knebel, AR, Kurth, AE, Madigan, EA, Malloy, P, Matzo, M, Mazanec, P, Meghani, SH, Monroe, TB, Moreland, PJ, Paice, JA, Phillips, JC, Rushton, CH, Shamian, J, Shattell, M, Snethen, JA, Ulrich, CM, Wholihan, D, Wocial, LD, Ferrell, BR, Rosa, WE, Buck, HG, Squires, AP, Kozachik, SL, Huijer, HA-S, Bakitas, M, Boit, JM, Bradley, PK, Cacchione, PZ, Chan, GK, Crisp, N, Dahlin, C, Daoust, P, Davidson, PM, Davis, S, Doumit, MAA, Fink, RM, Herr, KA, Hinds, PS, Hughes, TL, Karanja, V, Kenny, DJ, King, CR, Klopper, HC, Knebel, AR, Kurth, AE, Madigan, EA, Malloy, P, Matzo, M, Mazanec, P, Meghani, SH, Monroe, TB, Moreland, PJ, Paice, JA, Phillips, JC, Rushton, CH, Shamian, J, Shattell, M, Snethen, JA, Ulrich, CM, Wholihan, D, Wocial, LD, and Ferrell, BR

Abstract

The purpose of this consensus paper was to convene leaders and scholars from eight Expert Panels of the American Academy of Nursing and provide recommendations to advance nursing's roles and responsibility to ensure universal access to palliative care. Part I of this consensus paper herein provides the rationale and background to support the policy, education, research, and clinical practice recommendations put forward in Part II. On behalf of the Academy, the evidence-based recommendations will guide nurses, policy makers, government representatives, professional associations, and interdisciplinary and community partners to integrate palliative nursing services across health and social care settings. The consensus paper's 43 authors represent eight countries (Australia, Canada, England, Kenya, Lebanon, Liberia, South Africa, United States of America) and extensive international health experience, thus providing a global context for the subject matter. The authors recommend greater investments in palliative nursing education and nurse-led research, nurse engagement in policy making, enhanced intersectoral partnerships with nursing, and an increased profile and visibility of palliative nurses worldwide. By enacting these recommendations, nurses working in all settings can assume leading roles in delivering high-quality palliative care globally, particularly for minoritized, marginalized, and other at-risk populations.

Published
2021

9. Impact of COVID-19 Pandemic on Healthcare Delivery, Behavioral Outcomes, and Financial Stress in 1,253 Individuals with Cancer at Huntsman Cancer Institute (HCI)

Author

Peoples, AR, primary, Himbert, C, additional, Hathaway, CA, additional, Kirchhoff, AC, additional, Ose, J, additional, Lin, T, additional, Colman, H, additional, Jones, KB, additional, Akerley, WL, additional, Grossman, D, additional, Hunt, JP, additional, Penedo, FJ, additional, Siegel, EM, additional, Ulrich, CM, additional, and Tworoger, SS, additional

Published
2021
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10. 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

11. 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

12. Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

Author

Seyed Khoei, N, Jenab, M, Murphy, N, Banbury, BL, Carreras-Torres, R, Viallon, V, Kuehn, T, Bueno-de-Mesquita, B, Aleksandrova, K, Cross, AJ, Weiderpass, E, Stepien, M, Bulmer, A, Tjonneland, A, Boutron-Ruault, M-C, Severi, G, Carbonnel, F, Katzke, V, Boeing, H, Bergmann, MM, Trichopoulou, A, Karakatsani, A, Martimianaki, G, Palli, D, Tagliabue, G, Panico, S, Tumino, R, Sacerdote, C, Skeie, G, Merino, S, Bonet, C, Rodriguez-Barranco, M, Gil, L, Chirlaque, M-D, Ardanaz, E, Myte, R, Hultdin, J, Perez-Cornago, A, Aune, D, Tsilidis, K, Albanes, Baron, JA, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Gallinger, S, Gruber, SB, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, JR, Jenkins, MA, Joshi, AD, Kampman, E, Larsson, SC, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Lindor, NM, Martin, V, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Parfrey, PS, Pharoah, PDP, Rennert, G, Sakoda, LC, Schafmayer, C, Schmit, SL, Schoen, RE, Slattery, ML, Thibodeau, SN, Ulrich, CM, van Duijnhoven, FJB, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Zhang, X, Ferrari, P, Anton, G, Peters, A, Peters, U, Gunter, MJ, Wagner, K-H, Freisling, H, Seyed Khoei, N, Jenab, M, Murphy, N, Banbury, BL, Carreras-Torres, R, Viallon, V, Kuehn, T, Bueno-de-Mesquita, B, Aleksandrova, K, Cross, AJ, Weiderpass, E, Stepien, M, Bulmer, A, Tjonneland, A, Boutron-Ruault, M-C, Severi, G, Carbonnel, F, Katzke, V, Boeing, H, Bergmann, MM, Trichopoulou, A, Karakatsani, A, Martimianaki, G, Palli, D, Tagliabue, G, Panico, S, Tumino, R, Sacerdote, C, Skeie, G, Merino, S, Bonet, C, Rodriguez-Barranco, M, Gil, L, Chirlaque, M-D, Ardanaz, E, Myte, R, Hultdin, J, Perez-Cornago, A, Aune, D, Tsilidis, K, Albanes, Baron, JA, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Gallinger, S, Gruber, SB, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, JR, Jenkins, MA, Joshi, AD, Kampman, E, Larsson, SC, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Lindor, NM, Martin, V, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Parfrey, PS, Pharoah, PDP, Rennert, G, Sakoda, LC, Schafmayer, C, Schmit, SL, Schoen, RE, Slattery, ML, Thibodeau, SN, Ulrich, CM, van Duijnhoven, FJB, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Zhang, X, Ferrari, P, Anton, G, Peters, A, Peters, U, Gunter, MJ, Wagner, K-H, and Freisling, H

Abstract

BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, we

Published
2020

13. 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

14. 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

15. Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk

Author

Wang, T, Maden, SK, Luebeck, GE, Li, CI, Newcomb, PA, Ulrich, CM, Joo, J-HE, Buchanan, DD, Milne, RL, Southey, MC, Carter, KT, Willbanks, AR, Luo, Y, Yu, M, Grady, WM, Wang, T, Maden, SK, Luebeck, GE, Li, CI, Newcomb, PA, Ulrich, CM, Joo, J-HE, Buchanan, DD, Milne, RL, Southey, MC, Carter, KT, Willbanks, AR, Luo, Y, Yu, M, and Grady, WM

Abstract

BACKGROUND: Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual's susceptibility to age-related diseases such as CRC. METHODS: We conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual's chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk. RESULTS: Each epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10-30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group. CONCLUSIONS: Among the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigene

Published
2020

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

Author

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

Abstract

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

Published
2020

17. Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer (vol 138, pg 307, 2019)

Author

Bien, SA, Su, Y-R, Conti, DV, Harrison, TA, Qu, C, Guo, X, Lu, Y, Albanes, D, Auer, PL, Banbury, BL, Berndt, SI, Bezieau, S, Brenner, H, Buchanan, DD, Caan, BJ, Campbell, PT, Carlson, CS, Chan, AT, Chang-Claude, J, Chen, S, Connolly, CM, Easton, DF, Feskens, EJM, Gallinger, S, Giles, GG, Gunter, MJ, Hampe, J, Huyghe, JR, Hoffmeister, M, Hudson, TJ, Jacobs, EJ, Jenkins, MA, Kampman, E, Kang, HM, Kuehn, T, Kury, S, Lejbkowicz, F, Le Marchand, L, Milne, RL, Li, L, Li, CI, Lindblom, A, Lindor, NM, Martin, V, McNeil, CE, Melas, M, Moreno, V, Newcomb, PA, Offit, K, Pharaoh, PDP, Potter, JD, Riboli, E, Rennert, G, Sala, N, Schafmayer, C, Scacheri, PC, Schmit, SL, Severi, G, Slattery, ML, Smith, JD, Trichopoulou, A, Tumino, R, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Casey, G, Nickerson, DA, Gruber, SB, Hsu, L, Zheng, W, Peters, U, Bien, SA, Su, Y-R, Conti, DV, Harrison, TA, Qu, C, Guo, X, Lu, Y, Albanes, D, Auer, PL, Banbury, BL, Berndt, SI, Bezieau, S, Brenner, H, Buchanan, DD, Caan, BJ, Campbell, PT, Carlson, CS, Chan, AT, Chang-Claude, J, Chen, S, Connolly, CM, Easton, DF, Feskens, EJM, Gallinger, S, Giles, GG, Gunter, MJ, Hampe, J, Huyghe, JR, Hoffmeister, M, Hudson, TJ, Jacobs, EJ, Jenkins, MA, Kampman, E, Kang, HM, Kuehn, T, Kury, S, Lejbkowicz, F, Le Marchand, L, Milne, RL, Li, L, Li, CI, Lindblom, A, Lindor, NM, Martin, V, McNeil, CE, Melas, M, Moreno, V, Newcomb, PA, Offit, K, Pharaoh, PDP, Potter, JD, Riboli, E, Rennert, G, Sala, N, Schafmayer, C, Scacheri, PC, Schmit, SL, Severi, G, Slattery, ML, Smith, JD, Trichopoulou, A, Tumino, R, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Casey, G, Nickerson, DA, Gruber, SB, Hsu, L, Zheng, W, and Peters, U

Abstract

Every author has erroneously been assigned to the affiliation "62". The affiliation 62 belongs to the author Graham Casey.

Published
2019

18. Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Author

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

Abstract

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

Published
2019

19. Shared heritability and functional enrichment across six solid cancers

Author

Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboeller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, defazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Doerk, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuhl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Aguado-Barrera, ME, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, Mckay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, Lindstrom, S, Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboeller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, defazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Doerk, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuhl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Aguado-Barrera, ME, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, Mckay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, and Lindstrom, S

Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Published
2019

20. Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer

Author

Bien, SA, Su, Y-R, Conti, DV, Harrison, TA, Qu, C, Guo, X, Lu, Y, Albanes, D, Auer, PL, Banbury, BL, Berndt, SI, Bezieau, S, Brenner, H, Buchanan, DD, Caan, BJ, Campbell, PT, Carlson, CS, Chan, AT, Chang-Claude, J, Chen, S, Connolly, CM, Easton, DF, Feskens, EJM, Gallinger, S, Giles, GG, Gunter, MJ, Hampe, J, Huyghe, JR, Hoffmeister, M, Hudson, TJ, Jacobs, EJ, Jenkins, MA, Kampman, E, Kang, HM, Kuehn, T, Kury, S, Lejbkowicz, F, Le Marchand, L, Milne, RL, Li, L, Li, CI, Lindblom, A, Lindor, NM, Martin, V, McNeil, CE, Melas, M, Moreno, V, Newcomb, PA, Offit, K, Pharaoh, PDP, Potter, JD, Riboli, E, Rennert, G, Sala, N, Schafmayer, C, Scacheri, PC, Schmit, SL, Severi, G, Slattery, ML, Smith, JD, Trichopoulou, A, Tumino, R, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Casey, G, Nickerson, DA, Gruber, SB, Hsu, L, Zheng, W, Peters, U, Bien, SA, Su, Y-R, Conti, DV, Harrison, TA, Qu, C, Guo, X, Lu, Y, Albanes, D, Auer, PL, Banbury, BL, Berndt, SI, Bezieau, S, Brenner, H, Buchanan, DD, Caan, BJ, Campbell, PT, Carlson, CS, Chan, AT, Chang-Claude, J, Chen, S, Connolly, CM, Easton, DF, Feskens, EJM, Gallinger, S, Giles, GG, Gunter, MJ, Hampe, J, Huyghe, JR, Hoffmeister, M, Hudson, TJ, Jacobs, EJ, Jenkins, MA, Kampman, E, Kang, HM, Kuehn, T, Kury, S, Lejbkowicz, F, Le Marchand, L, Milne, RL, Li, L, Li, CI, Lindblom, A, Lindor, NM, Martin, V, McNeil, CE, Melas, M, Moreno, V, Newcomb, PA, Offit, K, Pharaoh, PDP, Potter, JD, Riboli, E, Rennert, G, Sala, N, Schafmayer, C, Scacheri, PC, Schmit, SL, Severi, G, Slattery, ML, Smith, JD, Trichopoulou, A, Tumino, R, Ulrich, CM, van Duijnhoven, FJB, Van Guelpen, B, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Casey, G, Nickerson, DA, Gruber, SB, Hsu, L, Zheng, W, and Peters, U

Abstract

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight in

Published
2019

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

Author

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

Abstract

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

Published
2019

22. Shared heritability and functional enrichment across six solid cancers (vol 10, 431, 2019)

Author

Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, deFazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Dork, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuehl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Elias Aguado-Barrera, M, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, McKay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, Lindstrom, S, Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, deFazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Dork, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuehl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Elias Aguado-Barrera, M, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, McKay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, and Lindstrom, S

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

23. Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk: A case-control study in unselected white European populations

Author

Sheth, H, Northwood, E, Ulrich, CM, Scherer, D, Elliott, F, Barrett, JH, Forman, D, Wolf, CR, Smith, G, Jackson, MS, Santibanez-Koref, M, Haile, R, Casey, G, Jenkins, M, Ko Win, A, Hopper, JL, Le Marchand, L, Lindor, NM, Thibodeau, SN, Potter, JD, Burn, J, and Bishop, DT

Subjects
Canada, Heredity, NSAIDs, lcsh:Medicine, Variant Genotypes, Research and Analysis Methods, Polymorphism, Single Nucleotide, White People, Molecular Genetics, Rectal Cancer, Mathematical and Statistical Techniques, Risk Factors, Gastrointestinal Tumors, Medicine and Health Sciences, Genetics, Humans, Statistical Methods, lcsh:Science, Molecular Biology, Alleles, Colorectal Cancer, Pharmacology, Analgesics, Aspirin, lcsh:R, Australia, Cancers and Neoplasms, Biology and Life Sciences, Drugs, Adenomas, Pain management, United States, Genetic Mapping, Oncology, Genetic Loci, Case-Control Studies, Physical Sciences, lcsh:Q, Colorectal Neoplasms, Mathematics, Statistics (Mathematics), Research Article, Meta-Analysis
Abstract

Regular aspirin use is associated with reduced risk of colorectal cancer (CRC). Variation in aspirin's chemoprevention efficacy has been attributed to the presence of single nucleotide polymorphisms (SNPs). We conducted a meta-analysis using two large population-based case-control datasets, the UK-Leeds Colorectal Cancer Study Group and the NIH-Colon Cancer Family Registry, having a combined total of 3325 cases and 2262 controls. The aim was to assess 42 candidate SNPs in 15 genes whose association with colorectal cancer risk was putatively modified by aspirin use, in the literature. Log odds ratios (ORs) and standard errors were estimated for each dataset separately using logistic regression adjusting for age, sex and study site, and dataset-specific results were combined using random effects meta-analysis. Meta-analysis showed association between SNPs rs6983267, rs11694911 and rs2302615 with CRC risk reduction (All P

Published
2018

24. Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer

Author

Neumeyer, S, Banbury, BL, Arndt, V, Berndt, SI, Bezieau, S, Bien, SA, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Casey, G, Chan, AT, Chanock, SJ, Dai, JY, Gallinger, S, Giovannucci, EL, Giles, GG, Grady, WM, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, L, Jenkins, MA, Joshi, A, Larsson, SC, Le Marchand, L, Lindblom, A, Moreno, V, Lemire, M, Li, L, Lin, Y, Offit, K, Newcomb, PA, Pharaoh, PD, Potter, JD, Qi, L, Rennert, G, Schafmayer, C, Schoen, RE, Slattery, ML, Song, M, Ulrich, CM, Win, AK, White, E, Wolk, A, Woods, MO, Wu, AH, Gruber, SB, Brenner, H, Peters, U, Chang-Claude, J, Neumeyer, S, Banbury, BL, Arndt, V, Berndt, SI, Bezieau, S, Bien, SA, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Casey, G, Chan, AT, Chanock, SJ, Dai, JY, Gallinger, S, Giovannucci, EL, Giles, GG, Grady, WM, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, L, Jenkins, MA, Joshi, A, Larsson, SC, Le Marchand, L, Lindblom, A, Moreno, V, Lemire, M, Li, L, Lin, Y, Offit, K, Newcomb, PA, Pharaoh, PD, Potter, JD, Qi, L, Rennert, G, Schafmayer, C, Schoen, RE, Slattery, ML, Song, M, Ulrich, CM, Win, AK, White, E, Wolk, A, Woods, MO, Wu, AH, Gruber, SB, Brenner, H, Peters, U, and Chang-Claude, J

Abstract

BACKGROUND: Substantial evidence supports an association between use of menopausal hormone therapy and decreased colorectal cancer (CRC) risk, indicating a role of exogenous sex hormones in CRC development. However, findings on endogenous oestrogen exposure and CRC are inconsistent. METHODS: We used a Mendelian randomisation approach to test for a causal effect of age at menarche and age at menopause as surrogates for endogenous oestrogen exposure on CRC risk. Weighted genetic risk scores based on 358 single-nucleotide polymorphisms associated with age at menarche and 51 single-nucleotide polymorphisms associated with age at menopause were used to estimate the association with CRC risk using logistic regression in 12,944 women diagnosed with CRC and 10,741 women without CRC from three consortia. Sensitivity analyses were conducted to address pleiotropy and possible confounding by body mass index. RESULTS: Genetic risk scores for age at menarche (odds ratio per year 0.98, 95% confidence interval: 0.95-1.02) and age at menopause (odds ratio 0.98, 95% confidence interval: 0.94-1.01) were not significantly associated with CRC risk. The sensitivity analyses yielded similar results. CONCLUSIONS: Our study does not support a causal relationship between genetic risk scores for age at menarche and age at menopause and CRC risk.

Published
2018

25. Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk: A case-control study in unselected white European populations

Author

Xu, Z, Sheth, H, Northwood, E, Ulrich, CM, Scherer, D, Elliott, F, Barrett, JH, Forman, D, Wolf, CR, Smith, G, Jackson, MS, Santibanez-Koref, M, Haile, R, Casey, G, Jenkins, M, Win, AK, Hopper, JL, Le Marchand, L, Lindor, NM, Thibodeau, SN, Potter, JD, Burn, J, Bishop, DT, Xu, Z, Sheth, H, Northwood, E, Ulrich, CM, Scherer, D, Elliott, F, Barrett, JH, Forman, D, Wolf, CR, Smith, G, Jackson, MS, Santibanez-Koref, M, Haile, R, Casey, G, Jenkins, M, Win, AK, Hopper, JL, Le Marchand, L, Lindor, NM, Thibodeau, SN, Potter, JD, Burn, J, and Bishop, DT

Abstract

Regular aspirin use is associated with reduced risk of colorectal cancer (CRC). Variation in aspirin's chemoprevention efficacy has been attributed to the presence of single nucleotide polymorphisms (SNPs). We conducted a meta-analysis using two large population-based case-control datasets, the UK-Leeds Colorectal Cancer Study Group and the NIH-Colon Cancer Family Registry, having a combined total of 3325 cases and 2262 controls. The aim was to assess 42 candidate SNPs in 15 genes whose association with colorectal cancer risk was putatively modified by aspirin use, in the literature. Log odds ratios (ORs) and standard errors were estimated for each dataset separately using logistic regression adjusting for age, sex and study site, and dataset-specific results were combined using random effects meta-analysis. Meta-analysis showed association between SNPs rs6983267, rs11694911 and rs2302615 with CRC risk reduction (All P<0.05). Association for SNP rs6983267 in the CCAT2 gene only was noteworthy after multiple test correction (P = 0.001). Site-specific analysis showed association between SNPs rs1799853 and rs2302615 with reduced colon cancer risk only (P = 0.01 and P = 0.004, respectively), however neither reached significance threshold following multiple test correction. Meta-analysis of SNPs rs2070959 and rs1105879 in UGT1A6 gene showed interaction between aspirin use and CRC risk (Pinteraction = 0.01 and 0.02, respectively); stratification by aspirin use showed an association for decreased CRC risk for aspirin users having a wild-type genotype (rs2070959 OR = 0.77, 95% CI = 0.68-0.86; rs1105879 OR = 0.77 95% CI = 0.69-0.86) compared to variant allele cariers. The direction of the interaction however is in contrast to that published in studies on colorectal adenomas. Both SNPs showed potential site-specific interaction with aspirin use and colon cancer risk only (Pinteraction = 0.006 and 0.008, respectively), with the direction of association similar to that observed

Published
2018

26. Smoking is associated with hypermethylation of the APC 1A promoter in colorectal cancer: the ColoCare Study

Author

Barrow, Timothy, Klett, H, Toth, R, Boehm, J, Gigic, B, Habermann, N, Scherer, D, Schrotz-King, P, Skender, S, Abbenhardt-Martin, C, Zielske, L, Schneider, M, Ulrich, A, Schirmacher, P, Herpel, E, Brenner, H, Busch, H, Boerries, M, Ulrich, CM, and Michels, KB

Subjects
Adult, Male, Lung Neoplasms, Adenomatous Polyposis Coli Protein, Smoking, DNA Methylation, Middle Aged, Article, Epigenesis, Genetic, Humans, Female, Colorectal Neoplasms, Promoter Regions, Genetic, sub_biomedicalsciences, Aged
Abstract

Smoking tobacco is a known risk factor for the development of colorectal cancer, and for mortality associated with the disease. Smoking has been reported to be associated with changes in DNA methylation in blood and in lung tumour tissues, although there has been scant investigation of how epigenetic factors may be implicated in the increased risk of developing colorectal cancer. To identify epigenetic changes associated with smoking behaviours, we performed epigenome-wide analysis of DNA methylation in colorectal tumours from 36 never smokers, 47 former smokers and 13 active smokers, and adjacent mucosa from 49 never smokers, 64 former smokers and 18 active smokers. Our analyses identified 15 CpG sites within the APC 1A promoter that were significantly hypermethylated and 14 CpG loci within the NFATC1 gene body that were significantly hypomethylated (pLIS

Published
2017

28. CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

Author

Garcia-Albeniz, X, Rudolph, A, Hutter, C, White, E, Lin, Y, Rosse, SA, Figueiredo, JC, Harrison, TA, Jiao, S, Brenner, H, Casey, G, Hudson, TJ, Thornquist, M, Le Marchand, L, Potter, J, Slattery, ML, Zanke, B, Baron, JA, Caan, BJ, Chanock, SJ, Berndt, SI, Stelling, D, Fuchs, CS, Hoffmeister, M, Butterbach, K, Du, M, Gauderman, WJ, Gunter, MJ, Lemire, M, Ogino, S, Lin, J, Hayes, RB, Haile, RW, Schoen, RE, SWarnick, G, Jenkins, MA, Thibodeau, SN, Schumacher, FR, Lindor, NM, Kolonel, LN, Hopper, JL, Gong, J, Seminara, D, Pflugeisen, BM, Ulrich, CM, Qu, C, Duggan, D, Cotterchio, M, Campbell, PT, Carlson, CS, Newcomb, PA, Giovannucci, E, Hsu, L, Chan, AT, Peters, U, Chang-Claude, J, Garcia-Albeniz, X, Rudolph, A, Hutter, C, White, E, Lin, Y, Rosse, SA, Figueiredo, JC, Harrison, TA, Jiao, S, Brenner, H, Casey, G, Hudson, TJ, Thornquist, M, Le Marchand, L, Potter, J, Slattery, ML, Zanke, B, Baron, JA, Caan, BJ, Chanock, SJ, Berndt, SI, Stelling, D, Fuchs, CS, Hoffmeister, M, Butterbach, K, Du, M, Gauderman, WJ, Gunter, MJ, Lemire, M, Ogino, S, Lin, J, Hayes, RB, Haile, RW, Schoen, RE, SWarnick, G, Jenkins, MA, Thibodeau, SN, Schumacher, FR, Lindor, NM, Kolonel, LN, Hopper, JL, Gong, J, Seminara, D, Pflugeisen, BM, Ulrich, CM, Qu, C, Duggan, D, Cotterchio, M, Campbell, PT, Carlson, CS, Newcomb, PA, Giovannucci, E, Hsu, L, Chan, AT, Peters, U, and Chang-Claude, J

Abstract

BACKGROUND: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT. METHODS: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test. RESULTS: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10(-9)). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10(-5) (alpha threshold=3.1 × 10(-4)). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively. CONCLUSIONS: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.

Published
2016

29. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer

Author

Williams, SM, Gong, J, Hutter, CM, Newcomb, PA, Ulrich, CM, Bien, SA, Campbell, PT, Baron, JA, Berndt, SI, Bezieau, S, Brenner, H, Casey, G, Chan, AT, Chang-Claude, J, Du, M, Duggan, D, Figueiredo, JC, Gallinger, S, Giovannucci, EL, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jeon, J, Jenkins, MA, Kocarnik, J, Kury, S, Le Marchand, L, Lin, Y, Lindor, NM, Nishihara, R, Ogino, S, Potter, JD, Rudolph, A, Schoen, RE, Schrotz-King, P, Seminara, D, Slattery, ML, Thibodeau, SN, Thornquist, M, Toth, R, Wallace, R, White, E, Jiao, S, Lemire, M, Hsu, L, Peters, U, Williams, SM, Gong, J, Hutter, CM, Newcomb, PA, Ulrich, CM, Bien, SA, Campbell, PT, Baron, JA, Berndt, SI, Bezieau, S, Brenner, H, Casey, G, Chan, AT, Chang-Claude, J, Du, M, Duggan, D, Figueiredo, JC, Gallinger, S, Giovannucci, EL, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jeon, J, Jenkins, MA, Kocarnik, J, Kury, S, Le Marchand, L, Lin, Y, Lindor, NM, Nishihara, R, Ogino, S, Potter, JD, Rudolph, A, Schoen, RE, Schrotz-King, P, Seminara, D, Slattery, ML, Thibodeau, SN, Thornquist, M, Toth, R, Wallace, R, White, E, Jiao, S, Lemire, M, Hsu, L, and Peters, U

Abstract

Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4) and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.

Published
2016

30. Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Author

Schumacher, FR, Schmit, SL, Jiao, S, Edlund, CK, Wang, H, Zhang, B, Hsu, L, Huang, S-C, Fischer, CP, Harju, JF, Idos, GE, Lejbkowicz, F, Manion, FJ, McDonnell, K, McNeil, CE, Melas, M, Rennert, HS, Shi, W, Thomas, DC, Van Den Berg, DJ, Hutter, CM, Aragaki, AK, Butterbach, K, Caan, BJ, Carlson, CS, Chanock, SJ, Curtis, KR, Fuchs, CS, Gala, M, Giocannucci, EL, Gogarten, SM, Hayes, RB, Henderson, B, Hunter, DJ, Jackson, RD, Kolonel, LN, Kooperberg, C, Kury, S, LaCroix, A, Laurie, CC, Laurie, CA, Lemire, M, Levine, D, Ma, J, Makar, KW, Qu, C, Taverna, D, Ulrich, CM, Wu, K, Kono, S, West, DW, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Coetzee, GA, Conti, DV, Duggan, D, Figueiredo, JC, Fortini, BK, Gallinger, SJ, Gauderman, WJ, Giles, G, Green, R, Haile, R, Harrison, TA, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jacobs, E, Iwasaki, M, Jee, SH, Jenkins, M, Jia, W-H, Joshi, A, Li, L, Lindor, NM, Matsuo, K, Moreno, V, Mukherjee, B, Newcomb, PA, Potter, JD, Raskin, L, Rennert, G, Rosse, S, Severi, G, Schoen, RE, Seminara, D, Shu, X-O, Slattery, ML, Tsugane, S, White, E, Xiang, Y-B, Zanke, BW, Zheng, W, Le Marchand, L, Casey, G, Gruber, SB, Peters, U, Schumacher, FR, Schmit, SL, Jiao, S, Edlund, CK, Wang, H, Zhang, B, Hsu, L, Huang, S-C, Fischer, CP, Harju, JF, Idos, GE, Lejbkowicz, F, Manion, FJ, McDonnell, K, McNeil, CE, Melas, M, Rennert, HS, Shi, W, Thomas, DC, Van Den Berg, DJ, Hutter, CM, Aragaki, AK, Butterbach, K, Caan, BJ, Carlson, CS, Chanock, SJ, Curtis, KR, Fuchs, CS, Gala, M, Giocannucci, EL, Gogarten, SM, Hayes, RB, Henderson, B, Hunter, DJ, Jackson, RD, Kolonel, LN, Kooperberg, C, Kury, S, LaCroix, A, Laurie, CC, Laurie, CA, Lemire, M, Levine, D, Ma, J, Makar, KW, Qu, C, Taverna, D, Ulrich, CM, Wu, K, Kono, S, West, DW, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Coetzee, GA, Conti, DV, Duggan, D, Figueiredo, JC, Fortini, BK, Gallinger, SJ, Gauderman, WJ, Giles, G, Green, R, Haile, R, Harrison, TA, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jacobs, E, Iwasaki, M, Jee, SH, Jenkins, M, Jia, W-H, Joshi, A, Li, L, Lindor, NM, Matsuo, K, Moreno, V, Mukherjee, B, Newcomb, PA, Potter, JD, Raskin, L, Rennert, G, Rosse, S, Severi, G, Schoen, RE, Seminara, D, Shu, X-O, Slattery, ML, Tsugane, S, White, E, Xiang, Y-B, Zanke, BW, Zheng, W, Le Marchand, L, Casey, G, Gruber, SB, and Peters, U

Abstract

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.

Published
2015

31. Mendelian randomization study of height and risk of colorectal cancer

Author

Thrift, AP, Gong, J, Peters, U, Chang-Claude, J, Rudolph, A, Slattery, ML, Chan, AT, Esko, T, Wood, AR, Yang, J, Vedantam, S, Gustafsson, S, Pers, TH, Baron, JA, Bezieau, S, Kuery, S, Ogino, S, Berndt, SI, Casey, G, Haile, RW, Du, M, Harrison, TA, Thornquist, M, Duggan, DJ, Le Marchand, L, Lemire, M, Lindor, NM, Seminara, D, Song, M, Thibodeau, SN, Cotterchio, M, Win, AK, Jenkins, MA, Hopper, JL, Ulrich, CM, Potter, JD, Newcomb, PA, Schoen, RE, Hoffmeister, M, Brenner, H, White, E, Hsu, L, Campbell, PT, Thrift, AP, Gong, J, Peters, U, Chang-Claude, J, Rudolph, A, Slattery, ML, Chan, AT, Esko, T, Wood, AR, Yang, J, Vedantam, S, Gustafsson, S, Pers, TH, Baron, JA, Bezieau, S, Kuery, S, Ogino, S, Berndt, SI, Casey, G, Haile, RW, Du, M, Harrison, TA, Thornquist, M, Duggan, DJ, Le Marchand, L, Lemire, M, Lindor, NM, Seminara, D, Song, M, Thibodeau, SN, Cotterchio, M, Win, AK, Jenkins, MA, Hopper, JL, Ulrich, CM, Potter, JD, Newcomb, PA, Schoen, RE, Hoffmeister, M, Brenner, H, White, E, Hsu, L, and Campbell, PT

Abstract

BACKGROUND: For men and women, taller height is associated with increased risk of all cancers combined. For colorectal cancer (CRC), it is unclear whether the differential association of height by sex is real or is due to confounding or bias inherent in observational studies. We performed a Mendelian randomization study to examine the association between height and CRC risk. METHODS: To minimize confounding and bias, we derived a weighted genetic risk score predicting height (using 696 genetic variants associated with height) in 10,226 CRC cases and 10,286 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height, genetically predicted height and CRC. RESULTS: Using conventional methods, increased height (per 10-cm increment) was associated with increased CRC risk (OR = 1.08, 95% CI = 1.02-1.15). In sex-specific analyses, height was associated with CRC risk for women (OR = 1.15, 95% CI = 1.05-1.26), but not men (OR = 0.98, 95% CI = 0.92-1.05). Consistent with these results, carrying greater numbers of (weighted) height-increasing alleles (per 1-unit increase) was associated with higher CRC risk for women and men combined (OR = 1.07, 95% CI = 1.01-1.14) and for women (OR = 1.09, 95% CI = .01-1.19). There was weaker evidence of an association for men (OR = 1.05, 95% CI = 0.96-1.15). CONCLUSION: We provide evidence for a causal association between height and CRC for women. The CRC-height association for men remains unclear and warrants further investigation in other large studies.

Published
2015

32. Mendelian Randomization Study of Body Mass Index and Colorectal Cancer Risk

Author

Thrift, AP, Gong, J, Peters, U, Chang-Claude, J, Rudolph, A, Slattery, ML, Chan, AT, Locke, A, Kahali, B, Justice, AE, Pers, TH, Gallinger, S, Hayes, RB, Baron, JA, Caan, BJ, Ogino, S, Berndt, SI, Chanock, SJ, Casey, G, Haile, RW, Du, M, Harrison, TA, Thornquist, M, Duggan, DJ, Le Marchand, L, Lindor, NM, Seminara, D, Song, M, Wu, K, Thibodeau, SN, Cotterchio, M, Win, AK, Jenkins, MA, Hopper, J, Ulrich, CM, Potter, JD, Newcomb, PA, Hoffmeister, M, Brenner, H, White, E, Hsu, L, Campbell, PT, Thrift, AP, Gong, J, Peters, U, Chang-Claude, J, Rudolph, A, Slattery, ML, Chan, AT, Locke, A, Kahali, B, Justice, AE, Pers, TH, Gallinger, S, Hayes, RB, Baron, JA, Caan, BJ, Ogino, S, Berndt, SI, Chanock, SJ, Casey, G, Haile, RW, Du, M, Harrison, TA, Thornquist, M, Duggan, DJ, Le Marchand, L, Lindor, NM, Seminara, D, Song, M, Wu, K, Thibodeau, SN, Cotterchio, M, Win, AK, Jenkins, MA, Hopper, J, Ulrich, CM, Potter, JD, Newcomb, PA, Hoffmeister, M, Brenner, H, White, E, Hsu, L, and Campbell, PT

Abstract

BACKGROUND: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer. METHODS: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study-identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. RESULTS: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10-1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m(2), 1.50; 95% CI, 1.13-2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m(2), 1.82; 95% CI, 1.26-2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m(2), 1.18; 95% CI, 0.73-1.92). CONCLUSIONS: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. IMPACT: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer.

Published
2015

33. Association between Body Mass Index and Mortality for Colorectal Cancer Survivors: Overall and by Tumor Molecular Phenotype

Author

Campbell, PT, Newton, CC, Newcomb, PA, Phipps, AI, Ahnen, DJ, Baron, JA, Buchanan, DD, Casey, G, Cleary, SP, Cotterchio, M, Farris, AB, Figueiredo, JC, Gallinger, S, Green, RC, Haile, RW, Hopper, JL, Jenkins, MA, Le Marchand, L, Makar, KW, McLaughlin, JR, Potter, JD, Renehan, AG, Sinicrope, FA, Thibodeau, SN, Ulrich, CM, Win, AK, Lindor, NM, Limburg, PJ, Campbell, PT, Newton, CC, Newcomb, PA, Phipps, AI, Ahnen, DJ, Baron, JA, Buchanan, DD, Casey, G, Cleary, SP, Cotterchio, M, Farris, AB, Figueiredo, JC, Gallinger, S, Green, RC, Haile, RW, Hopper, JL, Jenkins, MA, Le Marchand, L, Makar, KW, McLaughlin, JR, Potter, JD, Renehan, AG, Sinicrope, FA, Thibodeau, SN, Ulrich, CM, Win, AK, Lindor, NM, and Limburg, PJ

Abstract

BACKGROUND: Microsatellite instability (MSI) and BRAF mutation status are associated with colorectal cancer survival, whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF mutation, sex, and other factors. METHODS: This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Prediagnosis BMI was derived from self-reported weight approximately one year before diagnosis and height. Tumor MSI and BRAF mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from delayed-entry Cox proportional hazards models. RESULTS: In multivariable models, high prediagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m(2); HR, 1.10; 95% CI, 1.06-1.15), with similar associations stratified by sex (Pinteraction: 0.41), colon versus rectum (Pinteraction: 0.86), MSI status (Pinteraction: 0.84), and BRAF mutation status (Pinteraction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR, 1.32; P value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR, 0.86; P value: 0.29), and approximately the same for MSI-high and obese BMI (HR, 1.00; P value: 0.98). CONCLUSIONS: High prediagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype. IMPACT: High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors.

Published
2015

34. Genome-wide association study of colorectal cancer identifies six new susceptibility loci (vol 6, 7138, 2015)

Author

Schumacher, FR, Schmit, SL, Jiao, S, Edlund, CK, Wang, H, Zhang, B, Hsu, L, Huang, S-C, Fischer, CP, Harju, JF, Idos, GE, Lejbkowicz, F, Manion, FJ, McDonnell, K, McNeil, CE, Melas, M, Rennert, HS, Shi, W, Thomas, DC, Van den Berg, DJ, Hutter, CM, Aragaki, AK, Butterbach, K, Caan, BJ, Carlson, CS, Chanock, SJ, Curtis, KR, Fuchs, CS, Gala, M, Giovannucci, EL, Gogarten, SM, Hayes, RB, Henderson, B, Hunter, DJ, Jackson, RD, Kolonel, LN, Kooperberg, C, Kuery, S, LaCroix, A, Laurie, CC, Laurie, CA, Lemire, M, Levine, D, Ma, J, Makar, KW, Qu, C, Taverna, D, Ulrich, CM, Wu, K, Kono, S, West, DW, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Coetzee, GA, Conti, DV, Duggan, D, Figueiredo, JC, Fortini, BK, Gallinger, SJ, Gauderman, WJ, Giles, G, Green, R, Haile, R, Harrison, TA, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jacobs, E, Iwasaki, M, Jee, SH, Jenkins, M, Jia, W-H, Joshi, A, Li, L, Lindor, NM, Matsuo, K, Moreno, V, Mukherjee, B, Newcomb, PA, Potter, JD, Raskin, L, Rennert, G, Rosse, S, Severi, G, Schoen, RE, Seminara, D, Shu, X-O, Slattery, ML, Tsugane, S, White, E, Xiang, Y-B, Zanke, BW, Zheng, W, Le Marchand, L, Casey, G, Gruber, SB, Peters, U, Schumacher, FR, Schmit, SL, Jiao, S, Edlund, CK, Wang, H, Zhang, B, Hsu, L, Huang, S-C, Fischer, CP, Harju, JF, Idos, GE, Lejbkowicz, F, Manion, FJ, McDonnell, K, McNeil, CE, Melas, M, Rennert, HS, Shi, W, Thomas, DC, Van den Berg, DJ, Hutter, CM, Aragaki, AK, Butterbach, K, Caan, BJ, Carlson, CS, Chanock, SJ, Curtis, KR, Fuchs, CS, Gala, M, Giovannucci, EL, Gogarten, SM, Hayes, RB, Henderson, B, Hunter, DJ, Jackson, RD, Kolonel, LN, Kooperberg, C, Kuery, S, LaCroix, A, Laurie, CC, Laurie, CA, Lemire, M, Levine, D, Ma, J, Makar, KW, Qu, C, Taverna, D, Ulrich, CM, Wu, K, Kono, S, West, DW, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Coetzee, GA, Conti, DV, Duggan, D, Figueiredo, JC, Fortini, BK, Gallinger, SJ, Gauderman, WJ, Giles, G, Green, R, Haile, R, Harrison, TA, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jacobs, E, Iwasaki, M, Jee, SH, Jenkins, M, Jia, W-H, Joshi, A, Li, L, Lindor, NM, Matsuo, K, Moreno, V, Mukherjee, B, Newcomb, PA, Potter, JD, Raskin, L, Rennert, G, Rosse, S, Severi, G, Schoen, RE, Seminara, D, Shu, X-O, Slattery, ML, Tsugane, S, White, E, Xiang, Y-B, Zanke, BW, Zheng, W, Le Marchand, L, Casey, G, Gruber, SB, and Peters, U

Published
2015

35. Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants

Author

Nan, H, Hutter, CM, Lin, Y, Jacobs, EJ, Ulrich, CM, White, E, Baron, JA, Berndt, SI, Brenner, H, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Casey, G, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Duggan, D, Figueiredo, JC, Fuchs, CS, Giovannucci, EL, Gong, J, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jenkins, MA, Jiao, S, Lindor, NM, Lemire, M, Le Marchand, L, Newcomb, PA, Ogino, S, Pflugeisen, BM, Potter, JD, Qu, C, Rosse, SA, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Slattery, ML, Thibodeau, SN, Thomas, F, Thornquist, M, Warnick, GS, Zanke, BW, Gauderman, WJ, Peters, U, Hsu, L, Chan, AT, Nan, H, Hutter, CM, Lin, Y, Jacobs, EJ, Ulrich, CM, White, E, Baron, JA, Berndt, SI, Brenner, H, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Casey, G, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Duggan, D, Figueiredo, JC, Fuchs, CS, Giovannucci, EL, Gong, J, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jenkins, MA, Jiao, S, Lindor, NM, Lemire, M, Le Marchand, L, Newcomb, PA, Ogino, S, Pflugeisen, BM, Potter, JD, Qu, C, Rosse, SA, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Slattery, ML, Thibodeau, SN, Thomas, F, Thornquist, M, Warnick, GS, Zanke, BW, Gauderman, WJ, Peters, U, Hsu, L, and Chan, AT

Abstract

IMPORTANCE: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. OBJECTIVE: To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent. EXPOSURES: Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. MAIN OUTCOMES AND MEASURES: Colorectal cancer. RESULTS: Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals

Published
2015

36. Phospholipase A2A polymorphisms and risk of colorectal neoplasia

Author

Abbenhardt, C, Poole, EM, Xiao, L, Slattery, ML, Galbraith, RL, Duggan, D, Makar, KW, Kulmacz, RJ, Curtin, K, Potter, JD, Caan, BJ, Muehling, J, Taverna, D, Carlson, CS, and Ulrich, CM

Subjects
ddc: 610, lipids (amino acids, peptides, and proteins), colorectal cancer, 610 Medical sciences, Medicine, polymorphisms, SNPs
Abstract

Introduction: Pancreatic phospholipase A2 (also known as PLA2G1B or PLA2A) catalyzes the release of fatty acids from dietary phospholipids for adsorption in the small intestine. Some of the polyunsaturated fatty acids removed from the intestinal lumen are precursors to eicosanoids, which are linked [for full text, please go to the a.m. URL], Mainz//2011; 56. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 6. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi)

Published
2011
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37. Implementierung eines Audit Trails zur Erfüllung der Anforderungen nach der guten klinischen Praxis (GCP) – Ein Erfahrungsbericht

Author

Aamot, H, Kotzmann, J, Gigic, B, and Ulrich, CM

Subjects
Sicherheit, Validierung, ddc: 610, Datenerfassung, Studiendatenbank, Audit Trail, klinische Studien, 610 Medical sciences, Medicine, regulatorische Anforderungen, GCP
Abstract

Einleitung: In den letzten zehn Jahren wurden überproportional viele regulatorische Dokumente über IT-Systeme, die in klinischen Studien eingesetzt werden, erstellt [ref:1], [ref:2], [ref:3]. Der Grund für diese Entwicklung ist die ständig zunehmende[for full text, please go to the a.m. URL], Mainz//2011; 56. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 6. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi)

Published
2011
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38. Psychophysische Konstitution von Patienten im Vorfeld der allogenen hämatopoetischen Stammzelltransplantation (allo-HSCT)

Author

Vandenbergh, D, Nies, R, Ulrich, CM, Bohus, M, Jäger, D, Dreger, P, Schwerdtfeger, R, Huber, G, and Wiskemann, J

Subjects
ddc: 610, Quality of Life, Allogene Stammzelltransplantation, 610 Medical sciences, Medicine, Körperliche Leistungsfähigkeit, Fatigue
Abstract

Einleitung: Die allo-HSCT stellt in der Medizin ein komplikationsreiches Verfahren dar. Trotzallem ist es für viele Patienten die einzige Behandlungsoption mit Aussicht auf Heilung einer schweren hämatologischen Neoplasie. Es ist anzunehmen, dass allo-HSCT Patienten schon vor der Transplantation[for full text, please go to the a.m. URL], Mainz//2011; 56. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 6. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi)

Published
2011
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39. Genetic Variation in UGT Genes Modify the Associations of NSAIDs with Risk of Colorectal Cancer: Colon Cancer Family Registry

Author

Scherer, D, Koepl, LM, Poole, EM, Balavarca, Y, Xiao, L, Baron, JA, Hsu, L, Coghill, AE, Campbell, PT, Kleinstein, SE, Figueiredo, JC, Lampe, JW, Buck, K, Potter, JD, Kulmacz, RJ, Jenkins, MA, Hopper, JL, Win, AK, Newcomb, PA, Ulrich, CM, Makar, KW, Scherer, D, Koepl, LM, Poole, EM, Balavarca, Y, Xiao, L, Baron, JA, Hsu, L, Coghill, AE, Campbell, PT, Kleinstein, SE, Figueiredo, JC, Lampe, JW, Buck, K, Potter, JD, Kulmacz, RJ, Jenkins, MA, Hopper, JL, Win, AK, Newcomb, PA, Ulrich, CM, and Makar, KW

Abstract

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal neoplasia. Previous studies have reported that polymorphisms in NSAID-metabolizing enzymes central to NSAID metabolism including UDP-glucuronosyltransferases (UGT) and cytochrome P450 (CYP) 2C9 may modify this protective effect. We investigated whether 35 functionally relevant polymorphisms within CYP2C9 and UGT genes were associated with colorectal cancer risk or modified the protective effect of NSAIDs on colorectal cancer susceptibility, using 1,584 colorectal cancer cases and 2,516 unaffected sibling controls from the Colon Cancer Family Registry. A three-SNP genotype in UGT1A6 (G-A-A; Ala7-Thr181-Arg184) and the Asp85 variant in UGT2B15 increased the risk of colorectal cancer (OR 3.87; 95% CI 1.04-14.45 and OR 1.34; 95% CI 1.10-1.63, respectively). We observed interactions between UGT1A3 Thr78Thr (A>G) and NSAID use (P-interaction = 0.02), a three-SNP genotype within UGT2B4 and ibuprofen use (P-interaction = 0.0018), as well as UGT2B15 Tyr85Asp (T>G) and aspirin use (P-interaction = 0.01). The interaction with the UGT2B4 and the UGT2B15 polymorphisms were noteworthy at the 25% FDR level. This study highlights the need for further pharmacogenetic studies to identify individuals who might benefit from NSAID use as part of developing effective strategies for prevention of colorectal neoplasia. © 2014 Wiley Periodicals, Inc.

Published
2014

40. Gene-Environment Interaction Involving Recently Identified Colorectal Cancer Susceptibility Loci

Author

Kantor, ED, Hutter, CM, Minnier, J, Berndt, SI, Brenner, H, Caan, BJ, Campbell, PT, Carlson, CS, Casey, G, Chan, AT, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Du, M, Duggan, D, Fuchs, CS, Giovannucci, EL, Gong, J, Harrison, TA, Hayes, RB, Henderson, BE, Hoffmeister, M, Hopper, JL, Jenkins, MA, Jiao, S, Kolonel, LN, Le Marchand, L, Lemire, M, Ma, J, Newcomb, PA, Ochs-Balcom, HM, Pflugeisen, BM, Potter, JD, Rudolph, A, Schoen, RE, Seminara, D, Slattery, ML, Stelling, DL, Thomas, F, Thornquist, M, Ulrich, CM, Warnick, GS, Zanke, BW, Peters, U, Hsu, L, White, E, Kantor, ED, Hutter, CM, Minnier, J, Berndt, SI, Brenner, H, Caan, BJ, Campbell, PT, Carlson, CS, Casey, G, Chan, AT, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Du, M, Duggan, D, Fuchs, CS, Giovannucci, EL, Gong, J, Harrison, TA, Hayes, RB, Henderson, BE, Hoffmeister, M, Hopper, JL, Jenkins, MA, Jiao, S, Kolonel, LN, Le Marchand, L, Lemire, M, Ma, J, Newcomb, PA, Ochs-Balcom, HM, Pflugeisen, BM, Potter, JD, Rudolph, A, Schoen, RE, Seminara, D, Slattery, ML, Stelling, DL, Thomas, F, Thornquist, M, Ulrich, CM, Warnick, GS, Zanke, BW, Peters, U, Hsu, L, and White, E

Abstract

BACKGROUND: Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer. Prior research has evaluated the presence of gene-environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279. METHODS: Data on 9,160 cases and 9,280 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR) were used to evaluate the presence of interaction involving the above-listed SNPs and sex, body mass index (BMI), alcohol consumption, smoking, aspirin use, postmenopausal hormone (PMH) use, as well as intake of dietary calcium, dietary fiber, dietary folate, red meat, processed meat, fruit, and vegetables. Interaction was evaluated using a fixed effects meta-analysis of an efficient Empirical Bayes estimator, and permutation was used to account for multiple comparisons. RESULTS: None of the permutation-adjusted P values reached statistical significance. CONCLUSIONS: The associations between recently identified genetic susceptibility loci and colorectal cancer are not strongly modified by sex, BMI, alcohol, smoking, aspirin, PMH use, and various dietary factors. IMPACT: Results suggest no evidence of strong gene-environment interactions involving the recently identified 16 susceptibility loci for colorectal cancer taken one at a time.

Published
2014

41. Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer

Author

Figueiredo, JC, Hsu, L, Hutter, CM, Lin, Y, Campbell, PT, Baron, JA, Berndt, SI, Jiao, S, Casey, G, Fortini, B, Chan, AT, Cotterchio, M, Lemire, M, Gallinger, S, Harrison, TA, Le Marchand, L, Newcomb, PA, Slattery, ML, Caan, BJ, Carlson, CS, Zanke, BW, Rosse, SA, Brenner, H, Giovannucci, EL, Wu, K, Chang-Claude, J, Chanock, SJ, Curtis, KR, Duggan, D, Gong, J, Haile, RW, Hayes, RB, Hoffmeister, M, Hopper, JL, Jenkins, MA, Kolonel, LN, Qu, C, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Stelling, DL, Thibodeau, SN, Thornquist, M, Warnick, GS, Henderson, BE, Ulrich, CM, Gauderman, WJ, Potter, JD, White, E, Peters, U, Figueiredo, JC, Hsu, L, Hutter, CM, Lin, Y, Campbell, PT, Baron, JA, Berndt, SI, Jiao, S, Casey, G, Fortini, B, Chan, AT, Cotterchio, M, Lemire, M, Gallinger, S, Harrison, TA, Le Marchand, L, Newcomb, PA, Slattery, ML, Caan, BJ, Carlson, CS, Zanke, BW, Rosse, SA, Brenner, H, Giovannucci, EL, Wu, K, Chang-Claude, J, Chanock, SJ, Curtis, KR, Duggan, D, Gong, J, Haile, RW, Hayes, RB, Hoffmeister, M, Hopper, JL, Jenkins, MA, Kolonel, LN, Qu, C, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Stelling, DL, Thibodeau, SN, Thornquist, M, Warnick, GS, Henderson, BE, Ulrich, CM, Gauderman, WJ, Potter, JD, White, E, and Peters, U

Abstract

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention. © 2014.

Published
2014

42. Meta-analysis of new genome-wide association studies of colorectal cancer risk

Author

Peters, U, Hutter, CM, Hsu, L, Schumacher, FR, Conti, DV, Carlson, CS, Edlund, CK, Haile, RW, Gallinger, S, Zanke, BW, Lemire, M, Rangrej, J, Vijayaraghavan, R, Chan, AT, Hazra, A, Hunter, DJ, Ma, J, Fuchs, CS, Giovannucci, EL, Kraft, P, Liu, Y, Chen, L, Jiao, S, Makar, KW, Taverna, D, Gruber, SB, Rennert, G, Moreno, V, Ulrich, CM, Woods, MO, Green, RC, Parfrey, PS, Prentice, RL, Kooperberg, C, Jackson, RD, LaCroix, AZ, Caan, BJ, Hayes, RB, Berndt, SI, Chanock, SJ, Schoen, RE, Chang-Claude, J, Hoffmeister, M, Brenner, H, Frank, B, Bezieau, S, Kuery, S, Slattery, ML, Hopper, JL, Jenkins, MA, Le Marchand, L, Lindor, NM, Newcomb, PA, Seminara, D, Hudson, TJ, Duggan, DJ, Potter, JD, Casey, G, Peters, U, Hutter, CM, Hsu, L, Schumacher, FR, Conti, DV, Carlson, CS, Edlund, CK, Haile, RW, Gallinger, S, Zanke, BW, Lemire, M, Rangrej, J, Vijayaraghavan, R, Chan, AT, Hazra, A, Hunter, DJ, Ma, J, Fuchs, CS, Giovannucci, EL, Kraft, P, Liu, Y, Chen, L, Jiao, S, Makar, KW, Taverna, D, Gruber, SB, Rennert, G, Moreno, V, Ulrich, CM, Woods, MO, Green, RC, Parfrey, PS, Prentice, RL, Kooperberg, C, Jackson, RD, LaCroix, AZ, Caan, BJ, Hayes, RB, Berndt, SI, Chanock, SJ, Schoen, RE, Chang-Claude, J, Hoffmeister, M, Brenner, H, Frank, B, Bezieau, S, Kuery, S, Slattery, ML, Hopper, JL, Jenkins, MA, Le Marchand, L, Lindor, NM, Newcomb, PA, Seminara, D, Hudson, TJ, Duggan, DJ, Potter, JD, and Casey, G

Abstract

Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; co

Published
2012

43. Genome-Wide Search for Gene-Gene Interactions in Colorectal Cancer

Author

Yu, Z, Jiao, S, Hsu, L, Berndt, S, Bezieau, S, Brenner, H, Buchanan, D, Caan, BJ, Campbell, PT, Carlson, CS, Casey, G, Chan, AT, Chang-Claude, J, Chanock, S, Conti, DV, Curtis, KR, Duggan, D, Gallinger, S, Gruber, SB, Harrison, TA, Hayes, RB, Henderson, BE, Hoffmeister, M, Hopper, JL, Hudson, TJ, Hutter, CM, Jackson, RD, Jenkins, MA, Kantor, ED, Kolonel, LN, Kuery, S, Le Marchand, L, Lemire, M, Newcomb, PA, Potter, JD, Qu, C, Rosse, SA, Schoen, RE, Schumacher, FR, Seminara, D, Slattery, ML, Ulrich, CM, Zanke, BW, Peters, U, Yu, Z, Jiao, S, Hsu, L, Berndt, S, Bezieau, S, Brenner, H, Buchanan, D, Caan, BJ, Campbell, PT, Carlson, CS, Casey, G, Chan, AT, Chang-Claude, J, Chanock, S, Conti, DV, Curtis, KR, Duggan, D, Gallinger, S, Gruber, SB, Harrison, TA, Hayes, RB, Henderson, BE, Hoffmeister, M, Hopper, JL, Hudson, TJ, Hutter, CM, Jackson, RD, Jenkins, MA, Kantor, ED, Kolonel, LN, Kuery, S, Le Marchand, L, Lemire, M, Newcomb, PA, Potter, JD, Qu, C, Rosse, SA, Schoen, RE, Schumacher, FR, Seminara, D, Slattery, ML, Ulrich, CM, Zanke, BW, and Peters, U

Abstract

Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p<10(-4)). For the known locus rs10795668 (10p14), we found an interacting SNP rs367615 (5q21) with replication p = 0.01 and combined p = 4.19×10(-8). Among the top marginal SNPs after LD pruning (n = 163), we identified an interaction between rs1571218 (20p12.3) and rs10879357 (12q21.1) (nominal combined p = 2.51×10(-6); Bonferroni adjusted p = 0.03). Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.

Published
2012

46. CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatment.

Author

Barry EL, Poole EM, Baron JA, Makar KW, Mott LA, Sandler RS, Ahnen DJ, Bresalier RS, McKeown-Eyssen GE, Ulrich CM, Barry, Elizabeth L, Poole, Elizabeth M, Baron, John A, Makar, Karen W, Mott, Leila A, Sandler, Robert S, Ahnen, Dennis J, Bresalier, Robert S, McKeown-Eyssen, Gail E, and Ulrich, Cornelia M

Abstract

Purpose: The cytochrome P450 2C9 enzyme (CYP2C9) is involved in metabolism of endogenous compounds, drugs, and procarcinogens. Two common nonsynonymous polymorphisms in CYP2C9 are associated with reduced enzyme activity: CYP2C9*2 (rs1799853, R144C) and CYP2C9*3 (rs1057910, I359L).Methods: We investigated whether CYP2C9 genotype was associated with risk of colorectal adenoma and/or modified associations with aspirin treatment or cigarette smoking in a cohort of 928 participants in a randomized trial of aspirin chemoprevention. Generalized linear regression was used to compute relative risks (RRs) and 95 % confidence intervals (95 % CIs). Multiplicative interactions terms were used to assess effect modification.Results: CYP2C9 genotype was associated with increased risks for adenoma recurrence of 29 % (RR = 1.29, 95 % CI 1.09-1.51) for ≥1 variant allele (CYP2C9*2 or *3) and 47 % (RR = 1.47, 95 % CI 1.19-1.83) for ≥1 CYP2C9*3 allele. The risk for advanced lesions or multiple (≥3) adenomas was increased by 64 % (RR = 1.64, 95 % CI 1.18-2.28) for ≥1 variant allele (CYP2C9*2 or *3) and 79 % (RR = 1.79, 95 % CI 1.16-2.75) for ≥1 CYP2C9*3 allele. Genotype modified associations with smoking, but not aspirin treatment. The adenoma risk was increased by 26 % (RR = 1.26, 95 % CI 0.99-1.58) for former smokers and 60 % (RR = 1.60, 95 % CI 1.19-2.15) for current smokers among wild-type individuals, but there was no increased risk among individuals with ≥1 variant allele (CYP2C9*2 or *3) (p (interaction) = 0.04).Conclusions: Carriers of CYP2C9 variants with lower enzyme activity have increased overall risk of colorectal adenoma but reduced adenoma risk associated with cigarette smoking. These results may be due to effects on the synthesis of endogenous eicosanoids and/or reduced activation of procarcinogens in smoke by CYP2C9 variants. [ABSTRACT FROM AUTHOR]

Published
2013
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50. Case-control study of overweight, obesity, and colorectal cancer risk, overall and by tumor microsatellite instability status.

Author

Campbell PT, Jacobs ET, Ulrich CM, Figueiredo JC, Poynter JN, McLaughlin JR, Haile RW, Jacobs EJ, Newcomb PA, Potter JD, Le Marchand L, Green RC, Parfrey P, Younghusband HB, Cotterchio M, Gallinger S, Jenkins MA, Hopper JL, Baron JA, and Thibodeau SN

Abstract

Background: Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%-20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status.Methods: The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (> or =30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided.Results: Recent BMI, modeled in 5 kg/m(2) increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m(2), was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31).Conclusion: The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status. [ABSTRACT FROM AUTHOR]

Published
2010
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