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1. Machine learning to detect the SINEs of cancer.

Author: Douville, C, Lahouel, K, Kuo, A, Grant, H, Avigdor, BE, Curtis, SD, Summers, M, Cohen, JD, Wang, Y, Mattox, A, Dudley, J, Dobbyn, L, Popoli, M, Ptak, J, Nehme, N, Silliman, N, Blair, C, Romans, K, Thoburn, C, Gizzi, J, Schoen, RE, Tie, J, Gibbs, P, Ho-Pham, LT, Tran, BNH, Tran, TS, Nguyen, TV, Goggins, M, Wolfgang, CL, Wang, T-L, Shih, I-M, Lennon, AM, Hruban, RH, Bettegowda, C, Kinzler, KW, Papadopoulos, N, Vogelstein, B, Tomasetti, C, Douville, C, Lahouel, K, Kuo, A, Grant, H, Avigdor, BE, Curtis, SD, Summers, M, Cohen, JD, Wang, Y, Mattox, A, Dudley, J, Dobbyn, L, Popoli, M, Ptak, J, Nehme, N, Silliman, N, Blair, C, Romans, K, Thoburn, C, Gizzi, J, Schoen, RE, Tie, J, Gibbs, P, Ho-Pham, LT, Tran, BNH, Tran, TS, Nguyen, TV, Goggins, M, Wolfgang, CL, Wang, T-L, Shih, I-M, Lennon, AM, Hruban, RH, Bettegowda, C, Kinzler, KW, Papadopoulos, N, Vogelstein, B, and Tomasetti, C
Abstract: We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the validation cohort, at a specificity of 98.5%. Combining A-PLUS with aneuploidy and eight common protein biomarkers detected 51% of the cancers at 98.9% specificity. We found that part of the power of A-PLUS could be ascribed to a single feature-the global reduction of AluS subfamily elements in the circulating DNA of patients with solid cancer. We confirmed this reduction through the analysis of another independent dataset obtained with a different approach (whole-genome sequencing). The evaluation of Alu elements may therefore have the potential to enhance the performance of several methods designed for the earlier detection of cancer.
Published: 2024

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

Author: Murphy, N, Newton, CC, Song, M, Papadimitriou, N, Hoffmeister, M, Phipps, AI, Harrison, TA, Newcomb, PA, Aglago, EK, Berndt, SI, Brenner, H, Buchanan, DD, Cao, Y, Chan, AT, Chen, X, Cheng, I, Chang-Claude, J, Dimou, N, Drew, D, Farris, AB, French, AJ, Gallinger, S, Georgeson, P, Giannakis, M, Giles, GG, Gruber, SB, Harlid, S, Hsu, L, Huang, W-Y, Jenkins, MA, Laskar, RS, Le Marchand, L, Limburg, P, Lin, Y, Mandic, M, Nowak, JA, Obón-Santacana, M, Ogino, S, Qu, C, Sakoda, LC, Schoen, RE, Southey, MC, Stadler, ZK, Steinfelder, RS, Sun, W, Thibodeau, SN, Toland, AE, Trinh, QM, Tsilidis, KK, Ugai, T, Van Guelpen, B, Wang, X, Woods, MO, Zaidi, SH, Gunter, MJ, Peters, U, Campbell, PT, Murphy, N, Newton, CC, Song, M, Papadimitriou, N, Hoffmeister, M, Phipps, AI, Harrison, TA, Newcomb, PA, Aglago, EK, Berndt, SI, Brenner, H, Buchanan, DD, Cao, Y, Chan, AT, Chen, X, Cheng, I, Chang-Claude, J, Dimou, N, Drew, D, Farris, AB, French, AJ, Gallinger, S, Georgeson, P, Giannakis, M, Giles, GG, Gruber, SB, Harlid, S, Hsu, L, Huang, W-Y, Jenkins, MA, Laskar, RS, Le Marchand, L, Limburg, P, Lin, Y, Mandic, M, Nowak, JA, Obón-Santacana, M, Ogino, S, Qu, C, Sakoda, LC, Schoen, RE, Southey, MC, Stadler, ZK, Steinfelder, RS, Sun, W, Thibodeau, SN, Toland, AE, Trinh, QM, Tsilidis, KK, Ugai, T, Van Guelpen, B, Wang, X, Woods, MO, Zaidi, SH, Gunter, MJ, Peters, U, and Campbell, PT
Abstract: BACKGROUND: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. METHODS: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. RESULTS: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control). CONCLUSIONS: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.
Published: 2023

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

Author: Georgeson, P, Harrison, TA, Pope, BJ, Zaidi, SH, Qu, C, Steinfelder, RS, Lin, Y, Joo, JE, Mahmood, K, Clendenning, M, Walker, R, Amitay, EL, Berndt, S, Brenner, H, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Doheny, KF, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gsur, A, Gunter, MJ, Hoffmeister, M, Hsu, L, Huang, W-Y, Limburg, P, Manson, JE, Moreno, V, Nassir, R, Nowak, JA, Obon-Santacana, M, Ogino, S, Phipps, A, Potter, JD, Schoen, RE, Sun, W, Toland, AE, Trinh, QM, Ugai, T, Macrae, FA, Rosty, C, Hudson, TJ, Jenkins, MA, Thibodeau, SN, Winship, IM, Peters, U, Buchanan, DD, Georgeson, P, Harrison, TA, Pope, BJ, Zaidi, SH, Qu, C, Steinfelder, RS, Lin, Y, Joo, JE, Mahmood, K, Clendenning, M, Walker, R, Amitay, EL, Berndt, S, Brenner, H, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Doheny, KF, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gsur, A, Gunter, MJ, Hoffmeister, M, Hsu, L, Huang, W-Y, Limburg, P, Manson, JE, Moreno, V, Nassir, R, Nowak, JA, Obon-Santacana, M, Ogino, S, Phipps, A, Potter, JD, Schoen, RE, Sun, W, Toland, AE, Trinh, QM, Ugai, T, Macrae, FA, Rosty, C, Hudson, TJ, Jenkins, MA, Thibodeau, SN, Winship, IM, Peters, U, and Buchanan, DD
Abstract: Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.
Published: 2022

4. Genetic variants associated with circulating C-reactive protein levels and colorectal cancer survival: Sex-specific and lifestyle factors specific associations

Author: Huang, Y, Hua, X, Labadie, JD, Harrison, TA, Dai, JY, Lindstrom, S, Lin, Y, Berndt, S, Buchanan, DD, Campbell, PT, Casey, G, Gallinger, SJ, Gunter, MJ, Hoffmeister, M, Jenkins, MA, Sakoda, LC, Schoen, RE, Diergaarde, B, Slattery, ML, White, E, Giles, G, Brenner, H, Chang-Claude, J, Joshi, A, Ma, W, Pai, RK, Chan, AT, Peters, U, Newcomb, PA, Huang, Y, Hua, X, Labadie, JD, Harrison, TA, Dai, JY, Lindstrom, S, Lin, Y, Berndt, S, Buchanan, DD, Campbell, PT, Casey, G, Gallinger, SJ, Gunter, MJ, Hoffmeister, M, Jenkins, MA, Sakoda, LC, Schoen, RE, Diergaarde, B, Slattery, ML, White, E, Giles, G, Brenner, H, Chang-Claude, J, Joshi, A, Ma, W, Pai, RK, Chan, AT, Peters, U, and Newcomb, PA
Abstract: Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected Pinteraction = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.
Published: 2022

5. 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

6. Genetically Predicted Circulating C-Reactive Protein Concentration and Colorectal Cancer Survival: A Mendelian Randomization Consortium Study

Author: Hua, X, Dai, JY, Lindstrom, S, Harrison, TA, Lin, Y, Alberts, SR, Alwers, E, Berndt, S, Brenner, H, Buchanan, DD, Campbell, PT, Casey, G, Chang-Claude, J, Gallinger, S, Giles, GG, Goldberg, RM, Gunter, MJ, Hoffmeister, M, Jenkins, MA, Joshi, AD, Ma, W, Milne, RL, Murphy, N, Pai, RK, Sakoda, LC, Schoen, RE, Shi, Q, Slattery, ML, Song, M, White, E, Le Marchand, L, Chan, AT, Peters, U, Newcomb, PA, Hua, X, Dai, JY, Lindstrom, S, Harrison, TA, Lin, Y, Alberts, SR, Alwers, E, Berndt, S, Brenner, H, Buchanan, DD, Campbell, PT, Casey, G, Chang-Claude, J, Gallinger, S, Giles, GG, Goldberg, RM, Gunter, MJ, Hoffmeister, M, Jenkins, MA, Joshi, AD, Ma, W, Milne, RL, Murphy, N, Pai, RK, Sakoda, LC, Schoen, RE, Shi, Q, Slattery, ML, Song, M, White, E, Le Marchand, L, Chan, AT, Peters, U, and Newcomb, PA
Abstract: BACKGROUND: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival. METHODS: 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. We calculated 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. RESULTS: 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. CONCLUSIONS: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival. IMPACT: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.
Published: 2021

7. 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

8. Association Between Smoking and Molecular Subtypes of Colorectal Cancer

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

9. 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

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. 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

12. Meta-analysis of 16 studies of the association of alcohol with colorectal cancer

Author: McNabb, S, Harrison, TA, Albanes, D, Berndt, SI, Brenner, H, Caan, BJ, Campbell, PT, Cao, Y, Chang-Claude, J, Chan, A, Chen, Z, English, DR, Giles, GG, Giovannucci, EL, Goodman, PJ, Hayes, RB, Hoffmeister, M, Jacobs, EJ, Joshi, AD, Larsson, SC, Le Marchand, L, Li, L, Lin, Y, Mannisto, S, Milne, RL, Nan, H, Newton, CC, Ogino, S, Parfrey, PS, Petersen, PS, Potter, JD, Schoen, RE, Slattery, ML, Su, Y-R, Tangen, CM, Tucker, TC, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Phipps, AI, Peters, U, McNabb, S, Harrison, TA, Albanes, D, Berndt, SI, Brenner, H, Caan, BJ, Campbell, PT, Cao, Y, Chang-Claude, J, Chan, A, Chen, Z, English, DR, Giles, GG, Giovannucci, EL, Goodman, PJ, Hayes, RB, Hoffmeister, M, Jacobs, EJ, Joshi, AD, Larsson, SC, Le Marchand, L, Li, L, Lin, Y, Mannisto, S, Milne, RL, Nan, H, Newton, CC, Ogino, S, Parfrey, PS, Petersen, PS, Potter, JD, Schoen, RE, Slattery, ML, Su, Y-R, Tangen, CM, Tucker, TC, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Phipps, AI, and Peters, U
Abstract: Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.
Published: 2020

13. Genetic Predictors of Circulating 25-Hydroxyvitamin D and Prognosis after Colorectal Cancer.

Author: Neumeyer, S, Butterbach, K, Banbury, BL, Berndt, SI, Campbell, PT, Chlebowski, RT, Chan, AT, Giovannucci, EL, Joshi, AD, Ogino, S, Song, M, McCullough, ML, Maalmi, H, Manson, JE, Sakoda, LC, Schoen, RE, Slattery, ML, White, E, Win, AK, Figueiredo, JC, Hopper, JL, Macrae, FA, Peters, U, Brenner, H, Hoffmeister, M, Newcomb, PA, Chang-Claude, J, Neumeyer, S, Butterbach, K, Banbury, BL, Berndt, SI, Campbell, PT, Chlebowski, RT, Chan, AT, Giovannucci, EL, Joshi, AD, Ogino, S, Song, M, McCullough, ML, Maalmi, H, Manson, JE, Sakoda, LC, Schoen, RE, Slattery, ML, White, E, Win, AK, Figueiredo, JC, Hopper, JL, Macrae, FA, Peters, U, Brenner, H, Hoffmeister, M, Newcomb, PA, and Chang-Claude, J
Abstract: Background: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer–specific survival. Methods: Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer–specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer. Results: The 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D–binding protein) was associated with poorer colorectal cancer–specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86–2.78] and colorectal cancer–specific mortality (HR = 1.76; 95% CI, 0.86–3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45–7.33; Pheterogeneity = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50–11.43, Pheterogeneity = 0.02). Conclusions: Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer–specific survival, although power might have been an issue.
Published: 2020

14. 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

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: 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

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. DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility

Author: Pardini, B, Corrado, A, Paolicchi, E, Cugliari, G, Berndt, S, Bezieau, S, Bien, SA, Brenner, H, Caan, BJ, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Cotterchio, M, Gala, M, Gallinger, SJ, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, J, Jenkins, MA, Le Marchand, L, Lin, Y, Lindor, NM, Nan, H, Newcomb, PA, Ogino, S, Potter, JD, Schoen, RE, Slattery, ML, White, E, Vodickova, L, Vymetalkova, V, Vodicka, P, Gemignani, F, Peters, U, Naccarati, A, Landi, S, Pardini, B, Corrado, A, Paolicchi, E, Cugliari, G, Berndt, S, Bezieau, S, Bien, SA, Brenner, H, Caan, BJ, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Cotterchio, M, Gala, M, Gallinger, SJ, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, J, Jenkins, MA, Le Marchand, L, Lin, Y, Lindor, NM, Nan, H, Newcomb, PA, Ogino, S, Potter, JD, Schoen, RE, Slattery, ML, White, E, Vodickova, L, Vymetalkova, V, Vodicka, P, Gemignani, F, Peters, U, Naccarati, A, and Landi, S
Abstract: Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.
Published: 2020

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. 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

20. Mendelian randomization analysis of C-reactive protein on colorectal cancer risk

Author: Wang, X, Dai, JY, Albanes, D, Arndt, V, Berndt, SI, Bezieau, S, Brenner, H, Buchanan, DD, Butterbach, K, Caan, B, Casey, G, Campbell, PT, Chan, AT, Chen, Z, Chang-Claude, J, Cotterchio, M, Easton, DF, Giles, GG, Giovannucci, E, Grady, WM, Hoffmeister, M, Hopper, JL, Hsu, L, Jenkins, MA, Joshi, AD, Lampe, JW, Larsson, SC, Lejbkowicz, F, Li, L, Lindblom, A, Le Marchand, L, Martin, V, Milne, RL, Moreno, V, Newcomb, PA, Offitt, K, Ogino, S, Pharoah, PDP, Pinchev, M, Potter, JD, Rennert, HS, Rennert, G, Saliba, W, Schafmayer, C, Schoen, RE, Schrotz-King, P, Slattery, ML, Song, M, Stegmaier, C, Weinstein, SJ, Wolk, A, Woods, MO, Wu, AH, Gruber, SB, Peters, U, White, E, Wang, X, Dai, JY, Albanes, D, Arndt, V, Berndt, SI, Bezieau, S, Brenner, H, Buchanan, DD, Butterbach, K, Caan, B, Casey, G, Campbell, PT, Chan, AT, Chen, Z, Chang-Claude, J, Cotterchio, M, Easton, DF, Giles, GG, Giovannucci, E, Grady, WM, Hoffmeister, M, Hopper, JL, Hsu, L, Jenkins, MA, Joshi, AD, Lampe, JW, Larsson, SC, Lejbkowicz, F, Li, L, Lindblom, A, Le Marchand, L, Martin, V, Milne, RL, Moreno, V, Newcomb, PA, Offitt, K, Ogino, S, Pharoah, PDP, Pinchev, M, Potter, JD, Rennert, HS, Rennert, G, Saliba, W, Schafmayer, C, Schoen, RE, Schrotz-King, P, Slattery, ML, Song, M, Stegmaier, C, Weinstein, SJ, Wolk, A, Woods, MO, Wu, AH, Gruber, SB, Peters, U, and White, E
Abstract: BACKGROUND: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. METHODS: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. RESULTS: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. CONCLUSIONS: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.
Published: 2019

21. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity (vol 50, pg 26, 2018)

Author: Turcot, V, Lu, Y, Highland, HM, Schurmann, C, Justice, AE, Fine, RS, Bradfield, JP, Esko, T, Giri, A, Graff, M, Guo, X, Hendricks, AE, Karaderi, T, Lempradl, A, Locke, AE, Mahajan, A, Marouli, E, Sivapalaratnam, S, Young, KL, Alfred, T, Feitosa, MF, Masca, NGD, Manning, AK, Medina-Gomez, C, Mudgal, P, Ng, MCY, Reiner, AP, Vedantam, S, Willems, SM, Winkler, TW, Abecasis, G, Aben, KK, Alam, DS, Alharthi, SE, Allison, M, Amouyel, P, Asselbergs, FW, Auer, PL, Balkau, B, Bang, LE, Barroso, I, Bastarache, L, Benn, M, Bergmann, S, Bielak, LF, Bluher, M, Boehnke, M, Boeing, H, Boerwinkle, E, Boger, CA, Bork-Jensen, J, Bots, ML, Bottinger, EP, Bowden, DW, Brandslund, I, Breen, G, Brilliant, MH, Broer, L, Brumat, M, Burt, AA, Butterworth, AS, Campbell, PT, Cappellani, S, Carey, DJ, Catamo, E, Caulfield, MJ, Chambers, JC, Chasman, DI, Chen, Y-DI, Chowdhury, R, Christensen, C, Chu, AY, Cocca, M, Collins, FS, Cook, JP, Corley, J, Galbany, JC, Cox, AJ, Crosslin, DS, Cuellar-Partida, G, D'Eustacchio, A, Danesh, J, Davies, G, Bakker, PIW, Groot, MCH, Mutsert, R, Deary, IJ, Dedoussis, G, Demerath, EW, Heijer, M, Hollander, AI, Ruijter, HM, Dennis, JG, Denny, JC, Di Angelantonio, E, Drenos, F, Du, M, Dube, M-P, Dunning, AM, Easton, DF, Edwards, TL, Ellinghaus, D, Ellinor, PT, Elliott, P, Evangelou, E, Farmaki, A-E, Farooqi, IS, Faul, JD, Fauser, S, Feng, S, Ferrannini, E, Ferrieres, J, Florez, JC, Ford, I, Fornage, M, Franco, OH, Franke, A, Franks, PW, Friedrich, N, Frikke-Schmidt, R, Galesloot, TE, Gan, W, Gandin, I, Gasparini, P, Gibson, J, Giedraitis, V, Gjesing, AP, Gordon-Larsen, P, Gorski, M, Grabe, H-J, Grant, SFA, Grarup, N, Griffiths, HL, Grove, ML, Gudnason, V, Gustafsson, S, Haessler, J, Hakonarson, H, Hammerschlag, AR, Hansen, T, Harris, KM, Harris, TB, Hattersley, AT, Have, CT, Hayward, C, He, L, Heard-Costa, NL, Heath, AC, Heid, IM, Helgeland, O, Hernesniemi, J, Hewitt, AW, Holmen, OL, Hovingh, GK, Howson, JMM, Hu, Y, Huang, PL, Huffman, JE, Ikram, MA, Ingelsson, E, Jackson, AU, Jansson, J-H, Jarvik, GP, Jensen, GB, Jia, Y, Johansson, S, Jorgensen, ME, Jorgensen, T, Jukema, JW, Kahali, B, Kahn, RS, Kahonen, M, Kamstrup, PR, Kanoni, S, Kaprio, J, Karaleftheri, M, Kardia, SLR, Karpe, F, Kathiresan, S, Kee, F, Kiemeney, LA, Kim, E, Kitajima, H, Komulainen, P, Kooner, JS, Kooperberg, C, Korhonen, T, Kovacs, P, Kuivaniemi, H, Kutalik, Z, Kuulasmaa, K, Kuusisto, J, Laakso, M, Lakka, TA, Lamparter, D, Lange, EM, Lange, LA, Langenberg, C, Larson, EB, Lee, NR, Lehtimaki, T, Lewis, CE, Li, H, Li, J, Li-Gao, R, Lin, H, Lin, K-H, Lin, L-A, Lin, X, Lind, L, Lindstrom, J, Linneberg, A, Liu, C-T, Liu, DJ, Liu, Y, Lo, KS, Lophatananon, A, Lotery, AJ, Loukola, A, Luan, J, Lubitz, SA, Lyytikainen, L-P, Mannisto, S, Marenne, G, Mazul, AL, McCarthy, MI, McKean-Cowdin, R, Medland, SE, Meidtner, K, Milani, L, Mistry, V, Mitchell, P, Mohlke, KL, Moilanen, L, Moitry, M, Montgomery, GW, Mook-Kanamori, DO, Moore, C, Mori, TA, Morris, AD, Morris, AP, Mueller-Nurasyid, M, Munroe, PB, Nalls, MA, Narisu, N, Nelson, CP, Neville, M, Nielsen, SF, Nikus, K, Njolstad, PR, Nordestgaard, BG, Nyholt, DR, O'Connel, JR, O'Donoghue, ML, Loohuis, LMO, Ophoff, RA, Owen, KR, Packard, CJ, Padmanabhan, S, Palmer, CNA, Palmer, ND, Pasterkamp, G, Patel, AP, Pattie, A, Pedersen, O, Peissig, PL, Peloso, GM, Pennell, CE, Perola, M, Perry, JA, Perry, JRB, Pers, TH, Person, TN, Peters, A, Petersen, ERB, Peyser, PA, Pirie, A, Polasek, O, Polderman, TJ, Puolijoki, H, Raitakari, OT, Rasheed, A, Rauramaa, R, Reilly, DF, Renstrom, F, Rheinberger, M, Ridker, PM, Rioux, JD, Rivas, MA, Roberts, DJ, Robertson, NR, Robino, A, Rolandsson, O, Rudan, I, Ruth, KS, Saleheen, D, Salomaa, V, Samani, NJ, Sapkota, Y, Sattar, N, Schoen, RE, Schreiner, PJ, Schulze, MB, Scott, RA, Segura-Lepe, MP, Shah, SH, Sheu, WH-H, Sim, X, Slater, AJ, Small, KS, Smith, AV, Southam, L, Spector, TD, Speliotes, EK, Starr, JM, Stefansson, K, Steinthorsdottir, V, Stirrups, KE, Strauch, K, Stringham, HM, Stumvoll, M, Sun, L, Surendran, P, Swift, AJ, Tada, H, Tansey, KE, Tardif, J-C, Taylor, KD, Teumer, A, Thompson, DJ, Thorleifsson, G, Thorsteinsdottir, U, Thuesen, BH, Tonjes, A, Tromp, G, Trompet, S, Tsafantakis, E, Tuomilehto, J, Tybjaerg-Hansen, A, Tyrer, JP, Uher, R, Uitterlinden, AG, Uusitupa, M, Laan, SW, Duijn, CM, Leeuwen, N, van Setten, J, Vanhala, M, Varbo, A, Varga, TV, Varma, R, Edwards, DRV, Vermeulen, SH, Veronesi, G, Vestergaard, H, Vitart, V, Vogt, TF, Volker, U, Vuckovic, D, Wagenknecht, LE, Walker, M, Wallentin, L, Wang, F, Wang, CA, Wang, S, Wang, Y, Ware, EB, Wareham, NJ, Warren, HR, Waterworth, DM, Wessel, J, White, HD, Willer, CJ, Wilson, JG, Witte, DR, Wood, AR, Wu, Y, Yaghootkar, H, Yao, J, Yao, P, Yerges-Armstrong, LM, Young, R, Zeggini, E, Zhan, X, Zhang, W, Zhao, JH, Zhao, W, Zhou, W, Zondervan, KT, Consortium, GG, Rotter, JI, Pospisilik, JA, Rivadeneira, F, Borecki, IB, Deloukas, P, Frayling, TM, Lettre, G, North, KE, Lindgren, CM, Hirschhorn, JN, Loos, RJF, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, and Amsterdam Cardiovascular Sciences
Published: 2018

22. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity (vol 50, pg 765, 2017)

Author: Turcot, V, Lu, Y, Highland, HM, Schurmann, C, Justice, AE, Fine, RS, Bradfield, JP, Esko, T, Giri, A, Graff, M, Guo, X, Hendricks, AE, Karaderi, T, Lempradl, A, Locke, AE, Mahajan, A, Marouli, E, Sivapalaratnam, S, Young, KL, Alfred, T, Feitosa, MF, Masca, NGD, Manning, AK, Medina-Gomez, C, Mudgal, P, Ng, MCY, Reiner, AP, Vedantam, S, Willems, SM, Winkler, TW, Abecasis, G, Aben, KK, Alam, DS, Alharthi, SE, Allison, M, Amouyel, P, Asselbergs, FW, Auer, PL, Balkau, B, Bang, LE, Barroso, I, Bastarache, L, Benn, M, Bergmann, S, Bielak, LF, Bluher, M, Boehnke, M, Boeing, H, Boerwinkle, E, Boger, CA, Bork-Jensen, J, Bots, ML, Bottinger, EP, Bowden, DW, Brandslund, I, Breen, G, Brilliant, MH, Broer, L, Brumat, M, Burt, AA, Butterworth, AS, Campbell, PT, Cappellani, S, Carey, DJ, Catamo, E, Caulfield, MJ, Chambers, JC, Chasman, DI, Chen, Y-DI, Chowdhury, R, Christensen, C, Chu, AY, Cocca, M, Collins, FS, Cook, JP, Corley, J, Galbany, JC, Cox, AJ, Crosslin, DS, Cuellar-Partida, G, D'Eustacchio, A, Danesh, J, Davies, G, Bakker, PIW, Groot, MCH, Mutsert, R, Deary, IJ, Dedoussis, G, Demerath, EW, Heijer, M, Hollander, AI, Ruijter, HM, Dennis, JG, Denny, JC, Angelantonio, E, Drenos, F, Du, M, Dube, M-P, Dunning, AM, Easton, DF, Edwards, TL, Ellinghaus, D, Ellinor, PT, Elliott, P, Evangelou, E, Farmaki, A-E, Farooqi, IS, Faul, JD, Fauser, S, Feng, S, Ferrannini, E, Ferrieres, J, Florez, JC, Ford, I, Fornage, M, Franco, OH, Franke, A, Franks, PW, Friedrich, N, Frikke-Schmidt, R, Galesloot, TE, Gan, W, Gandin, I, Gasparini, P, Gibson, J, Giedraitis, V, Gjesing, AP, Gordon-Larsen, P, Gorski, M, Grabe, H-J, Grant, SFA, Grarup, N, Griffiths, HL, Grove, ML, Gudnason, V, Gustafsson, S, Haessler, J, Hakonarson, H, Hammerschlag, AR, Hansen, T, Harris, KM, Harris, TB, Hattersley, AT, Have, CT, Hayward, C, He, L, Heard-Costa, NL, Heath, AC, Heid, IM, Helgeland, O, Hernesniemi, J, Hewitt, AW, Holmen, OL, Hovingh, GK, Howson, JMM, Hu, Y, Huang, PL, Huffman, JE, Ikram, MA, Ingelsson, E, Jackson, AU, Jansson, J-H, Jarvik, GP, Jensen, GB, Jia, Y, Johansson, S, Jorgensen, ME, Jorgensen, T, Jukema, JW, Kahali, B, Kahn, RS, Kahonen, M, Kamstrup, PR, Kanoni, S, Kaprio, J, Karaleftheri, M, Kardia, SLR, Karpe, F, Kathiresan, S, Kee, F, Kiemeney, LA, Kim, E, Kitajima, H, Komulainen, P, Kooner, JS, Kooperberg, C, Korhonen, T, Kovacs, P, Kuivaniemi, H, Kutalik, Z, Kuulasmaa, K, Kuusisto, J, Laakso, M, Lakka, TA, Lamparter, D, Lange, EM, Lange, LA, Langenberg, C, Larson, EB, Lee, NR, Lehtimaki, T, Lewis, CE, Li, H, Li, J, Li-Gao, R, Lin, H, Lin, K-H, Lin, L-A, Lin, X, Lind, L, Lindstrom, J, Linneberg, A, Liu, C-T, Liu, DJ, Liu, Y, Lo, KS, Lophatananon, A, Lotery, AJ, Loukola, A, Luan, J, Lubitz, SA, Lyytikainen, L-P, Mannisto, S, Marenne, G, Mazul, AL, McCarthy, MI, McKean-Cowdin, R, Medland, SE, Meidtner, K, Milani, L, Mistry, V, Mitchell, P, Mohlke, KL, Moilanen, L, Moitry, M, Montgomery, GW, Mook-Kanamori, DO, Moore, C, Mori, TA, Morris, AD, Morris, AP, Mueller-Nurasyid, M, Munroe, PB, Nalls, MA, Narisu, N, Nelson, CP, Neville, M, Nielsen, SF, Nikus, K, Njolstad, PR, Nordestgaard, BG, Nyholt, DR, O'Connel, JR, O'Donoghue, ML, Loohuis, LMO, Ophoff, RA, Owen, KR, Packard, CJ, Padmanabhan, S, Palmer, CNA, Palmer, ND, Pasterkamp, G, Patel, AP, Pattie, A, Pedersen, O, Peissig, PL, Peloso, GM, Pennell, CE, Perola, M, Perry, JA, Perry, JRB, Pers, TH, Person, TN, Peters, A, Petersen, ERB, Peyser, PA, Pirie, A, Polasek, O, Polderman, TJ, Puolijoki, H, Raitakari, OT, Rasheed, A, Rauramaa, R, Reilly, DF, Renstrom, F, Rheinberger, M, Ridker, PM, Rioux, JD, Rivas, MA, Roberts, DJ, Robertson, NR, Robino, A, Rolandsson, O, Rudan, I, Ruth, KS, Saleheen, D, Salomaa, V, Samani, NJ, Sapkota, Y, Sattar, N, Schoen, RE, Schreiner, PJ, Schulze, MB, Scott, RA, Segura-Lepe, MP, Shah, SH, Sheu, WH-H, Sim, X, Slater, AJ, Small, KS, Smith, AV, Southam, L, Spector, TD, Speliotes, EK, Starr, JM, Stefansson, K, Steinthorsdottir, V, Stirrups, KE, Strauch, K, Stringham, HM, Stumvoll, M, Sun, L, Surendran, P, Swift, AJ, Tada, H, Tansey, KE, Tardif, J-C, Taylor, KD, Teumer, A, Thompson, DJ, Thorleifsson, G, Thorsteinsdottir, U, Thuesen, BH, Tonjes, A, Tromp, G, Trompet, S, Tsafantakis, E, Tuomilehto, J, Tybjaerg-Hansen, A, Tyrer, JP, Uher, R, Uitterlinden, AG, Uusitupa, M, Laan, SW, Duijn, CM, Leeuwen, N, van Setten, J, Vanhala, M, Varbo, A, Varga, TV, Varma, R, Edwards, DRV, Vermeulen, SH, Veronesi, G, Vestergaard, H, Vitart, V, Vogt, TF, Volker, U, Vuckovic, D, Wagenknecht, LE, Walker, M, Wallentin, L, Wang, F, Wang, CA, Wang, S, Wang, Y, Ware, EB, Wareham, NJ, Warren, HR, Waterworth, DM, Wessel, J, White, HD, Willer, CJ, Wilson, JG, Witte, DR, Wood, AR, Wu, Y, Yaghootkar, H, Yao, J, Yao, P, Yerges-Armstrong, LM, Young, R, Zeggini, E, Zhan, X, Zhang, W, Zhao, JH, Zhao, W, Zhou, W, Zondervan, KT, Rotter, JI, Pospisilik, JA, Rivadeneira, F, Borecki, IB, Deloukas, P, Frayling, TM, Lettre, G, North, KE, Lindgren, CM, Hirschhorn, JN, Loos, RJF, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, and Amsterdam Cardiovascular Sciences
Published: 2018

23. 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

24. Enrichment of colorectal cancer associations in functional regions: Insight for using epigenomics data in the analysis of whole genome sequence-imputed GWAS data

Author: Zhao, Z, Bien, SA, Auer, PL, Harrison, TA, Qu, C, Connolly, CM, Greenside, PG, Chen, S, Berndt, SI, Bezieau, S, Kang, HM, Huyghe, J, Brenner, H, Casey, G, Chan, AT, Hopper, JL, Banbury, BL, Chang-Claude, J, Chanock, SJ, Haile, RW, Hoffmeister, M, Fuchsberger, C, Jenkins, MA, Leal, SM, Lemire, M, Newcomb, PA, Gallinger, S, Potter, JD, Schoen, RE, Slattery, ML, Smith, JD, Le Marchand, L, White, E, Zanke, BW, Abecasis, GR, Carlson, CS, Peters, U, Nickerson, DA, Kundaje, A, Hsu, L, Zhao, Z, Bien, SA, Auer, PL, Harrison, TA, Qu, C, Connolly, CM, Greenside, PG, Chen, S, Berndt, SI, Bezieau, S, Kang, HM, Huyghe, J, Brenner, H, Casey, G, Chan, AT, Hopper, JL, Banbury, BL, Chang-Claude, J, Chanock, SJ, Haile, RW, Hoffmeister, M, Fuchsberger, C, Jenkins, MA, Leal, SM, Lemire, M, Newcomb, PA, Gallinger, S, Potter, JD, Schoen, RE, Slattery, ML, Smith, JD, Le Marchand, L, White, E, Zanke, BW, Abecasis, GR, Carlson, CS, Peters, U, Nickerson, DA, Kundaje, A, and Hsu, L
Abstract: BACKGROUND: The evaluation of less frequent genetic variants and their effect on complex disease pose new challenges for genomic research. To investigate whether epigenetic data can be used to inform aggregate rare-variant association methods (RVAM), we assessed whether variants more significantly associated with colorectal cancer (CRC) were preferentially located in non-coding regulatory regions, and whether enrichment was specific to colorectal tissues. METHODS: Active regulatory elements (ARE) were mapped using data from 127 tissues and cell-types from NIH Roadmap Epigenomics and Encyclopedia of DNA Elements (ENCODE) projects. We investigated whether CRC association p-values were more significant for common variants inside versus outside AREs, or 2) inside colorectal (CR) AREs versus AREs of other tissues and cell-types. We employed an integrative epigenomic RVAM for variants with allele frequency <1%. Gene sets were defined as ARE variants within 200 kilobases of a transcription start site (TSS) using either CR ARE or ARE from non-digestive tissues. CRC-set association p-values were used to evaluate enrichment of less frequent variant associations in CR ARE versus non-digestive ARE. RESULTS: ARE from 126/127 tissues and cell-types were significantly enriched for stronger CRC-variant associations. Strongest enrichment was observed for digestive tissues and immune cell types. CR-specific ARE were also enriched for stronger CRC-variant associations compared to ARE combined across non-digestive tissues (p-value = 9.6 × 10-4). Additionally, we found enrichment of stronger CRC association p-values for rare variant sets of CR ARE compared to non-digestive ARE (p-value = 0.029). CONCLUSIONS: Integrative epigenomic RVAM may enable discovery of less frequent variants associated with CRC, and ARE of digestive and immune tissues are most informative. Although distance-based aggregation of less frequent variants in CR ARE surrounding TSS showed modest enrichment, future asso
Published: 2017

25. 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

26. 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

27. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

Author: Wang, J, Du, M, Jiao, S, Bien, SA, Gala, M, Abecasis, G, Bezieau, S, Brenner, H, Butterbach, K, Caan, BJ, Carlson, CS, Casey, G, Chang-Claude, J, Conti, DV, Curtis, KR, Duggan, D, Gallinger, S, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jenkins, MA, Kury, S, Le Marchand, L, Leal, SM, Newcomb, PA, Nickerson, DA, Potter, JD, Schoen, RE, Schumacher, FR, Seminara, D, Slattery, ML, Hsu, L, Chan, AT, White, E, Berndt, SI, Peters, U, Wang, J, Du, M, Jiao, S, Bien, SA, Gala, M, Abecasis, G, Bezieau, S, Brenner, H, Butterbach, K, Caan, BJ, Carlson, CS, Casey, G, Chang-Claude, J, Conti, DV, Curtis, KR, Duggan, D, Gallinger, S, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jenkins, MA, Kury, S, Le Marchand, L, Leal, SM, Newcomb, PA, Nickerson, DA, Potter, JD, Schoen, RE, Schumacher, FR, Seminara, D, Slattery, ML, Hsu, L, Chan, AT, White, E, Berndt, SI, and Peters, U
Abstract: Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).
Published: 2016

28. 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

29. 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

30. 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

31. 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

32. A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

Author: Lemire, M, Qu, C, Loo, LWM, Zaidi, SHE, Wang, H, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Du, M, Edlund, CK, Gallinger, S, Haile, RW, Harrison, TA, Hoffmeister, M, Hopper, JL, Hou, L, Hsu, L, Jacobs, EJ, Jenkins, MA, Jeon, J, Kuery, S, Li, L, Lindor, NM, Newcomb, PA, Potter, JD, Rennert, G, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Severi, G, Slattery, ML, White, E, Woods, MO, Cotterchio, M, Le Marchand, L, Casey, G, Gruber, SB, Peters, U, Hudson, TJ, Lemire, M, Qu, C, Loo, LWM, Zaidi, SHE, Wang, H, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Du, M, Edlund, CK, Gallinger, S, Haile, RW, Harrison, TA, Hoffmeister, M, Hopper, JL, Hou, L, Hsu, L, Jacobs, EJ, Jenkins, MA, Jeon, J, Kuery, S, Li, L, Lindor, NM, Newcomb, PA, Potter, JD, Rennert, G, Rudolph, A, Schoen, RE, Schumacher, FR, Seminara, D, Severi, G, Slattery, ML, White, E, Woods, MO, Cotterchio, M, Le Marchand, L, Casey, G, Gruber, SB, Peters, U, and Hudson, TJ
Abstract: Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10(-10); odds ratio estimated by re-including all controls (OR) = 0.87, 95% confidence interval (CI) 0.83-0.91; minor allele frequency (MAF) = 13%]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95% CI 0.77-0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10(-8)).
Published: 2015

33. 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

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

Author: Amos, CI, 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, C, Gauderman, WJ, Potter, JD, White, E, Peters, U, Amos, CI, 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, C, 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.
Published: 2014

35. Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia

Author: Cheng, I, Kocarnik, JM, Dumitrescu, L, Lindor, NM, Chang-Claude, J, Avery, CL, Caberto, CP, Love, S-A, Slattery, ML, Chan, AT, Baron, JA, Hindorff, LA, Park, SL, Schumacher, FR, Hoffmeister, M, Kraft, P, Butler, AM, Duggan, DJ, Hou, L, Carlson, CS, Monroe, KR, Lin, Y, Carty, CL, Mann, S, Ma, J, Giovannucci, EL, Fuchs, CS, Newcomb, PA, Jenkins, MA, Hopper, JL, Haile, RW, Conti, DV, Campbell, PT, Potter, JD, Caan, BJ, Schoen, RE, Hayes, RB, Chanock, SJ, Berndt, SI, Kuery, S, Bezieau, S, Ambite, JL, Kumaraguruparan, G, Richardson, DM, Goodloe, RJ, Dilks, HH, Baker, P, Zanke, BW, Lemire, M, Gallinger, S, Hsu, L, Jiao, S, Harrison, TA, Seminara, D, Haiman, CA, Kooperberg, C, Wilkens, LR, Hutter, CM, White, E, Crawford, DC, Heiss, G, Hudson, TJ, Brenner, H, Bush, WS, Casey, G, Le Marchand, L, Peters, U, Cheng, I, Kocarnik, JM, Dumitrescu, L, Lindor, NM, Chang-Claude, J, Avery, CL, Caberto, CP, Love, S-A, Slattery, ML, Chan, AT, Baron, JA, Hindorff, LA, Park, SL, Schumacher, FR, Hoffmeister, M, Kraft, P, Butler, AM, Duggan, DJ, Hou, L, Carlson, CS, Monroe, KR, Lin, Y, Carty, CL, Mann, S, Ma, J, Giovannucci, EL, Fuchs, CS, Newcomb, PA, Jenkins, MA, Hopper, JL, Haile, RW, Conti, DV, Campbell, PT, Potter, JD, Caan, BJ, Schoen, RE, Hayes, RB, Chanock, SJ, Berndt, SI, Kuery, S, Bezieau, S, Ambite, JL, Kumaraguruparan, G, Richardson, DM, Goodloe, RJ, Dilks, HH, Baker, P, Zanke, BW, Lemire, M, Gallinger, S, Hsu, L, Jiao, S, Harrison, TA, Seminara, D, Haiman, CA, Kooperberg, C, Wilkens, LR, Hutter, CM, White, E, Crawford, DC, Heiss, G, Hudson, TJ, Brenner, H, Bush, WS, Casey, G, Le Marchand, L, and Peters, U
Abstract: OBJECTIVE: Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. DESIGN: We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10(-4) was used to determine statistical significance of the associations. RESULTS: Two correlated SNPs--rs10090154 and rs4242382--in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10(-5)), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. CONCLUSIONS: This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.
Published: 2014

36. 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

37. Genetic Predictors of Circulating 25-Hydroxyvitamin D and Risk of Colorectal Cancer

Author: Hiraki, LT, Qu, C, Hutter, CM, Baron, JA, Berndt, SI, Bezieau, S, Brenner, H, Caan, BJ, Casey, G, Chang-Claude, J, Chanock, SJ, Conti, DV, Duggan, D, Fuchs, CS, Gallinger, S, Giovannucci, EL, Harrison, TA, Hayes, RB, Hazra, A, Henderson, B, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jenkins, MA, Kuery, SE, Le Marchand, L, Lemire, M, Ma, J, Manson, JE, Nan, H, Newcomb, PA, Ng, K, Potter, JD, Schoen, RE, Schumacher, FR, Seminara, D, Slattery, ML, Wactawski-Wende, J, White, E, Wu, K, Zanke, BW, Kraft, P, Peters, U, Chan, AT, Hiraki, LT, Qu, C, Hutter, CM, Baron, JA, Berndt, SI, Bezieau, S, Brenner, H, Caan, BJ, Casey, G, Chang-Claude, J, Chanock, SJ, Conti, DV, Duggan, D, Fuchs, CS, Gallinger, S, Giovannucci, EL, Harrison, TA, Hayes, RB, Hazra, A, Henderson, B, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jenkins, MA, Kuery, SE, Le Marchand, L, Lemire, M, Ma, J, Manson, JE, Nan, H, Newcomb, PA, Ng, K, Potter, JD, Schoen, RE, Schumacher, FR, Seminara, D, Slattery, ML, Wactawski-Wende, J, White, E, Wu, K, Zanke, BW, Kraft, P, Peters, U, and Chan, AT
Abstract: BACKGROUND: Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D. METHODS: We investigated whether five polymorphisms in GC, CYP2R1, CYP24A1, and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with colorectal cancer risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We conducted a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and associated confidence intervals for SNPs individually, SNPs simultaneously, and for a vitamin D additive genetic risk score (GRS). RESULTS: We did not observe a statistically significant association between the 25(OH)D-associated SNPs and colorectal cancer marginally, conditionally, or as a GRS, or for colon or rectal cancer separately. CONCLUSIONS: Our findings do not support an association between SNPs associated with circulating 25(OH)D and risk of colorectal cancer. Additional work is warranted to investigate the complex relationship between 25(OH)D and colorectal cancer risk. IMPACT: There was no association observed between genetic markers of circulating 25(OH)D and colorectal cancer. These genetic markers account for a small proportion of the variance in 25(OH)D.
Published: 2013

38. 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

39. 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

40. Intestinal and multivisceral transplantation: dynamics of nutritional management and functional autonomy

Author: Rovera, GM, primary, Schoen, RE, additional, Goldbach, B, additional, Janson, D, additional, Bond, G, additional, Rakela, J, additional, Graham, TO, additional, O'Keefe, S, additional, and Abu-Elmagd, K, additional
Published: 2003
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41. Patient satisfaction with screening flexible sigmoidoscopy

Author: Schoen, RE, primary, Weissfeld, JL, additional, Bowen, NJ, additional, and Baun, A, additional
Published: 1998
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42. Sagittal diameter in comparison with single slice CT as a predictor of total visceral adipose tissue volume

Author: Schoen, RE, primary, Thaete, FL, additional, Sankey, SS, additional, Weissfeld, JL, additional, and Kuller, LH, additional
Published: 1998
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43. Body size, increased blood blucose and insulin, and colorectal cancer (CRC)

Author: Schoen, RE, primary, Kuller, LK, additional, Tangen, C, additional, Burke, G, additional, Tracy, R, additional, Dobs, A, additional, and Savage, P, additional
Published: 1998
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44. Flexible sigmoidoscopy in the randomized prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial: added yield from a second screening examination.

Author: Weissfeld JL, Schoen RE, Pinsky PF, Bresalier RS, Doria-Rose VP, Laiyemo AO, Church T, Yokochi LA, Yurgalevitch S, Rathmell J, Andriole GL, Buys S, Crawford ED, Fouad M, Isaacs C, Lamerato L, Reding D, Prorok PC, Berg CD, and PLCO Project Team
Abstract: Background: Among randomized trials evaluating flexible sigmoidoscopy (FSG) for its effect on colorectal cancer mortality, only the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial screened its participants more than one time. We report outcomes from the PLCO screening FSG program and evaluate the increased yield produced by a second FSG.Methods: Participants were screened by 60-cm FSG in 10 regional screening centers at study entry and 3 or 5 years later, depending on the time of random assignment. Results from subsequent diagnostic intervention were tracked and recorded in a standardized fashion, and outcomes were compared according to sex and age. The protocol discouraged repeat FSG in persons with colorectal cancer or adenoma diagnosed after the initial FSG.Results: Of 77 447 enrollees, 67 073 (86.6%) had at least one FSG and 39 443 (50.9%) had two FSGs. Diagnostic intervention occurred in 74.9% after a positive first FSG and in 78.7% after a positive repeat FSG. The second FSG increased the screening yield by 32%: Colorectal cancer or advanced adenoma was detected in 37.8 per 1000 persons after first screening and in 49.8 per 1000 persons after all screenings. The second FSG increased the yield of cancer or advanced adenoma by 26% in women and by 34% in men. Of 223 subjects who received a diagnosis of colorectal carcinoma within 1 year of a positive FSG, 64.6% had stage I and 17.5% had stage II disease.Conclusions: Repeat FSG increased the detection of colorectal cancer or advanced adenoma in women by one-fourth and in men by one-third. Screen-detected carcinomas were early stage (stage I or II) in greater than 80% of screened persons. Colorectal cancer mortality data from the PLCO, as the definitive endpoint, will follow in later publications. [ABSTRACT FROM AUTHOR]
Published: 2012
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45. Aberrant crypt foci: are they intermediate endpoints of colon carcinogenesis in humans?

Author: Gupta AK and Schoen RE
Published: 2009
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46. Analysis of colorectal cancer occurrence during surveillance colonoscopy in the dietary Polyp Prevention Trial.

Author: Pabby A, Schoen RE, Weissfeld JL, Burt R, Kikendall JW, Lance P, Shike M, Lanza E, and Schatzkin A
Published: 2005
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47. Results of repeat sigmoidoscopy 3 years after a negative examination.

Author: Schoen RE, Pinsky PF, Weissfeld JL, Bresalier RS, Church T, Prorok P, Gohagan JK, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Group, Schoen, Robert E, Pinsky, Paul F, Weissfeld, Joel L, Bresalier, Robert S, Church, Timothy, Prorok, Philip, and Gohagan, John K
Abstract: Context: The necessary frequency of endoscopic colorectal cancer screening after a negative examination is uncertain.Objective: To examine the yield of adenomas and cancer in the distal colon found by repeat flexible sigmoidoscopy (FSG) 3 years after a negative examination.Design, Setting, and Participants: Participants were drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), a randomized, controlled community-based study of cancer screening. The mean (SD) age was 65.7 (4.0) years at study entry (1993-1995) and 61.6% were men. Individuals underwent screening FSG at baseline and at 3 years as part of the protocol and were referred to their personal physicians for further evaluation of screen-detected abnormalities. Results from subsequent diagnostic evaluations were tracked in a standardized fashion. Of 11 583 eligible for repeat screening FSG 3 years after an initial negative examination, 9317 (80.4%) returned.Main Outcome Measures: Polyp or mass detection in distal colon at year 3 repeat FSG; incidence of adenoma or cancer in distal colon at year 3 examination; determination of reason for detection (increased depth of insertion or improved preparation at the year 3 examination or detection in a previously examined area).Results: A total of 1292 returning participants (13.9%) had a polyp or mass detected by FSG 3 years after the initial examination. In the distal colon, 3.1% (292/9317) were found to have an adenoma or cancer. The incidence of advanced adenoma (n = 72) or cancer (n = 6) in the distal colon was 78 (0.8%) of 9317. Of individuals with advanced distal adenomas detected at the year 3 examination, 80.6% (58/72) had lesions found in a portion of the colon that had been adequately examined at the initial sigmoidoscopy.Conclusions: Repeat FSG 3 years after a negative examination will detect advanced adenomas and distal colon cancer. Although the overall percentage with detected abnormalities is modest, these data raise concern about the impact of a prolonged screening interval after a negative examination. [ABSTRACT FROM AUTHOR]
Published: 2003
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48. Factors associated with the use of screening mammography in a primary care setting.

Author: Schoen RE, Marcus M, and Braham RL
Abstract: Despite consensus recommendations the use of screening mammography remains low. We examined physician and patient related variables associated with requests to undergo screening mammography in a primary care setting, in order to assess current barriers to screening mammography at the level of the physician-patient interaction. A sample of 261 women over the age of 50, whose primary care was provided by resident physicians in a large, urban, academic medical center were examined. Data concerning patients and physicians demographic and clinical characteristics were abstracted. The data were analyzed by Chi-square and stepwise logistic regression. Forty-five percent of the patients were offered screening mammography within the study year and 53% were offered mammography over the preceding two years. Variables significantly associated with a request for screening included a previous history of breast disease (p<.001) and the severity of the patient's overall medical condition. Patients with an overall medical condition rated as mild were more likely to be requested to undergo screening than patients rated as moderately or severely ill (p<.01). Patients with higher educational levels were also more likely to be offered screening (P=.06). First year postgraduate (PGY 1) physicians requested more mammograms than PGY 2 or PGY 3 physicians (P<.05). A multivariable model utilizing logistic regression confirmed the association of the significant variables above with screening requests. Physicians were more likely to request mammography in patients at higher risk for developing breast cancer and less likely to request it in patients who had co-morbid illness. Increasing physician understanding of the importance and benefits of mammography and further investigation of strategies to ensure physician compliance with mammography recommendations are necessary to increase utilization. [ABSTRACT FROM AUTHOR]
Published: 1994
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49. Five-year risk of colorectal neoplasia after negative colonoscopy.

Author: Schoen RE, Pinsky PF, Brenner H, Haug U, Hoffmeister M, Maisonneuve P, Botteri E, Lowenfels AB, Imperiale TF, and Ransohoff DF
Published: 2008

50. Optimal intervals and techniques for screening sigmoidoscopy.

Author: Lev I, Lahad A, Ben-Yehuda A, Sonnenberg A, Lieberman D, Wender RC, Schoen RE, Weissfeld JL, Sonnenberg, Amnon, and Lieberman, David
Published: 2003
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