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3. Perceived Barriers to Lung Cancer Screening in Asian Americans

Author

Sakoda, L.C., primary, Zhu, Z., additional, Morris, M.J., additional, Hsieh, K.S., additional, Vu, D.T., additional, Altschuler, A., additional, Ip, J., additional, Prochaska, J., additional, Young-Wolff, K.C., additional, Quesenberry, C.P., additional, and Hsing, A.W., additional

Published
2024
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4. Response to Li and Hopper.

Author

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

Published
2021

5. Genetically predicted circulating c-reactive protein concentration and colorectal cancer survival: A mendelian randomization consortium study.

Author

Hua X., Dai J.Y., Lindstrom S., Harrison T.A., Lin Y., Alberts S.R., Alwers E., Berndt S.I., Brenner H., Buchanan D.D., Campbell P.T., Casey G., Chang-Claude J., Gallinger S., Giles G.G., Goldberg R.M., Gunter M.J., Hoffmeister M., Jenkins M.A., Joshi A.D., Ma W., Milne R.L., Murphy N., Pai R.K., Sakoda L.C., Schoen R.E., Shi Q., Slattery M.L., Song M., White E., Le Marchand L., Chan A.T., Peters U., Newcomb P.A., Hua X., Dai J.Y., Lindstrom S., Harrison T.A., Lin Y., Alberts S.R., Alwers E., Berndt S.I., Brenner H., Buchanan D.D., Campbell P.T., Casey G., Chang-Claude J., Gallinger S., Giles G.G., Goldberg R.M., Gunter M.J., Hoffmeister M., Jenkins M.A., Joshi A.D., Ma W., Milne R.L., Murphy N., Pai R.K., Sakoda L.C., Schoen R.E., Shi Q., Slattery M.L., Song M., White E., Le Marchand L., Chan A.T., Peters U., and Newcomb P.A.

Abstract

Background: A positive association between circulating Creactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality.Weused a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival. Method(s): We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. Wecalculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components. Result(s): Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer-specific survival (HD, 1.15; 95% CI, 2.76 to 0.47 per 100,000 person-years; P = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location. Conclusion(s): Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival.Copyright © 2021 American Association for Cancer Research Inc.. All rights reserved.

Published
2021

6. Association of body mass index with colorectal cancer risk by genome-wide variants.

Author

Giles G.G., Lin Y., Bien S.A., Figueiredo J.C., Harrison T.A., Guinter M.A., Berndt S.I., Brenner H., Chan A.T., Chang-Claude J., Gallinger S.J., Gapstur S.M., Campbell P.T., Giovannucci E., Gruber S.B., Gunter M., Ogino S., Potter J.D., Rennert G., Rennert H.S., Robinson J., Sakoda L.C., Slattery M.L., Song Y., White E., Woods M.O., Casey G., Hsu L., Peters U., Hoffmeister M., Jacobs E.J., Jenkins M.A., Le Marchand L., Li L., McLaughlin J.R., Murphy N., Milne R.L., Newcomb P.A., Newton C., Giles G.G., Lin Y., Bien S.A., Figueiredo J.C., Harrison T.A., Guinter M.A., Berndt S.I., Brenner H., Chan A.T., Chang-Claude J., Gallinger S.J., Gapstur S.M., Campbell P.T., Giovannucci E., Gruber S.B., Gunter M., Ogino S., Potter J.D., Rennert G., Rennert H.S., Robinson J., Sakoda L.C., Slattery M.L., Song Y., White E., Woods M.O., Casey G., Hsu L., Peters U., Hoffmeister M., Jacobs E.J., Jenkins M.A., Le Marchand L., Li L., McLaughlin J.R., Murphy N., Milne R.L., Newcomb P.A., and Newton C.

Abstract

Background: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. Method(s): We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedomtest) procedures. All statistical tests were two-sided. Result(s): Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 x 10-17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 x 10-24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 x 10-10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 x 10-10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 x 10-8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes. Conclusion(s): These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.Copyright © The Author(s) 2020.

Published
2021

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

Author

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

Abstract

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

Published
2021

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

Author

Nounu A., Richmond R.C., Stewart I.D., Surendran P., Wareham N.J., Butterworth A., Weinstein S.J., Albanes D., Baron J.A., Hopper J.L., Figueiredo J.C., Newcomb P.A., Lindor N.M., Casey G., Platz E.A., Marchand L.L., Ulrich C.M., Li C.I., van Dujinhoven F.J.B., Gsur A., Campbell P.T., Moreno V., Vodicka P., Vodickova L., Amitay E., Alwers E., Chang-Claude J., Sakoda L.C., Slattery M.L., Schoen R.E., Gunter M.J., Castellvi-Bel S., Kim H.-R., Kweon S.-S., Chan A.T., Li L., Zheng W., Bishop D.T., Buchanan D.D., Giles G.G., Gruber S.B., Rennert G., Stadler Z.K., Harrison T.A., Lin Y., Keku T.O., Woods M.O., Schafmayer C., Van Guelpen B., Gallinger S., Hampel H., Berndt S.I., Pharoah P.D.P., Lindblom A., Wolk A., Wu A.H., White E., Peters U., Drew D.A., Scherer D., Bermejo J.L., Brenner H., Hoffmeister M., Williams A.C., Relton C.L., Nounu A., Richmond R.C., Stewart I.D., Surendran P., Wareham N.J., Butterworth A., Weinstein S.J., Albanes D., Baron J.A., Hopper J.L., Figueiredo J.C., Newcomb P.A., Lindor N.M., Casey G., Platz E.A., Marchand L.L., Ulrich C.M., Li C.I., van Dujinhoven F.J.B., Gsur A., Campbell P.T., Moreno V., Vodicka P., Vodickova L., Amitay E., Alwers E., Chang-Claude J., Sakoda L.C., Slattery M.L., Schoen R.E., Gunter M.J., Castellvi-Bel S., Kim H.-R., Kweon S.-S., Chan A.T., Li L., Zheng W., Bishop D.T., Buchanan D.D., Giles G.G., Gruber S.B., Rennert G., Stadler Z.K., Harrison T.A., Lin Y., Keku T.O., Woods M.O., Schafmayer C., Van Guelpen B., Gallinger S., Hampel H., Berndt S.I., Pharoah P.D.P., Lindblom A., Wolk A., Wu A.H., White E., Peters U., Drew D.A., Scherer D., Bermejo J.L., Brenner H., Hoffmeister M., Williams A.C., and Relton C.L.

Abstract

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR:1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI:0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.Copyright © 2021 by the authors. Li-censee MDPI, Basel, Switzerland.

Published
2021

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

Author

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

Abstract

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

Published
2021

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

Author

Labadie J.D., Harrison T.A., Banbury B., Amtay E.L., Bernd S., Brenner H., Buchanan D.D., Campbell P.T., Cao Y., Chan A.T., Chang-Claude J., Englishc D., Figueiredo J.C., Gallingerc S.J., Gilesc G.G., Gunter M.J., Hoffmeisterc M., Hsu L., Jenkins M.A., Lin Y., Milnec R.L., Moreno V., Murphyc N., Ogino S., Phipps A.I., Sakoda L.C., Slattery M.L., Southey M.C., Sun W., Thibodeau S.N., Van Guelpen B., Zaidi S.H., Peters U., Newcomb P.A., Labadie J.D., Harrison T.A., Banbury B., Amtay E.L., Bernd S., Brenner H., Buchanan D.D., Campbell P.T., Cao Y., Chan A.T., Chang-Claude J., Englishc D., Figueiredo J.C., Gallingerc S.J., Gilesc G.G., Gunter M.J., Hoffmeisterc M., Hsu L., Jenkins M.A., Lin Y., Milnec R.L., Moreno V., Murphyc N., Ogino S., Phipps A.I., Sakoda L.C., Slattery M.L., Southey M.C., Sun W., Thibodeau S.N., Van Guelpen B., Zaidi S.H., Peters U., and Newcomb P.A.

Abstract

Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. Method(s): We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: Adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2- sided. Result(s): Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; Phet =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; Phet =.01) tumors. Conclusion(s): We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.Copy

Published
2021

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

Author

Pharoah P.D.P., Nounu A., Greenhough A., Heesom K.J., Richmond R.C., Zheng J., Weinstein S.J., Albanes D., Gallinger S., Hampel H., Berndt S.I., Lindblom A., Wolk A., Wu A.H., White E., Peters U., Drew D.A., Scherer D., Bermejo J.L., Williams A.C., Relton C.L., Baron J.A., Hopper J.L., Figueiredo J.C., Newcomb P.A., Lindor N.M., Casey G., Platz E.A., Le Marchand L., Ulrich C.M., Li C.I., van Duijnhoven F.J.B., Gsur A., Campbell P.T., Moreno V., Vodicka P., Vodickova L., Brenner H., Chang-Claude J., Hoffmeister M., Sakoda L.C., Slattery M.L., Schoen R.E., Gunter M.J., Castellvi-Bel S., Kim H.R., Kweon S.-S., Chan A.T., Li L., Zheng W., Bishop D.T., Buchanan D.D., Giles G.G., Gruber S.B., Rennert G., Stadler Z.K., Harrison T.A., Lin Y., Keku T.O., Woods M.O., Schafmayer C., van Guelpen B., Pharoah P.D.P., Nounu A., Greenhough A., Heesom K.J., Richmond R.C., Zheng J., Weinstein S.J., Albanes D., Gallinger S., Hampel H., Berndt S.I., Lindblom A., Wolk A., Wu A.H., White E., Peters U., Drew D.A., Scherer D., Bermejo J.L., Williams A.C., Relton C.L., Baron J.A., Hopper J.L., Figueiredo J.C., Newcomb P.A., Lindor N.M., Casey G., Platz E.A., Le Marchand L., Ulrich C.M., Li C.I., van Duijnhoven F.J.B., Gsur A., Campbell P.T., Moreno V., Vodicka P., Vodickova L., Brenner H., Chang-Claude J., Hoffmeister M., Sakoda L.C., Slattery M.L., Schoen R.E., Gunter M.J., Castellvi-Bel S., Kim H.R., Kweon S.-S., Chan A.T., Li L., Zheng W., Bishop D.T., Buchanan D.D., Giles G.G., Gruber S.B., Rennert G., Stadler Z.K., Harrison T.A., Lin Y., Keku T.O., Woods M.O., Schafmayer C., and van Guelpen B.

Abstract

Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. Method(s): Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N 1/4 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N 1/4 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). Result(s): Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively). Conclusion(s): MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.Copyright ©2020 American Association for Cancer Research.

Published
2021

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

Author

Seyed Khoei, N., Jenab, M., Murphy, N., Banbury, B.L., Carreras-Torres, R., Viallon, V., Kühn, T., Bueno-de-Mesquita, B., Aleksandrova, K., Cross, A.J., Weiderpass, E., Stepien, M., Bulmer, A., Tjønneland, A., Boutron-Ruault, M.C., Severi, G., Carbonnel, F., Katzke, V., Boeing, H., Bergmann, M.M., Trichopoulou, A., Karakatsani, A., Martimianaki, G., Palli, D., Tagliabue, G., Panico, S., Tumino, R., Sacerdote, C., Skeie, G., Merino, S., Bonet, C., Rodríguez-Barranco, M., Gil, L., Chirlaque, M.D., Ardanaz, E., Myte, R., Hultdin, J., Perez-Cornago, A., Aune, D., Tsilidis, K.K., Albanes, D., Baron, J.A., Berndt, S.I., Bézieau, S., Brenner, H., Campbell, P.T., Casey, G., Chang-Claude, J., Chanock, S.J., Cotterchio, M., Gallinger, S., Gruber, S.B., Haile, R.W., Hampe, J., Hoffmeister, M., Hopper, J.L., Hsu, L., Huyghe, J.R., Jenkins, M.A., Joshi, A.D., Kampman, E., Larsson, S.C., Le Marchand, L., Li, C.I., Li, L., Lindblom, A., Lindor, N.M., Martín, V., Moreno, V., Newcomb, P.A., Offit, K., Ogino, S., Parfrey, P.S., Pharoah, P.D.P., Rennert, G., Sakoda, L.C., Schafmayer, C., Schmit, S.L., Schoen, R.E., Slattery, M.L., Thibodeau, S.N., Ulrich, C.M., van Duijnhoven, F.J.B., Weigl, K., Weinstein, S.J., White, E., Wolk, A., Woods, M.O., Wu, A.H., Zhang, X., Ferrari, P., Anton, G., Peters, A., Peters, U., Gunter, M.J., Wagner, K.H., and Freisling, H.

Subjects
Bilirubin, Cancer, Colorectal Cancer, Anti-oxidants, Mendelian Randomization Analysis
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 x 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 (P-heterogeneity = 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 mainUGT1A1SNP (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, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P-heterogeneity >= 0.2). Conclusions Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

Published
2020

13. Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses

Author

Seyed Khoei, N. Jenab, M. Murphy, N. Banbury, B.L. Carreras-Torres, R. Viallon, V. Kühn, T. Bueno-De-Mesquita, B. Aleksandrova, K. Cross, A.J. Weiderpass, E. Stepien, M. Bulmer, A. Tjønneland, A. Boutron-Ruault, M.-C. Severi, G. Carbonnel, F. Katzke, V. Boeing, H. Bergmann, M.M. Trichopoulou, A. Karakatsani, A. Martimianaki, G. Palli, D. Tagliabue, G. Panico, S. Tumino, R. Sacerdote, C. Skeie, G. Merino, S. Bonet, C. Rodríguez-Barranco, M. Gil, L. Chirlaque, M.-D. Ardanaz, E. Myte, R. Hultdin, J. Perez-Cornago, A. Aune, D. Tsilidis, K.K. Albanes, D. Baron, J.A. Berndt, S.I. Bézieau, S. Brenner, H. Campbell, P.T. Casey, G. Chan, A.T. Chang-Claude, J. Chanock, S.J. Cotterchio, M. Gallinger, S. Gruber, S.B. Haile, R.W. Hampe, J. Hoffmeister, M. Hopper, J.L. Hsu, L. Huyghe, J.R. Jenkins, M.A. Joshi, A.D. Kampman, E. Larsson, S.C. Le Marchand, L. Li, C.I. Li, L. Lindblom, A. Lindor, N.M. Martín, V. Moreno, V. Newcomb, P.A. Offit, K. Ogino, S. Parfrey, P.S. Pharoah, P.D.P. Rennert, G. Sakoda, L.C. Schafmayer, C. Schmit, S.L. Schoen, R.E. Slattery, M.L. Thibodeau, S.N. Ulrich, C.M. Van Duijnhoven, F.J.B. Weigl, K. Weinstein, S.J. White, E. Wolk, A. Woods, M.O. Wu, A.H. Zhang, X. Ferrari, P. Anton, G. Peters, A. Peters, U. Gunter, M.J. Wagner, K.-H. 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 (P heterogeneity = 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, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P heterogeneity ≥ 0.2). Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development. © 2020 The Author(s).

Published
2020

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

Author

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

Abstract

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might be

Published
2020

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

Author

English D., Van Guelpen B., Visvanathan K., Vodicka P., Vodickova L., Vymetalkova V., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Zheng W., Peters U., Gunter M.J., Murphy N., Carreras-Torres R., Song M., Chan A.T., Martin R.M., Papadimitriou N., Dimou N., Tsilidis K.K., Banbury B., Bradbury K.E., Besevic J., Rinaldi S., Riboli E., Cross A.J., Travis R.C., Agnoli C., Albanes D., Berndt S.I., Bezieau S., Bishop D.T., Brenner H., Buchanan D.D., Onland-Moret N.C., Burnett-Hartman A., Campbell P.T., Casey G., Castellvi-Bel S., Chang-Claude J., Chirlaque M.-D., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Giles G.G., Gruber S.B., Gsur A., Hampe J., Hampel H., Harrison T.A., Hoffmeister M., Hsu L., Huang W.-Y., Huyghe J.R., Jenkins M.A., Keku T.O., Kuhn T., Kweon S.-S., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., Milne R.L., Moreno V., Newcomb P.A., Offit K., Ogino S., Ose J., Perduca V., Phipps A.I., Platz E.A., Potter J.D., Qu C., Rennert G., Sakoda L.C., Schafmayer C., Schoen R.E., Slattery M.L., Tangen C.M., Ulrich C.M., van Duijnhoven F.J.B., English D., Van Guelpen B., Visvanathan K., Vodicka P., Vodickova L., Vymetalkova V., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Zheng W., Peters U., Gunter M.J., Murphy N., Carreras-Torres R., Song M., Chan A.T., Martin R.M., Papadimitriou N., Dimou N., Tsilidis K.K., Banbury B., Bradbury K.E., Besevic J., Rinaldi S., Riboli E., Cross A.J., Travis R.C., Agnoli C., Albanes D., Berndt S.I., Bezieau S., Bishop D.T., Brenner H., Buchanan D.D., Onland-Moret N.C., Burnett-Hartman A., Campbell P.T., Casey G., Castellvi-Bel S., Chang-Claude J., Chirlaque M.-D., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Giles G.G., Gruber S.B., Gsur A., Hampe J., Hampel H., Harrison T.A., Hoffmeister M., Hsu L., Huang W.-Y., Huyghe J.R., Jenkins M.A., Keku T.O., Kuhn T., Kweon S.-S., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., Milne R.L., Moreno V., Newcomb P.A., Offit K., Ogino S., Ose J., Perduca V., Phipps A.I., Platz E.A., Potter J.D., Qu C., Rennert G., Sakoda L.C., Schafmayer C., Schoen R.E., Slattery M.L., Tangen C.M., Ulrich C.M., and van Duijnhoven F.J.B.

Abstract

Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. Method(s): Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) Results: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 x 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 x 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene re

Published
2020

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

Author

Hsu L., Berndt S.I., Bezieau S., Bishop D.T., Brenner H., Buchanan D.D., Burnett-Hartman A., Casey G., Castellvi-Bel S., Chan A.T., Chang-Claude J., Cross A.J., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Gapstur S.M., Giles G.G., Gruber S.B., Gsur A., Hampe J., Hampel H., Harrison T.A., Hoffmeister M., Huang W.-Y., Huyghe J.R., Jenkins M.A., Joshu C.E., Keku T.O., Kuhn T., Kweon S.-S., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., May A.M., Milne R.L., Moreno V., Newcomb P.A., Offit K., Ogino S., Phipps A.I., Platz E.A., Potter J.D., Qu C., Quiros J.R., Rennert G., Riboli E., Sakoda L.C., Schafmayer C., Schoen R.E., Slattery M.L., Tangen C.M., Tsilidis K.K., Ulrich C.M., van Duijnhoven F.J.B., van Guelpen B., Visvanathan K., Vodicka P., Vodickova L., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Campbell P.T., Zheng W., Peters U., Vincent E.E., Gunter M.J., Bull C.J., Bell J.A., Murphy N., Sanderson E., Davey Smith G., Timpson N.J., Banbury B.L., Albanes D., Hsu L., Berndt S.I., Bezieau S., Bishop D.T., Brenner H., Buchanan D.D., Burnett-Hartman A., Casey G., Castellvi-Bel S., Chan A.T., Chang-Claude J., Cross A.J., de la Chapelle A., Figueiredo J.C., Gallinger S.J., Gapstur S.M., Giles G.G., Gruber S.B., Gsur A., Hampe J., Hampel H., Harrison T.A., Hoffmeister M., Huang W.-Y., Huyghe J.R., Jenkins M.A., Joshu C.E., Keku T.O., Kuhn T., Kweon S.-S., Le Marchand L., Li C.I., Li L., Lindblom A., Martin V., May A.M., Milne R.L., Moreno V., Newcomb P.A., Offit K., Ogino S., Phipps A.I., Platz E.A., Potter J.D., Qu C., Quiros J.R., Rennert G., Riboli E., Sakoda L.C., Schafmayer C., Schoen R.E., Slattery M.L., Tangen C.M., Tsilidis K.K., Ulrich C.M., van Duijnhoven F.J.B., van Guelpen B., Visvanathan K., Vodicka P., Vodickova L., Wang H., White E., Wolk A., Woods M.O., Wu A.H., Campbell P.T., Zheng W., Peters U., Vincent E.E., Gunter M.J., Bull C.J., Bell J.A., Murphy N., Sanderson E., Davey Smith G., Timpson N.J., Banbury B.L., and Albanes D.

Abstract

Background: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Method(s): We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Result(s): In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P <= 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative

Published
2020

17. Genetic associations and architecture of asthma-chronic obstructive pulmonary disease overlap

Author

John, C., primary, Guyatt, A.L., additional, Shrine, N., additional, Packer, R., additional, Olafsdottir, T.A., additional, Liu, J., additional, Hayden, L.P., additional, Chu, S.H., additional, Koskela, J.T., additional, Luan, J., additional, Li, X., additional, Terzikhan, N., additional, Xu, H., additional, Bartz, T.M., additional, Petersen, H., additional, Leng, S., additional, Belinsky, S.A., additional, Cepelis, A., additional, Hernández Cordero, A.I., additional, Obeidat, M., additional, Thorleifsson, G., additional, Meyers, D.A., additional, Bleecker, E.R., additional, Sakoda, L.C., additional, Iribarren, C., additional, Tesfaigzi, Y., additional, Gharib, S.A., additional, Dupuis, J., additional, Brusselle, G., additional, Lahousse, L., additional, Ortega, V.E., additional, Jonsdottir, I., additional, Sin, D. D., additional, Bossé, Y., additional, van den Berge, M., additional, Nickle, D., additional, Quint, J.K., additional, Sayers, I., additional, Hall, I.P., additional, Langenberg, C., additional, Ripatti, S., additional, Laitinen, T., additional, Wu, A.C., additional, Lasky-Su, J., additional, Bakke, P., additional, Gulsvik, A., additional, Hersh, C.P., additional, Hayward, C., additional, Langhammer, A., additional, Brumpton, B., additional, Stefansson, K., additional, Cho, M.H., additional, Wain, L.V., additional, and Tobin, M.D., additional

Published
2020
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18. Discovery of common and rare genetic risk variants for colorectal cancer

Author

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

Abstract

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

Published
2019

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