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201. Associations between molecular characteristics of colorectal serrated polyps and subsequent advanced colorectal neoplasia

Author: Aruna Kamineni, Michelle A. Wurscher, Andrea N. Burnett-Hartman, Sushma S. Thomas, Melissa P. Upton, Hana Newman, Sheetal Hardikar, Rebecca Ziebell, Jessica Chubak, Polly A. Newcomb, Xinwei Hua, Lee-Ching Zhu, and Rachel C. Malen
Subjects: Adenoma, Adult, Male, Proto-Oncogene Proteins B-raf, Washington, Cancer Research, medicine.medical_specialty, Colorectal cancer, MLH1, Gastroenterology, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, Epidemiology, Surveillance, Epidemiology, and End Results, Medicine, Humans, 030212 general & internal medicine, Longitudinal Studies, neoplasms, Aged, CpG Island Methylator Phenotype, business.industry, Intestinal Polyps, Odds ratio, Colonoscopy, DNA Methylation, Middle Aged, medicine.disease, digestive system diseases, Cross-Sectional Studies, Phenotype, Oncology, Hyperplastic Polyp, 030220 oncology & carcinogenesis, Case-Control Studies, Mutation, Female, business, Colorectal Neoplasms, Index Colonoscopy, SEER Program
Abstract: PURPOSE: BRAF mutation and DNA hypermethylation have linked sessile serrated adenomas/polyps (SSA/Ps) to serrated colorectal cancer (CRC) in cross-sectional studies, but they have not been evaluated in a longitudinal study. We aimed to evaluate the associations between molecular markers of serrated polyps and subsequent advanced colorectal neoplasia. METHODS: Study subjects included Kaiser Permanente Washington members aged 20–75 years who received an index colonoscopy between 1/1/1998 and 12/31/2007 and had hyperplastic polyps (HPs) or SSA/Ps according to study pathology review. Polyps from index colonoscopies were removed and assayed for BRAF mutation, CpG island methylator phenotype (CIMP), and MLH1 methylation. Pathology reports and biopsies from the subsequent lower gastrointestinal endoscopy through 1/1/2013 were reviewed for advanced colorectal neoplasia. We identified additional incident CRC cases through linkage to the Seattle-Puget Sound Surveillance Epidemiology and End Results registry. We used generalized estimating equations to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for subsequent advanced colorectal neoplasia, comparing index serrated polyps with different molecular markers. RESULTS: We included 553 individuals with index serrated polyps (420 HPs and 133 SSA/Ps) and 795 subsequent endoscopies. The prevalence of BRAF-mutant, CIMP-high, and MLH1-methylated serrated polyps were 51%, 4%, and 2%, respectively. BRAF and CIMP were not associated with subsequent advanced colorectal neoplasia. MLH1-methylated SSP/As were significantly more likely to have subsequent advanced neoplasia (OR = 4.66, 95% CI 1.06–20.51). CONCLUSION: Our results suggest that BRAF-mutant and CIMP-high serrated polyps are not associated with subsequent advanced colorectal neoplasia. Among SSA/Ps, MLH1 methylation may be an important marker to identify high-risk CRC precursors.
Published: 2020

202. Real-world Clinical Implementation of Lung Cancer Screening—Evaluating Processes to Improve Screening Guidelines-Concordance

Author: William Kinnard, Caroline Joyce, Eric J Harker, Erica Blum-Barnett, Virginia Hall, Nikki M. Carroll, Debra P. Ritzwoller, Julie S Steiner, and Andrea N. Burnett-Hartman
Subjects: medicine.medical_specialty, Colorado, Lung Neoplasms, Concordance, 01 natural sciences, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Humans, Mass Screening, In patient, 030212 general & internal medicine, 0101 mathematics, Lung cancer, Early Detection of Cancer, Original Research, Retrospective Studies, integumentary system, business.industry, 010102 general mathematics, Smoking, Retrospective cohort study, medicine.disease, Comorbidity, Cohort, National Lung Screening Trial, business, Lung cancer screening
Abstract: BACKGROUND: Lung cancer screening (LCS) requires complex processes to identify eligible patients, provide appropriate follow-up, and manage findings. It is unclear whether LCS in real-world clinical settings will realize the same benefits as the National Lung Screening Trial (NLST). OBJECTIVE: To evaluate the impact of process modifications on compliance with LCS guidelines during LCS program implementation, and to compare patient characteristics and outcomes with those in NLST. DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Colorado (KPCO), a non-profit integrated healthcare system. PATIENTS: A total of 3375 patients who underwent a baseline lung cancer screening low-dose computed tomography (S-LDCT) scan between May 2014 and June 2017. MEASUREMENTS: Among those receiving an S-LDCT, proportion who met guidelines-based LCS eligibility criteria before and after LCS process modifications, differences in patient characteristics and outcomes between KPCO LCS patients and the NLST cohort, and factors associated with a positive screen. RESULTS: After modifying LCS eligibility confirmation processes, patients receiving S-LDCT who met guidelines-based LCS eligibility criteria increased from 45.6 to 92.7% (P
Published: 2020

203. A Population-Based Survey to Assess Cannabis on Quality of Life among Colorectal Cancer Survivors

Author: Powers Jd, Burnett-Hartman An, Feigelson Hs, Pawloski Pa, Calcaterra S, Corley Da, and McMullen Cm
Subjects: Quality of life (healthcare), biology, business.industry, Colorectal cancer, Environmental health, Medicine, Cannabis, business, biology.organism_classification, medicine.disease, Population based survey
Abstract: Background: As more states legalize cannabis for medical and recreational use, people increasingly use cannabis to treat medical conditions and associated symptoms. The prevalence and utility of cannabis for cancer-related symptoms may be clarified by examining cannabis use among patients with a common cancer diagnosis. We aimed to determine the prevalence of cannabis use among colorectal cancer (CRC) survivors and its associations with quality of life (QoL) and cancer-related symptomatology. Methods: A cross-sectional survey of patient-reported QoL outcomes and behaviors, including cannabis use, was conducted within the Patient Outcomes To Advance Learning network’s (PORTAL) CRC Cohort. The cohort included a population-based sample of healthcare system members ≥ 18 years old diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2016. We assessed the association between cannabis use and QoL using the European Organization for Research and Treatment of Cancer QLQ-C30 summary score. Results: Of the 1,784 respondents, 293 (16.4%) reported cannabis use following CRC diagnosis. Current tobacco smokers were more likely to use cannabis compared to former or never tobacco smokers (adjusted odds ratio [aOR] 2.71, 95% CI 1.56 to 4.70). Greater alcohol use (> 4 drinks per month versus ≤ 4 drinks per month) was associated with cannabis use (aOR 2.17, 95% CI 1.65 to 2.85). There was an association between cannabis use and cancer stage at diagnosis, with stage 3 or 4 CRC patients more likely to use cannabis than stage 1 or 2 CRC patients (aOR 1.68, 95% CI 1.25 to 2.25). After adjusting for demographics, medical comorbidities, stage and site of CRC diagnosis, and prescription opioid use, people who used cannabis had significantly lower QoL than people who did not use cannabis (difference of -6.14, 95% CI -8.07 to -4.20). Conclusion: Among CRC survivors, cannabis use was common, associated with more advanced stages of disease, associated with tobacco and alcohol use, and not associated with better QoL. Clinicians should inquire about cannabis use among their patients and provide evidence-based recommendations for cancer-related symptoms.
Published: 2020

204. 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: Elio Riboli, Jochen Hampe, Ruth C. Travis, Andrea N. Burnett-Hartman, Anna H. Wu, Steven Gallinger, Stephen B. Gruber, Christopher I. Li, Bethany Van Guelpen, Kala Visvanathan, Loic Le Marchand, Veronika Vymetalkova, Demetrius Albanes, Jeroen R. Huyghe, Lori C. Sakoda, Jennifer Ose, Daniel D. Buchanan, Kenneth Offit, D. Timothy Bishop, John D. Potter, Sonja I. Berndt, Neil Murphy, Vittorio Perduca, Roger L. Milne, Niki Dimou, Marc J. Gunter, Ulrike Peters, Wen Yi Huang, Sergi Castellví-Bel, Graham Casey, Robert E. Schoen, Martha L. Slattery, Kathryn E. Bradbury, Albert de la Chapelle, Temitope O. Keku, Andrea Gsur, Wei Zheng, Gad Rennert, Hermann Brenner, Tabitha A. Harrison, Claudia Agnoli, Fränzel J.B. Van Duijnhoven, Sabina Rinaldi, Catherine M. Tangen, Jane C. Figueiredo, Ludmila Vodickova, Andrew T. Chan, Tilman Kühn, Hansong Wang, Mingyang Song, Sun-Seog Kweon, Annika Lindblom, Amanda I. Phipps, Cornelia M. Ulrich, Victor Moreno, Mark A. Jenkins, Li Hsu, Emily White, Conghui Qu, Peter T. Campbell, Stéphane Bézieau, Nikos Papadimitriou, Michael O. Woods, Jelena Bešević, Polly A. Newcomb, Pavel Vodicka, Heather Hampel, Barbara L. Banbury, Amanda J. Cross, Robert Carreras-Torres, Alicja Wolk, Graham G. Giles, Michael Hoffmeister, Elizabeth A. Platz, N. Charlotte Onland-Moret, Dallas R. English, Li Li, Jenny Chang-Claude, Vicente Martín, Richard M. Martin, María Dolores Chirlaque, Konstantinos K. Tsilidis, Clemens Schafmayer, Shuji Ogino, Nutrition and Metabolism Section, International Agency for Research on Cancer, Centre international de Recherche sur le Cancer (CIRC), School of Public Health - Department of Epidemiology and Biostatistics, Imperial College London, Nuffield Department of Population Health - Cancer Epidemiology Unit, University of Oxford [Oxford], International Agency for Cancer Research (IACR), School of Public Health [London, UK] (Faculty of Medicine), Candiolo Cancer Institute (IRCCS), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Interactions récepteurs ligands en immunocancérologie et immunopathologie, IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), St. James's University Hospital, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University Medical Center [Utrecht], The Cancer, Ageing and Somatic Mutation Programme [Cambridgeshire, UK], The Wellcome Trust Sanger Institute [Cambridge], Department of Preventive Medicine, University of Southern California (USC), Division of Cancer Epidemiology, Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), Ohio State University [Columbus] (OSU), Cancer Epidemiology Centre, Cancer Council Victoria, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), University of Melbourne, Department of Internal Medicine, Epidemiology, Human Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Medical Department 1 [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), FESTO, Universität Stuttgart [Stuttgart], Division of Cancer Epidemiology and Genetics, Department of Medical Genetics, HMNC Brain Health, University of Hawai‘i [Mānoa] (UHM), Chinese Center for Disease Control and Prevention, Department of Clinical Genetics, Karolinska University Hospital [Stockholm], Dell-EMC, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Memorial Sloane Kettering Cancer Center [New York], Department of Pathology, Brigham and Women's Hospital [Boston], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Department of Visceral and Thoracic Surgery [Kiel, Germany], University Hospital Schleswig-Holstein [Kiel, Germany], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Helmholtz Centre for Ocean Research [Kiel] (GEOMAR), Department of Medical Biosciences and Pathology, Umeå University, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Karolinska Institutet [Stockholm], and Center for Astrophysical Sciences [Baltimore]
Subjects: Oncology, Male, Nutrition and Disease, Colorectal cancer, BMI, body mass index, PLASMA-INSULIN, IGFBP3, IGF1, insulin-like growth factor 1, Genome-wide association study, GWAS, genome-wide association studies, MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, FACTOR (IGF)-I, 0302 clinical medicine, Risk Factors, Voeding en Ziekte, Insulina, Medicine, Insulin, GWAS, Registries, Insulin-Like Growth Factor I, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, ICC, intraclass correlation coefficient, Incidence, Hazard ratio, MR, Mendelian randomization, Gastroenterology, MEN, SNP, single nucleotide polymorphism, Middle Aged, SERUM-LEVELS, 3. Good health, IGF-I, CRC, 030220 oncology & carcinogenesis, CRP, C-reactive protein, Female, Colorectal Neoplasms, Life Sciences & Biomedicine, Medical Genetics, REGRESSION DILUTION, Signal Transduction, medicine.medical_specialty, HbA1c, glycolated hemoglobin, FACTOR-I, Polymorphism, Single Nucleotide, Risk Assessment, Article, C-PEPTIDE, 03 medical and health sciences, Sex Factors, Insulin-Like Growth Factor II, Càncer colorectal, Internal medicine, COLON, Mendelian randomization, Biomarkers, Tumor, Journal Article, Humans, IGFBP3, insulin-like growth factor binding protein 3, 030304 developmental biology, Aged, VLAG, Medicinsk genetik, Cancer och onkologi, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Case-control study, Cancer, IGFBP-3, 1103 Clinical Sciences, Odds ratio, Mendelian Randomization Analysis, medicine.disease, HR, hazard ratio, United Kingdom, CI, confidence interval, OR, odds ratio, Insulin-Like Growth Factor Binding Protein 3, Case-Control Studies, Cancer and Oncology, SHBG, sex hormone binding globulin, 1114 Paediatrics and Reproductive Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, SD, standard deviation, 1109 Neurosciences, Follow-Up Studies
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 region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. Conclusions In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis., Graphical abstract
Published: 2020

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

Author: Barbara L. Banbury, Christopher I. Li, Joshua A. Bell, Elizabeth A. Platz, Kenneth Offit, Stephen B. Gruber, Gad Rennert, Tabitha A. Harrison, Li Hsu, Emily White, Conghui Qu, Peter T. Campbell, Li Li, Nicholas J. Timpson, Sonja I. Berndt, Roger L. Milne, Jeroen R. Huyghe, Steven Gallinger, Pavel Vodicka, Anne M. May, Loic Le Marchand, Annika Lindblom, Graham Casey, Lori C. Sakoda, Wei Zheng, Fränzel J.B. van Duijnhoven, Corinne E. Joshu, Martha L. Slattery, Amanda I. Phipps, Bethany Van Guelpen, Marc J. Gunter, Hermann Brenner, John D. Potter, Vicente Martín, Andrew T. Chan, Temitope O. Keku, Ludmila Vodickova, D. Timothy Bishop, Graham G. Giles, Susan M. Gapstur, Daniel D. Buchanan, Hansong Wang, Catherine M. Tangen, Alicja Wolk, Michael O. Woods, Sun-Seog Kweon, Jane C. Figueiredo, Stéphane Bézieau, Caroline J. Bull, Wen-Yi Huang, Michael Hoffmeister, Cornelia M. Ulrich, Robert E. Schoen, Eleanor Sanderson, Demetrius Albanes, Victor Moreno, Jenny Chang-Claude, Tilman Kühn, Clemens Schafmayer, J. Ramón Quirós, Shuji Ogino, Polly A. Newcomb, Ulrike Peters, Elio Riboli, Jochen Hampe, Heather Hampel, Kala Visvanathan, Sergi Castellví-Bel, Anna H. Wu, Neil Murphy, Mark A. Jenkins, Kostas Tsilidis, Andrea Gsur, Andrea N. Burnett-Hartman, George Davey Smith, Albert de la Chapelle, Emma E. Vincent, and Amanda J. Cross
Subjects: Male, 0301 basic medicine, Oncology, Nutrition and Disease, Colorectal cancer, CCFR, Epidemiology, lcsh:Medicine, chemistry.chemical_compound, 0302 clinical medicine, Waist–hip ratio, Risk Factors, Voeding en Ziekte, 11 Medical and Health Sciences, Body mass index, Adiposity, 2. Zero hunger, 0303 health sciences, INSULIN-RESISTANCE, Nutrition and Dietetics, General Medicine, ASSOCIATION, Middle Aged, 3. Good health, Europe, Näringslära, CORECT, BIAS, 030220 oncology & carcinogenesis, Metabolome, Female, ICEP, Colorectal Neoplasms, Life Sciences & Biomedicine, Research Article, Adult, Mediation (statistics), medicine.medical_specialty, PROTEINS, Pes corporal, Polymorphism, Single Nucleotide, 03 medical and health sciences, Sex Factors, Medicine, General & Internal, Càncer colorectal, Internal medicine, General & Internal Medicine, Mendelian randomization, DISTAL, medicine, Humans, Genetic Predisposition to Disease, Obesity, METAANALYSIS, 030304 developmental biology, Genetic association, GECCO, Science & Technology, Cholesterol, Waist-Hip Ratio, business.industry, Waist-to-hip ratio, lcsh:R, Case-control study, GENOME-WIDE, Cancer, nutritional and metabolic diseases, Mendelian Randomization Analysis, Body weight, INSTRUMENTS, medicine.disease, digestive system diseases, NMR, BODY-MASS INDEX, 030104 developmental biology, Metabolism, chemistry, FAT, Case-Control Studies, business, Lipoprotein, Genome-Wide Association Study
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 metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
Published: 2020

206. Cumulative Burden of Colorectal Cancer–Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer

Author: Ludmila Vodickova, Douglas A. Corley, Phyllis J. Goodman, Albert de la Chapelle, Cornelia M. Ulrich, Gianluca Severi, Alexi N. Archambault, Douglas F. Easton, Stephanie L. Schmit, Victor Moreno, Tilman Kühn, Fredrick R. Schumacher, D. Timothy Bishop, Sonja I. Berndt, Domenico Palli, Fränzel J.B. Van Duijnhoven, Jose E. Castelao, Mingyang Song, Anna H. Wu, Wen Yi Huang, Sergi Castellví-Bel, Ulrike Peters, Stephen J. Chanock, Sanford D. Markowitz, Heather Hampel, Jenny Chang-Claude, Andrea Gsur, Stephanie J. Weinstein, Edith J. M. Feskens, Christopher A. Haiman, Mengmeng Du, Melissa C. Southey, John A. Baron, Bethany Van Guelpen, Kala Visvanathan, Loic Le Marchand, Victor Muñoz-Garzón, Ellen Kampman, Andrea N. Burnett-Hartman, Polly A. Newcomb, Paul D.P. Pharoah, Erin M. Siegel, Mark A. Jenkins, Gad Rennert, Tabitha A. Harrison, Neil Murphy, Antonia Trichopoulou, Sébastien Küry, Elizabeth L. Barry, Stephan Buch, Jochen Hampe, Minta Thomas, Vicente Martín, Michael O. Woods, Demetrius Albanes, Jeroen R. Huyghe, Robert S. Sandler, Li Hsu, Emily White, John L. Hopper, Rachel Pearlman, Peter T. Campbell, Peter S. Liang, Yin Cao, Amanda J. Cross, Graham G. Giles, Robert E. Schoen, Robert J. MacInnis, David Duggan, Michael Hoffmeister, Corinne E. Joshu, Christopher K. Edlund, Elizabeth A. Platz, Liesel M. FitzGerald, Anne Zeleniuch-Jacquotte, Hermann Brenner, Heinz-Josef Lenz, Lori C. Sakoda, Jane C. Figueiredo, Yu Ru Su, Stephen B. Gruber, Satu Männistö, Stephen N. Thibodeau, Christoph Mancao, Dallas R. English, Thomas J. Hudson, Li Li, John D. Potter, Andreana N. Holowatyj, David V. Conti, Temitope O. Keku, Sophia Harlid, Eric J. Jacobs, Jihyoun Jeon, Amit Joshi, Clemens Schafmayer, Pavel Vodicka, Leticia Moreira, María Dolores Chirlaque, Yi Lin, David J. Hunter, Michelle Cotterchio, Martha L. Slattery, Alicja Wolk, Roger L. Milne, Marc J. Gunter, Susanna C. Larsson, Annika Lindblom, Graham Casey, Christopher I. Li, Aung Ko Win, Ban Younghusband, Stefanie Brezina, Stephanie A. Bien, Lynne R. Wilkens, Daniela Seminara, Daniel D. Buchanan, Stéphane Bézieau, Manuela Gago-Dominguez, Patrick S. Parfrey, Hedy S. Rennert, Ann G. Zauber, Elisabeth F.P. Peterse, Faye Elliott, Catherine M. Tangen, Andrew T. Chan, Richard B. Hayes, Steven Gallinger, Amanda E. Toland, Noralane M. Lindor, María José Sánchez, Korbinian Weigl, Kenneth Offit, Iris Lansdorp-Vogelaar, Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, and Public Health
Subjects: 0301 basic medicine, Oncology, Male, COLONOSCOPY, Genotyping Techniques, Nutrition and Disease, DNA Mutational Analysis, Datasets as Topic, Penetrance, HEREDITARY, Cohort Studies, 0302 clinical medicine, Mutation Rate, Risk Factors, Voeding en Ziekte, Family history, Age of Onset, Medical History Taking, education.field_of_study, Colon Cancer, HERITABILITY, Gastroenterology, Middle Aged, Lynch syndrome, Cohort, 030211 gastroenterology & hepatology, Female, Colorectal Neoplasms, Life Sciences & Biomedicine, EOCRC, Cohort study, medicine.medical_specialty, EPIDEMIOLOGY RESEARCH, Population, SNP, LYNCH-SYNDROME, Polymorphism, Single Nucleotide, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Life Style, VLAG, Global Nutrition, Wereldvoeding, Science & Technology, Hepatology, Gastroenterology & Hepatology, Whole Genome Sequencing, business.industry, MUTATIONS, Case-control study, Cancer, 1103 Clinical Sciences, Odds ratio, medicine.disease, digestive system diseases, 030104 developmental biology, Case-Control Studies, LOW-PENETRANCE SUSCEPTIBILITY, 1114 Paediatrics and Reproductive Medicine, ADULT HEALTH, RACE/ETHNICITY, business, 1109 Neurosciences, Genome-Wide Association Study
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 more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
Published: 2020

207. Gut Microbes, Diet, and Cancer

Author: Hullar, Meredith A. J., primary, Burnett-Hartman, Andrea N., additional, and Lampe, Johanna W., additional
Published: 2013
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208. Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Author: Thomas, Minta, Sakoda, Lori C, Hoffmeister, Michael, Rosenthal, Elisabeth A, Lee, Jeffrey K, van Duijnhoven, Franzel J B, Platz, Elizabeth A, Wu, Anna H, Dampier, Christopher H, de la Chapelle, Albert, Wolk, Alicja, Joshi, Amit D, Burnett-Hartman, Andrea, Gsur, Andrea, Lindblom, Annika, Castells, Antoni, Win, Aung Ko, Namjou, Bahram, Van Guelpen, Bethany, Tangen, Catherine M, He, Qianchuan, Li, Christopher I, Schafmayer, Clemens, Joshu, Corinne E, Ulrich, Cornelia M, Bishop, D Timothy, Buchanan, Daniel D, Schaid, Daniel, Drew, David A, Muller, David C, Duggan, David, Crosslin, David R, Albanes, Demetrius, Giovannucci, Edward L, Larson, Eric, Qu, Flora, Mentch, Frank, Giles, Graham G, Hakonarson, Hakon, Hampel, Heather, Stanaway, Ian B, Figueiredo, Jane C, Huyghe, Jeroen R, Minnier, Jessica, Chang-Claude, Jenny, Hampe, Jochen, Harley, John B, Visvanathan, Kala, Curtis, Keith R, Offit, Kenneth, Li, Li, Le Marchand, Loic, Vodickova, Ludmila, Gunter, Marc J, Jenkins, Mark A, Slattery, Martha L, Lemire, Mathieu, Woods, Michael O, Song, Mingyang, Murphy, Neil, Lindor, Noralane M, Dikilitas, Ozan, Pharoah, Paul D P, Campbell, Peter T, Newcomb, Polly A, Milne, Roger L, MacInnis, Robert J, Castellví-Bel, Sergi, Ogino, Shuji, Berndt, Sonja I, Bézieau, Stéphane, Thibodeau, Stephen N, Gallinger, Steven J, Zaidi, Syed H, Harrison, Tabitha A, Keku, Temitope O, Hudson, Thomas J, Vymetalkova, Veronika, Moreno, Victor, Martín, Vicente, Arndt, Volker, Wei, Wei-Qi, Chung, Wendy, Su, Yu-Ru, Hayes, Richard B, White, Emily, Vodicka, Pavel, Casey, Graham, Gruber, Stephen B, Schoen, Robert E, Chan, Andrew T, Potter, John D, Brenner, Hermann, Jarvik, Gail P, Corley, Douglas A, Peters, Ulrike, Hsu, Li, Thomas, Minta, Sakoda, Lori C, Hoffmeister, Michael, Rosenthal, Elisabeth A, Lee, Jeffrey K, van Duijnhoven, Franzel J B, Platz, Elizabeth A, Wu, Anna H, Dampier, Christopher H, de la Chapelle, Albert, Wolk, Alicja, Joshi, Amit D, Burnett-Hartman, Andrea, Gsur, Andrea, Lindblom, Annika, Castells, Antoni, Win, Aung Ko, Namjou, Bahram, Van Guelpen, Bethany, Tangen, Catherine M, He, Qianchuan, Li, Christopher I, Schafmayer, Clemens, Joshu, Corinne E, Ulrich, Cornelia M, Bishop, D Timothy, Buchanan, Daniel D, Schaid, Daniel, Drew, David A, Muller, David C, Duggan, David, Crosslin, David R, Albanes, Demetrius, Giovannucci, Edward L, Larson, Eric, Qu, Flora, Mentch, Frank, Giles, Graham G, Hakonarson, Hakon, Hampel, Heather, Stanaway, Ian B, Figueiredo, Jane C, Huyghe, Jeroen R, Minnier, Jessica, Chang-Claude, Jenny, Hampe, Jochen, Harley, John B, Visvanathan, Kala, Curtis, Keith R, Offit, Kenneth, Li, Li, Le Marchand, Loic, Vodickova, Ludmila, Gunter, Marc J, Jenkins, Mark A, Slattery, Martha L, Lemire, Mathieu, Woods, Michael O, Song, Mingyang, Murphy, Neil, Lindor, Noralane M, Dikilitas, Ozan, Pharoah, Paul D P, Campbell, Peter T, Newcomb, Polly A, Milne, Roger L, MacInnis, Robert J, Castellví-Bel, Sergi, Ogino, Shuji, Berndt, Sonja I, Bézieau, Stéphane, Thibodeau, Stephen N, Gallinger, Steven J, Zaidi, Syed H, Harrison, Tabitha A, Keku, Temitope O, Hudson, Thomas J, Vymetalkova, Veronika, Moreno, Victor, Martín, Vicente, Arndt, Volker, Wei, Wei-Qi, Chung, Wendy, Su, Yu-Ru, Hayes, Richard B, White, Emily, Vodicka, Pavel, Casey, Graham, Gruber, Stephen B, Schoen, Robert E, Chan, Andrew T, Potter, John D, Brenner, Hermann, Jarvik, Gail P, Corley, Douglas A, Peters, Ulrike, and Hsu, Li
Abstract: Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might be
Published: 2020
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209. 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, Neil, Carreras-Torres, Robert, Song, Mingyang, Chan, Andrew T., Martin, Richard M., Papadimitriou, Nikos, Dimou, Niki, Tsilidis, Konstantinos K., Banbury, Barbara, Bradbury, Kathryn E., Besevic, Jelena, Rinaldi, Sabina, Riboli, Elio, Cross, Amanda J., Travis, Ruth C., Agnoli, Claudia, Albanes, Demetrius, Berndt, Sonja I., Bezieau, Stephane, Bishop, D. Timothy, Brenner, Hermann, Buchanan, Daniel D., Onland-Moret, N. Charlotte, Burnett-Hartman, Andrea, Campbell, Peter T., Casey, Graham, Castellvi-Bel, Sergi, Chang-Claude, Jenny, Chirlaque, Maria-Dolores, de la Chapelle, Albert, English, Dallas, Figueiredo, Jane C., Gallinger, Steven J., Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Hsu, Li, Huang, Wen-Yi, Huyghe, Jeroen R., Jenkins, Mark A., Keku, Temitope O., Kuhn, Tilman, Kweon, Sun-Seog, Le Marchand, Loic, Li, Christopher I., Li, Li, Lindblom, Annika, Martin, Vicente, Milne, Roger L., Moreno, Victor, Newcomb, Polly A., Offit, Kenneth, Ogino, Shuji, Ose, Jennifer, Perduca, Vittorio, Phipps, Amanda I., Platz, Elizabeth A., Potter, John D., Qu, Conghui, Rennert, Gad, Sakoda, Lori C., Schafmayer, Clemens, Schoen, Robert E., Slattery, Martha L., Tangen, Catherine M., Ulrich, Cornelia M., van Duijnhoven, Franzel J. B., Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Wang, Hansong, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zheng, Wei, Peters, Ulrike, Gunter, Marc J., Murphy, Neil, Carreras-Torres, Robert, Song, Mingyang, Chan, Andrew T., Martin, Richard M., Papadimitriou, Nikos, Dimou, Niki, Tsilidis, Konstantinos K., Banbury, Barbara, Bradbury, Kathryn E., Besevic, Jelena, Rinaldi, Sabina, Riboli, Elio, Cross, Amanda J., Travis, Ruth C., Agnoli, Claudia, Albanes, Demetrius, Berndt, Sonja I., Bezieau, Stephane, Bishop, D. Timothy, Brenner, Hermann, Buchanan, Daniel D., Onland-Moret, N. Charlotte, Burnett-Hartman, Andrea, Campbell, Peter T., Casey, Graham, Castellvi-Bel, Sergi, Chang-Claude, Jenny, Chirlaque, Maria-Dolores, de la Chapelle, Albert, English, Dallas, Figueiredo, Jane C., Gallinger, Steven J., Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Hsu, Li, Huang, Wen-Yi, Huyghe, Jeroen R., Jenkins, Mark A., Keku, Temitope O., Kuhn, Tilman, Kweon, Sun-Seog, Le Marchand, Loic, Li, Christopher I., Li, Li, Lindblom, Annika, Martin, Vicente, Milne, Roger L., Moreno, Victor, Newcomb, Polly A., Offit, Kenneth, Ogino, Shuji, Ose, Jennifer, Perduca, Vittorio, Phipps, Amanda I., Platz, Elizabeth A., Potter, John D., Qu, Conghui, Rennert, Gad, Sakoda, Lori C., Schafmayer, Clemens, Schoen, Robert E., Slattery, Martha L., Tangen, Catherine M., Ulrich, Cornelia M., van Duijnhoven, Franzel J. B., Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Wang, Hansong, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Zheng, Wei, Peters, Ulrike, and Gunter, Marc J.
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 genomewide 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 multivariableadjusted 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] 1.051.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 x 10(-4)). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 x 10(-5)). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene
Published: 2020
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210. Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects

Author: Guo, Xingyi, Lin, Weiqiang, Wen, Wanqing, Huyghe, Jeroen, Bien, Stephanie, Cai, Qiuyin, Harrison, Tabitha, Chen, Zhishan, Qu, Conghui, Bao, Jiandong, Long, Jirong, Yuan, Yuan, Wang, Fangqin, Bai, Mengqiu, Abecasis, Goncalo R, Albanes, Demetrius, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Brenner, Hermann, Buch, Stephan, Burnett-Hartman, Andrea, Campbell, Peter T, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Cho, Sang Hee, Conti, David V, Chapelle, Albert de la, Feskens, Edith J M, Gallinger, Steven J, Giles, Graham G, Goodman, Phyllis J, Gsur, Andrea, Guinter, Mark, Gunter, Marc J, Hampe, Jochen, Hampel, Heather, Hayes, Richard B, Hoffmeister, Michael, Kampman, Ellen, Kang, Hyun Min, Keku, Temitope O, Kim, Hyeong Rok, Le Marchand, Loic, Lee, Soo Chin, Li, Christopher I, Li, Li, Lindblom, Annika, Lindor, Noralane, Milne, Roger L, Moreno, Victor, Murphy, Neil, Newcomb, Polly A, Nickerson, Deborah A, Offit, Kenneth, Pearlman, Rachel, Pharoah, Paul D P, Platz, Elizabeth A, Potter, John D, Rennert, Gad, Sakoda, Lori C, Schafmayer, Clemens, Schmit, Stephanie L, Schoen, Robert E, Schumacher, Fredrick R, Slattery, Martha L, Su, Yu-Ru, Tangen, Catherine M, Ulrich, Cornelia M, van Duijnhoven, Franzel J B, Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Wang, Xiaolong, White, Emily, Wolk, Alicja, Woods, Michael O, Casey, Graham, Hsu, Li, Jenkins, Mark A, Gruber, Stephen B, Peters, Ulrike, Zheng, Wei, Guo, Xingyi, Lin, Weiqiang, Wen, Wanqing, Huyghe, Jeroen, Bien, Stephanie, Cai, Qiuyin, Harrison, Tabitha, Chen, Zhishan, Qu, Conghui, Bao, Jiandong, Long, Jirong, Yuan, Yuan, Wang, Fangqin, Bai, Mengqiu, Abecasis, Goncalo R, Albanes, Demetrius, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Brenner, Hermann, Buch, Stephan, Burnett-Hartman, Andrea, Campbell, Peter T, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Cho, Sang Hee, Conti, David V, Chapelle, Albert de la, Feskens, Edith J M, Gallinger, Steven J, Giles, Graham G, Goodman, Phyllis J, Gsur, Andrea, Guinter, Mark, Gunter, Marc J, Hampe, Jochen, Hampel, Heather, Hayes, Richard B, Hoffmeister, Michael, Kampman, Ellen, Kang, Hyun Min, Keku, Temitope O, Kim, Hyeong Rok, Le Marchand, Loic, Lee, Soo Chin, Li, Christopher I, Li, Li, Lindblom, Annika, Lindor, Noralane, Milne, Roger L, Moreno, Victor, Murphy, Neil, Newcomb, Polly A, Nickerson, Deborah A, Offit, Kenneth, Pearlman, Rachel, Pharoah, Paul D P, Platz, Elizabeth A, Potter, John D, Rennert, Gad, Sakoda, Lori C, Schafmayer, Clemens, Schmit, Stephanie L, Schoen, Robert E, Schumacher, Fredrick R, Slattery, Martha L, Su, Yu-Ru, Tangen, Catherine M, Ulrich, Cornelia M, van Duijnhoven, Franzel J B, Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Wang, Xiaolong, White, Emily, Wolk, Alicja, Woods, Michael O, Casey, Graham, Hsu, Li, Jenkins, Mark A, Gruber, Stephen B, Peters, Ulrike, and Zheng, Wei
Abstract: BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
Published: 2020
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211. Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer

Author: Archambault, Alexi N., Su, Yu-Ru, Jeon, Jihyoun, Thomas, Minta, Lin, Yi, Conti, David V., Win, Aung Ko, Sakoda, Lori C., Lansdorp-Vogelaar, Iris, Peterse, Elisabeth F. P., Zauber, Ann G., Duggan, David, Holowatyj, Andreana N., Huyghe, Jeroen R., Brenner, Hermann, Cotterchio, Michelle, Bezieau, Stephane, Schmit, Stephanie L., Edlund, Christopher K., Southey, Melissa C., MacInnis, Robert J., Campbell, Peter T., Chang-Claude, Jenny, Slattery, Martha L., Chan, Andrew T., Joshi, Amit D., Song, Mingyang, Cao, Yin, Woods, Michael O., White, Emily, Weinstein, Stephanie J., Ulrich, Cornelia M., Hoffmeister, Michael, Bien, Stephanie A., Harrison, Tabitha A., Hampe, Jochen, Li, Christopher I., Schafmayer, Clemens, Offit, Kenneth, Pharoah, Paul D., Moreno, Victor, Lindblom, Annika, Wolk, Alicja, Wu, Anna H., Li, Li, Gunter, Marc J., Gsur, Andrea, Keku, Temitope O., Pearlman, Rachel, Bishop, D. Timothy, Castellvi-Bel, Sergi, Moreira, Leticia, Vodicka, Pavel, Kampman, Ellen, Giles, Graham G., Albanes, Demetrius, Baron, John A., Berndt, Sonja I., Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D., Trichopoulou, Antonia, Severi, Gianluca, Chirlaque, Maria-Dolores, Sanchez, Maria-Jose, Palli, Domenico, Kuhn, Tilman, Murphy, Neil, Cross, Amanda J., Burnett-Hartman, Andrea N., Chanock, Stephen J., de la Chapelle, Albert, Easton, Douglas F., Elliott, Faye, English, Dallas R., Feskens, Edith J. M., FitzGerald, Liesel M., Goodman, Phyllis J., Hopper, John L., Hudson, Thomas J., Hunter, David J., Jacobs, Eric J., Joshu, Corinne E., Kury, Sebastien, Markowitz, Sanford D., Milne, Roger L., Platz, Elizabeth A., Rennert, Gad, Rennert, Hedy S., Schumacher, Fredrick R., Sandler, Robert S., Seminara, Daniela, Tangen, Catherine M., Thibodeau, Stephen N., Toland, Amanda E., van Duijnhoven, Franzel J. B., Visvanathan, Kala, Vodickova, Ludmila, Potter, John D., Mannisto, Satu, Weigl, Korbinian, Figueiredo, Jane, Martin, Vicente, Larsson, Susanna C, Parfrey, Patrick S., Huang, Wen-Yi, Lenz, Heinz-Josef, Castelao, Jose E., Gago-Dominguez, Manuela, Munoz-Garzon, Victor, Mancao, Christoph, Haiman, Christopher A., Wilkens, Lynne R., Siegel, Erin, Barry, Elizabeth, Younghusband, Ban, Van Guelpen, Bethany, Harlid, Sophia, Zeleniuch-Jacquotte, Anne, Liang, Peter S., Du, Mengmeng, Casey, Graham, Lindor, Noralane M., Le Marchand, Loic, Gallinger, Steven J., Jenkins, Mark A., Newcomb, Polly A., Gruber, Stephen B., Schoen, Robert E., Hampel, Heather, Corley, Douglas A., Hsu, Li, Peters, Ulrike, Hayes, Richard B., Archambault, Alexi N., Su, Yu-Ru, Jeon, Jihyoun, Thomas, Minta, Lin, Yi, Conti, David V., Win, Aung Ko, Sakoda, Lori C., Lansdorp-Vogelaar, Iris, Peterse, Elisabeth F. P., Zauber, Ann G., Duggan, David, Holowatyj, Andreana N., Huyghe, Jeroen R., Brenner, Hermann, Cotterchio, Michelle, Bezieau, Stephane, Schmit, Stephanie L., Edlund, Christopher K., Southey, Melissa C., MacInnis, Robert J., Campbell, Peter T., Chang-Claude, Jenny, Slattery, Martha L., Chan, Andrew T., Joshi, Amit D., Song, Mingyang, Cao, Yin, Woods, Michael O., White, Emily, Weinstein, Stephanie J., Ulrich, Cornelia M., Hoffmeister, Michael, Bien, Stephanie A., Harrison, Tabitha A., Hampe, Jochen, Li, Christopher I., Schafmayer, Clemens, Offit, Kenneth, Pharoah, Paul D., Moreno, Victor, Lindblom, Annika, Wolk, Alicja, Wu, Anna H., Li, Li, Gunter, Marc J., Gsur, Andrea, Keku, Temitope O., Pearlman, Rachel, Bishop, D. Timothy, Castellvi-Bel, Sergi, Moreira, Leticia, Vodicka, Pavel, Kampman, Ellen, Giles, Graham G., Albanes, Demetrius, Baron, John A., Berndt, Sonja I., Brezina, Stefanie, Buch, Stephan, Buchanan, Daniel D., Trichopoulou, Antonia, Severi, Gianluca, Chirlaque, Maria-Dolores, Sanchez, Maria-Jose, Palli, Domenico, Kuhn, Tilman, Murphy, Neil, Cross, Amanda J., Burnett-Hartman, Andrea N., Chanock, Stephen J., de la Chapelle, Albert, Easton, Douglas F., Elliott, Faye, English, Dallas R., Feskens, Edith J. M., FitzGerald, Liesel M., Goodman, Phyllis J., Hopper, John L., Hudson, Thomas J., Hunter, David J., Jacobs, Eric J., Joshu, Corinne E., Kury, Sebastien, Markowitz, Sanford D., Milne, Roger L., Platz, Elizabeth A., Rennert, Gad, Rennert, Hedy S., Schumacher, Fredrick R., Sandler, Robert S., Seminara, Daniela, Tangen, Catherine M., Thibodeau, Stephen N., Toland, Amanda E., van Duijnhoven, Franzel J. B., Visvanathan, Kala, Vodickova, Ludmila, Potter, John D., Mannisto, Satu, Weigl, Korbinian, Figueiredo, Jane, Martin, Vicente, Larsson, Susanna C, Parfrey, Patrick S., Huang, Wen-Yi, Lenz, Heinz-Josef, Castelao, Jose E., Gago-Dominguez, Manuela, Munoz-Garzon, Victor, Mancao, Christoph, Haiman, Christopher A., Wilkens, Lynne R., Siegel, Erin, Barry, Elizabeth, Younghusband, Ban, Van Guelpen, Bethany, Harlid, Sophia, Zeleniuch-Jacquotte, Anne, Liang, Peter S., Du, Mengmeng, Casey, Graham, Lindor, Noralane M., Le Marchand, Loic, Gallinger, Steven J., Jenkins, Mark A., Newcomb, Polly A., Gruber, Stephen B., Schoen, Robert E., Hampel, Heather, Corley, Douglas A., Hsu, Li, Peters, Ulrike, and Hayes, Richard B.
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 x 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
Published: 2020
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212. Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

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

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

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

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

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

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

Author: Jarvik, Gail P., Wang, Xiaoliang, Fontanillas, Pierre, Kim, Esther, Chanprasert, Sirisak, Gordon, Adam S., Bastarache, Lisa, Kowdley, Kris, V, Harrison, Tabitha, Rosenthal, Elisabeth A., Stanaway, Ian B., Bezieau, Stephane, Weinstein, Stephanie J., Newcomb, Polly A., Casey, Graham, Platz, Elizabeth A., Visvanathan, Kala, Le Marchand, Loic, Ulrich, Cornelia M., Hardikar, Sheetal, Li, Christopher, I, van Duijnhoven, Franzel J. B., Gsur, Andrea, Campbell, Peter T., Moreno, Victor, Vodicka, Pavel, Brenner, Hermann, Chang-Claude, Jenny, Hoffmeister, Michael, Slattery, Martha L., Gunter, Marc J., Aglago, Elom K., Castellvi-Bel, Sergi, Kweon, Sun-Seog, Chan, Andrew T., Li, Li, Zheng, Wei, Bishop, D. Timothy, Giles, Graham G., Rennert, Gad, Offit, Kenneth, Keku, Temitope O., Woods, Michael O., Hampe, Jochen, Van Guelpen, Bethan, Gallinger, Steven J., de la Chapelle, Albert, Hampel, Heather, Berndt, Sonja, I, Tangen, Catherine M., Lindblom, Annika, Wolk, Alicja, Burnett-Hartman, Andrea, Wu, Anna H., White, Emily, Gruber, Stephen B., Jenkins, Mark A., Mountain, Joanna, Peters, Ulrike, Crosslin, David R., Jarvik, Gail P., Wang, Xiaoliang, Fontanillas, Pierre, Kim, Esther, Chanprasert, Sirisak, Gordon, Adam S., Bastarache, Lisa, Kowdley, Kris, V, Harrison, Tabitha, Rosenthal, Elisabeth A., Stanaway, Ian B., Bezieau, Stephane, Weinstein, Stephanie J., Newcomb, Polly A., Casey, Graham, Platz, Elizabeth A., Visvanathan, Kala, Le Marchand, Loic, Ulrich, Cornelia M., Hardikar, Sheetal, Li, Christopher, I, van Duijnhoven, Franzel J. B., Gsur, Andrea, Campbell, Peter T., Moreno, Victor, Vodicka, Pavel, Brenner, Hermann, Chang-Claude, Jenny, Hoffmeister, Michael, Slattery, Martha L., Gunter, Marc J., Aglago, Elom K., Castellvi-Bel, Sergi, Kweon, Sun-Seog, Chan, Andrew T., Li, Li, Zheng, Wei, Bishop, D. Timothy, Giles, Graham G., Rennert, Gad, Offit, Kenneth, Keku, Temitope O., Woods, Michael O., Hampe, Jochen, Van Guelpen, Bethan, Gallinger, Steven J., de la Chapelle, Albert, Hampel, Heather, Berndt, Sonja, I, Tangen, Catherine M., Lindblom, Annika, Wolk, Alicja, Burnett-Hartman, Andrea, Wu, Anna H., White, Emily, Gruber, Stephen B., Jenkins, Mark A., Mountain, Joanna, Peters, Ulrike, and Crosslin, David R.
Abstract: Homozygotes for the higher penetrance hemochromatosis risk allele, HFE c.845G>A (p.Cys282Tyr, or C282Y), have been reported to be at a 2- to 3-fold increased risk for colorectal cancer (CRC). These results have been reported for small sample size studies with no information about age at diagnosis for CRC. An association with age at diagnosis might alter CRC screening recommendations. We analyzed two large European ancestry datasets to assess the association of HFE genotype with CRC risk and age at CRC diagnosis. The first dataset included 59,733 CRC or advanced adenoma cases and 72,351 controls from a CRC epidemiological study consortium. The second dataset included 13,564 self-reported CRC cases and 2,880,218 controls from the personal genetics company, 23andMe. No association of the common hereditary hemochromatosis (HH) risk genotype and CRC was found in either dataset. The odds ratios (ORs) for the association of CRC and HFE C282Y homozygosity were 1.08 (95% confidence interval [CI], 0.91-1.29; p = 0.4) and 1.01 (95% CI, 0.78-1.31, p = 0.9) in the two cohorts, respectively. Age at CRC diagnosis also did not differ by HFE C282Y/C282Y genotype in either dataset. These results indicate no increased CRC risk in individuals with HH genotypes and suggest that persons with HH risk genotypes can follow population screening recommendations for CRC.
Published: 2020
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216. 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

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

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

218. 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

219. 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

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

Author: Bull, Caroline J, Bell, Joshua A, Murphy, Neil, Sanderson, Eleanor, Davey Smith, George, Timpson, Nicholas J, Banbury, Barbara L, Albanes, Demetrius, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D, Burnett-Hartman, Andrea, Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Cross, Amanda J, de la Chapelle, Albert, Figueiredo, Jane C, Gallinger, Steven J, Gapstur, Susan M, Giles, Graham G, Gruber, Stephen B, Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A, Hoffmeister, Michael, Hsu, Li, Huang, Wen-Yi, Huyghe, Jeroen R, Jenkins, Mark A, Joshu, Corinne E, Keku, Temitope O, Kühn, Tilman, Kweon, Sun-Seog, Le Marchand, Loic, Li, Christopher I, Li, Li, Lindblom, Annika, Martín, Vicente, May, Anne M, Milne, Roger L, Moreno, Victor, Newcomb, Polly A, Offit, Kenneth, Ogino, Shuji, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Qu, Conghui, Quirós, J Ramón, Rennert, Gad, Riboli, Elio, Sakoda, Lori C, Schafmayer, Clemens, Schoen, Robert E, Slattery, Martha L, Tangen, Catherine M, Tsilidis, Kostas K, Ulrich, Cornelia M, van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Wang, Hansong, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Campbell, Peter T, Zheng, Wei, Peters, Ulrike, Vincent, Emma E, Gunter, Marc J, Bull, Caroline J, Bell, Joshua A, Murphy, Neil, Sanderson, Eleanor, Davey Smith, George, Timpson, Nicholas J, Banbury, Barbara L, Albanes, Demetrius, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D, Burnett-Hartman, Andrea, Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Cross, Amanda J, de la Chapelle, Albert, Figueiredo, Jane C, Gallinger, Steven J, Gapstur, Susan M, Giles, Graham G, Gruber, Stephen B, Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A, Hoffmeister, Michael, Hsu, Li, Huang, Wen-Yi, Huyghe, Jeroen R, Jenkins, Mark A, Joshu, Corinne E, Keku, Temitope O, Kühn, Tilman, Kweon, Sun-Seog, Le Marchand, Loic, Li, Christopher I, Li, Li, Lindblom, Annika, Martín, Vicente, May, Anne M, Milne, Roger L, Moreno, Victor, Newcomb, Polly A, Offit, Kenneth, Ogino, Shuji, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Qu, Conghui, Quirós, J Ramón, Rennert, Gad, Riboli, Elio, Sakoda, Lori C, Schafmayer, Clemens, Schoen, Robert E, Slattery, Martha L, Tangen, Catherine M, Tsilidis, Kostas K, Ulrich, Cornelia M, van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Wang, Hansong, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Campbell, Peter T, Zheng, Wei, Peters, Ulrike, Vincent, Emma E, and Gunter, Marc J
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
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221. 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: Cardiovasculaire Epi Team 3, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, JC onderzoeksprogramma Kanker, CMM Groep Burgering, Murphy, Neil, Carreras-Torres, Robert, Song, Mingyang, Chan, Andrew T, Martin, Richard M, Papadimitriou, Nikos, Dimou, Niki, Tsilidis, Konstantinos K, Banbury, Barbara, Bradbury, Kathryn E, Besevic, Jelena, Rinaldi, Sabina, Riboli, Elio, Cross, Amanda J, Travis, Ruth C, Agnoli, Claudia, Albanes, Demetrius, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D, Onland-Moret, N Charlotte, Burnett-Hartman, Andrea, Campbell, Peter T, Casey, Graham, Castellví-Bel, Sergi, Chang-Claude, Jenny, Chirlaque, María-Dolores, Chapelle, Albert de la, English, Dallas, Figueiredo, Jane C, Gallinger, Steven J, Giles, Graham G, Gruber, Stephen B, Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A, Hoffmeister, Michael, Hsu, Li, Huang, Wen-Yi, Huyghe, Jeroen R, Jenkins, Mark A, Keku, Temitope O, Kühn, Tilman, Kweon, Sun-Seog, Le Marchand, Loic, Li, Christopher I, Li, Li, Lindblom, Annika, Martín, Vicente, Milne, Roger L, Moreno, Victor, Newcomb, Polly A, Offit, Kenneth, Ogino, Shuji, Ose, Jennifer, Perduca, Vittorio, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Qu, Conghui, Rennert, Gad, Sakoda, Lori C, Schafmayer, Clemens, Schoen, Robert E, Slattery, Martha L, Tangen, Catherine M, Ulrich, Cornelia M, van Duijnhoven, Franzel Jb, Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Wang, Hansong, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Zheng, Wei, Peters, Ulrike, Gunter, Marc J, Cardiovasculaire Epi Team 3, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, JC onderzoeksprogramma Kanker, CMM Groep Burgering, Murphy, Neil, Carreras-Torres, Robert, Song, Mingyang, Chan, Andrew T, Martin, Richard M, Papadimitriou, Nikos, Dimou, Niki, Tsilidis, Konstantinos K, Banbury, Barbara, Bradbury, Kathryn E, Besevic, Jelena, Rinaldi, Sabina, Riboli, Elio, Cross, Amanda J, Travis, Ruth C, Agnoli, Claudia, Albanes, Demetrius, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D, Onland-Moret, N Charlotte, Burnett-Hartman, Andrea, Campbell, Peter T, Casey, Graham, Castellví-Bel, Sergi, Chang-Claude, Jenny, Chirlaque, María-Dolores, Chapelle, Albert de la, English, Dallas, Figueiredo, Jane C, Gallinger, Steven J, Giles, Graham G, Gruber, Stephen B, Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A, Hoffmeister, Michael, Hsu, Li, Huang, Wen-Yi, Huyghe, Jeroen R, Jenkins, Mark A, Keku, Temitope O, Kühn, Tilman, Kweon, Sun-Seog, Le Marchand, Loic, Li, Christopher I, Li, Li, Lindblom, Annika, Martín, Vicente, Milne, Roger L, Moreno, Victor, Newcomb, Polly A, Offit, Kenneth, Ogino, Shuji, Ose, Jennifer, Perduca, Vittorio, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Qu, Conghui, Rennert, Gad, Sakoda, Lori C, Schafmayer, Clemens, Schoen, Robert E, Slattery, Martha L, Tangen, Catherine M, Ulrich, Cornelia M, van Duijnhoven, Franzel Jb, Van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Wang, Hansong, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Zheng, Wei, Peters, Ulrike, and Gunter, Marc J
Published: 2020

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

Author: Bull, Caroline J., Bell, Joshua A., Murphy, Neil, Sanderson, Eleanor, Davey Smith, George, Timpson, Nicholas J., Banbury, Barbara L., Albanes, Demetrius, Berndt, Sonja I., Bézieau, Stéphane, Bishop, Timothy, Brenner, Hermann, Buchanan, Daniel D., Burnett-Hartman, Andrea, Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Cross, Amanda J., de la Chapelle, Albert, Figueiredo, Jane C., Gallinger, Steven J., Gapstur, Susan M., Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Hsu, Li, Huang, Wen Yi, Huyghe, Jeroen R., Jenkins, Mark A., Joshu, Corinne E., Keku, Temitope O., Kühn, Tilman, Kweon, Sun Seog, Le Marchand, Loic, Li, Christopher I., Li, Li, Lindblom, Annika, Martín, Vicente, May, Anne M., Milne, Roger L., Moreno, Victor, Newcomb, Polly A., Offit, Kenneth, Ogino, Shuji, Phipps, Amanda I., Platz, Elizabeth A., Potter, John D., Qu, Conghui, Quirós, José Ramón, Rennert, Gad, Riboli, Elio, Sakoda, Lori C., Schafmayer, Clemens, Schoen, Robert E., Slattery, Martha L., Tangen, Catherine M., Tsilidis, Kostas K., Ulrich, Cornelia M., van Duijnhoven, Fränzel J.B., van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Wang, Hansong, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Campbell, Peter T., Zheng, Wei, Peters, Ulrike, Vincent, Emma E., Gunter, Marc J., Bull, Caroline J., Bell, Joshua A., Murphy, Neil, Sanderson, Eleanor, Davey Smith, George, Timpson, Nicholas J., Banbury, Barbara L., Albanes, Demetrius, Berndt, Sonja I., Bézieau, Stéphane, Bishop, Timothy, Brenner, Hermann, Buchanan, Daniel D., Burnett-Hartman, Andrea, Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T., Chang-Claude, Jenny, Cross, Amanda J., de la Chapelle, Albert, Figueiredo, Jane C., Gallinger, Steven J., Gapstur, Susan M., Giles, Graham G., Gruber, Stephen B., Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A., Hoffmeister, Michael, Hsu, Li, Huang, Wen Yi, Huyghe, Jeroen R., Jenkins, Mark A., Joshu, Corinne E., Keku, Temitope O., Kühn, Tilman, Kweon, Sun Seog, Le Marchand, Loic, Li, Christopher I., Li, Li, Lindblom, Annika, Martín, Vicente, May, Anne M., Milne, Roger L., Moreno, Victor, Newcomb, Polly A., Offit, Kenneth, Ogino, Shuji, Phipps, Amanda I., Platz, Elizabeth A., Potter, John D., Qu, Conghui, Quirós, José Ramón, Rennert, Gad, Riboli, Elio, Sakoda, Lori C., Schafmayer, Clemens, Schoen, Robert E., Slattery, Martha L., Tangen, Catherine M., Tsilidis, Kostas K., Ulrich, Cornelia M., van Duijnhoven, Fränzel J.B., van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Wang, Hansong, White, Emily, Wolk, Alicja, Woods, Michael O., Wu, Anna H., Campbell, Peter T., Zheng, Wei, Peters, Ulrike, Vincent, Emma E., and Gunter, Marc J.
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

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

Author: CMM Groep Burgering, Epidemiology & Health Economics, Cancer, JC onderzoeksprogramma Kanker, Bull, Caroline J, Bell, Joshua A, Murphy, Neil, Sanderson, Eleanor, Davey Smith, George, Timpson, Nicholas J, Banbury, Barbara L, Albanes, Demetrius, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D, Burnett-Hartman, Andrea, Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Cross, Amanda J, de la Chapelle, Albert, Figueiredo, Jane C, Gallinger, Steven J, Gapstur, Susan M, Giles, Graham G, Gruber, Stephen B, Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A, Hoffmeister, Michael, Hsu, Li, Huang, Wen-Yi, Huyghe, Jeroen R, Jenkins, Mark A, Joshu, Corinne E, Keku, Temitope O, Kühn, Tilman, Kweon, Sun-Seog, Le Marchand, Loic, Li, Christopher I, Li, Li, Lindblom, Annika, Martín, Vicente, May, Anne M, Milne, Roger L, Moreno, Victor, Newcomb, Polly A, Offit, Kenneth, Ogino, Shuji, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Qu, Conghui, Quirós, J Ramón, Rennert, Gad, Riboli, Elio, Sakoda, Lori C, Schafmayer, Clemens, Schoen, Robert E, Slattery, Martha L, Tangen, Catherine M, Tsilidis, Kostas K, Ulrich, Cornelia M, van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Wang, Hansong, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Campbell, Peter T, Zheng, Wei, Peters, Ulrike, Vincent, Emma E, Gunter, Marc J, CMM Groep Burgering, Epidemiology & Health Economics, Cancer, JC onderzoeksprogramma Kanker, Bull, Caroline J, Bell, Joshua A, Murphy, Neil, Sanderson, Eleanor, Davey Smith, George, Timpson, Nicholas J, Banbury, Barbara L, Albanes, Demetrius, Berndt, Sonja I, Bézieau, Stéphane, Bishop, D Timothy, Brenner, Hermann, Buchanan, Daniel D, Burnett-Hartman, Andrea, Casey, Graham, Castellví-Bel, Sergi, Chan, Andrew T, Chang-Claude, Jenny, Cross, Amanda J, de la Chapelle, Albert, Figueiredo, Jane C, Gallinger, Steven J, Gapstur, Susan M, Giles, Graham G, Gruber, Stephen B, Gsur, Andrea, Hampe, Jochen, Hampel, Heather, Harrison, Tabitha A, Hoffmeister, Michael, Hsu, Li, Huang, Wen-Yi, Huyghe, Jeroen R, Jenkins, Mark A, Joshu, Corinne E, Keku, Temitope O, Kühn, Tilman, Kweon, Sun-Seog, Le Marchand, Loic, Li, Christopher I, Li, Li, Lindblom, Annika, Martín, Vicente, May, Anne M, Milne, Roger L, Moreno, Victor, Newcomb, Polly A, Offit, Kenneth, Ogino, Shuji, Phipps, Amanda I, Platz, Elizabeth A, Potter, John D, Qu, Conghui, Quirós, J Ramón, Rennert, Gad, Riboli, Elio, Sakoda, Lori C, Schafmayer, Clemens, Schoen, Robert E, Slattery, Martha L, Tangen, Catherine M, Tsilidis, Kostas K, Ulrich, Cornelia M, van Duijnhoven, Fränzel J B, van Guelpen, Bethany, Visvanathan, Kala, Vodicka, Pavel, Vodickova, Ludmila, Wang, Hansong, White, Emily, Wolk, Alicja, Woods, Michael O, Wu, Anna H, Campbell, Peter T, Zheng, Wei, Peters, Ulrike, Vincent, Emma E, and Gunter, Marc J
Published: 2020

224. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, Jeroen R, primary, Harrison, Tabitha A, additional, Bien, Stephanie A, additional, Hampel, Heather, additional, Figueiredo, Jane C, additional, Schmit, Stephanie L, additional, Conti, David V, additional, Chen, Sai, additional, Qu, Conghui, additional, Lin, Yi, additional, Barfield, Richard, additional, Baron, John A, additional, Cross, Amanda J, additional, Diergaarde, Brenda, additional, Duggan, David, additional, Harlid, Sophia, additional, Imaz, Liher, additional, Kang, Hyun Min, additional, Levine, David M, additional, Perduca, Vittorio, additional, Perez-Cornago, Aurora, additional, Sakoda, Lori C, additional, Schumacher, Fredrick R, additional, Slattery, Martha L, additional, Toland, Amanda E, additional, van Duijnhoven, Fränzel J B, additional, Van Guelpen, Bethany, additional, Agudo, Antonio, additional, Albanes, Demetrius, additional, Alonso, M Henar, additional, Anderson, Kristin, additional, Arnau-Collell, Coral, additional, Arndt, Volker, additional, Banbury, Barbara L, additional, Bassik, Michael C, additional, Berndt, Sonja I, additional, Bézieau, Stéphane, additional, Bishop, D Timothy, additional, Boehm, Juergen, additional, Boeing, Heiner, additional, Boutron-Ruault, Marie-Christine, additional, Brenner, Hermann, additional, Brezina, Stefanie, additional, Buch, Stephan, additional, Buchanan, Daniel D, additional, Burnett-Hartman, Andrea, additional, Caan, Bette J, additional, Campbell, Peter T, additional, Carr, Prudence R, additional, Castells, Antoni, additional, Castellví-Bel, Sergi, additional, Chan, Andrew T, additional, Chang-Claude, Jenny, additional, Chanock, Stephen J, additional, Curtis, Keith R, additional, de la Chapelle, Albert, additional, Easton, Douglas F, additional, English, Dallas R, additional, Feskens, Edith J M, additional, Gala, Manish, additional, Gallinger, Steven J, additional, Gauderman, W James, additional, Giles, Graham G, additional, Goodman, Phyllis J, additional, Grady, William M, additional, Grove, John S, additional, Gsur, Andrea, additional, Gunter, Marc J, additional, Haile, Robert W, additional, Hampe, Jochen, additional, Hoffmeister, Michael, additional, Hopper, John L, additional, Hsu, Wan-Ling, additional, Huang, Wen-Yi, additional, Hudson, Thomas J, additional, Jenab, Mazda, additional, Jenkins, Mark A, additional, Joshi, Amit D, additional, Keku, Temitope O, additional, Kooperberg, Charles, additional, Kühn, Tilman, additional, Küry, Sébastien, additional, Le Marchand, Loic, additional, Lejbkowicz, Flavio, additional, Li, Christopher I, additional, Li, Li, additional, Lieb, Wolfgang, additional, Lindblom, Annika, additional, Lindor, Noralane M, additional, Männistö, Satu, additional, Markowitz, Sanford D, additional, Milne, Roger L, additional, Moreno, Lorena, additional, Murphy, Neil, additional, Nassir, Rami, additional, Offit, Kenneth, additional, Ogino, Shuji, additional, Panico, Salvatore, additional, Parfrey, Patrick S, additional, Pearlman, Rachel, additional, Pharoah, Paul D P, additional, Phipps, Amanda I, additional, Platz, Elizabeth A, additional, Potter, John D, additional, Prentice, Ross L, additional, Qi, Lihong, additional, Raskin, Leon, additional, Rennert, Gad, additional, Rennert, Hedy S, additional, Riboli, Elio, additional, Schafmayer, Clemens, additional, Schoen, Robert E, additional, Seminara, Daniela, additional, Song, Mingyang, additional, Su, Yu-Ru, additional, Tangen, Catherine M, additional, Thibodeau, Stephen N, additional, Thomas, Duncan C, additional, Trichopoulou, Antonia, additional, Ulrich, Cornelia M, additional, Visvanathan, Kala, additional, Vodicka, Pavel, additional, Vodickova, Ludmila, additional, Vymetalkova, Veronika, additional, Weigl, Korbinian, additional, Weinstein, Stephanie J, additional, White, Emily, additional, Wolk, Alicja, additional, Woods, Michael O, additional, Wu, Anna H, additional, Abecasis, Goncalo R, additional, Nickerson, Deborah A, additional, Scacheri, Peter C, additional, Kundaje, Anshul, additional, Casey, Graham, additional, Gruber, Stephen B, additional, Hsu, Li, additional, Moreno, Victor, additional, Hayes, Richard B, additional, Newcomb, Polly A, additional, and Peters, Ulrike, additional
Published: 2021
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225. Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

Author: Bull, Caroline J., primary, Bell, Joshua A., additional, Murphy, Neil, additional, Sanderson, Eleanor, additional, Davey Smith, George, additional, Timpson, Nicholas J., additional, Banbury, Barbara L., additional, Albanes, Demetrius, additional, Berndt, Sonja I., additional, Bézieau, Stéphane, additional, Bishop, D. Timothy, additional, Brenner, Hermann, additional, Buchanan, Daniel D., additional, Burnett-Hartman, Andrea, additional, Casey, Graham, additional, Castellví-Bel, Sergi, additional, Chan, Andrew T., additional, Chang-Claude, Jenny, additional, Cross, Amanda J., additional, de la Chapelle, Albert, additional, Figueiredo, Jane C., additional, Gallinger, Steven J., additional, Gapstur, Susan M., additional, Giles, Graham G., additional, Gruber, Stephen B., additional, Gsur, Andrea, additional, Hampe, Jochen, additional, Hampel, Heather, additional, Harrison, Tabitha A., additional, Hoffmeister, Michael, additional, Hsu, Li, additional, Huang, Wen-Yi, additional, Huyghe, Jeroen R., additional, Jenkins, Mark A., additional, Joshu, Corinne E., additional, Keku, Temitope O., additional, Kühn, Tilman, additional, Kweon, Sun-Seog, additional, Le Marchand, Loic, additional, Li, Christopher I., additional, Li, Li, additional, Lindblom, Annika, additional, Martín, Vicente, additional, May, Anne M., additional, Milne, Roger L., additional, Moreno, Victor, additional, Newcomb, Polly A., additional, Offit, Kenneth, additional, Ogino, Shuji, additional, Phipps, Amanda I., additional, Platz, Elizabeth A., additional, Potter, John D., additional, Qu, Conghui, additional, Quirós, J. Ramón, additional, Rennert, Gad, additional, Riboli, Elio, additional, Sakoda, Lori C., additional, Schafmayer, Clemens, additional, Schoen, Robert E., additional, Slattery, Martha L., additional, Tangen, Catherine M., additional, Tsilidis, Kostas K., additional, Ulrich, Cornelia M., additional, van Duijnhoven, Fränzel J. B., additional, van Guelpen, Bethany, additional, Visvanathan, Kala, additional, Vodicka, Pavel, additional, Vodickova, Ludmila, additional, Wang, Hansong, additional, White, Emily, additional, Wolk, Alicja, additional, Woods, Michael O., additional, Wu, Anna H., additional, Campbell, Peter T., additional, Zheng, Wei, additional, Peters, Ulrike, additional, Vincent, Emma E., additional, and Gunter, Marc J., additional
Published: 2020
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226. Differences in Epidemiologic Risk Factors for Colorectal Adenomas and Serrated Polyps by Lesion Severity and Anatomical Site

Author: Burnett-Hartman, Andrea N., Passarelli, Michael N., Adams, Scott V., Upton, Melissa P., Zhu, Lee-Ching, Potter, John D., and Newcomb, Polly A.
Published: 2013
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227. Evaluation of Population-Level Changes Associated With the 2021 US Preventive Services Task Force Lung Cancer Screening Recommendations in Community-Based Health Care Systems

Author: Rafael Meza, Stacey Honda, Christine Neslund-Dudas, Katharine A. Rendle, Debra P. Ritzwoller, Andrea N. Burnett-Hartman, Nikki M. Carroll, Robert T. Greenlee, Erica Blum-Barnett, and Anil Vachani
Subjects: Adult, Male, Community-Based Participatory Research, Lung Neoplasms, Population Dynamics, Population, Cohort Studies, Health care, Cancer screening, Humans, Medicine, education, Early Detection of Cancer, Aged, Aged, 80 and over, education.field_of_study, business.industry, General Medicine, Middle Aged, medicine.disease, Comorbidity, United States, Cohort, Pacific islanders, Female, Preventive Medicine, business, Lung cancer screening, Demography, Cohort study
Abstract: Importance The US Preventive Services Task Force (USPSTF) released updated lung cancer screening recommendations in 2021, lowering the screening age from 55 to 50 years and smoking history from 30 to 20 pack-years. These changes are expected to expand screening access to women and racial and ethnic minority groups. Objective To estimate the population-level changes associated with the 2021 USPSTF expansion of lung cancer screening eligibility by sex, race and ethnicity, sociodemographic factors, and comorbidities in 5 community-based health care systems. Design, setting, and participants This cohort study analyzed data of patients who received care from any of 5 community-based health care systems (which are members of the Population-based Research to Optimize the Screening Process Lung Consortium, a collaboration that conducts research to better understand how to improve the cancer screening processes in community health care settings) from January 1, 2010, through September 30, 2019. Individuals who had complete smoking history and were engaged with the health care system for 12 or more continuous months were included. Those who had never smoked or who had unknown smoking history were excluded. Exposures Electronic health record-derived age, sex, race and ethnicity, socioeconomic status (SES), comorbidities, and smoking history. Main outcomes and measures Differences in the proportion of the newly eligible population by age, sex, race and ethnicity, Charlson Comorbidity Index, chronic obstructive pulmonary disease diagnosis, and SES as well as lung cancer diagnoses under the 2013 recommendations vs the expected cases under the 2021 recommendations were evaluated using χ2 tests. Results As of September 2019, there were 341 163 individuals aged 50 to 80 years who currently or previously smoked. Among these, 34 528 had electronic health record data that captured pack-year and quit-date information and were eligible for lung cancer screening according to the 2013 USPSTF recommendations. The 2021 USPSTF recommendations expanded screening eligibility to 18 533 individuals, representing a 53.7% increase. Compared with the 2013 cohort, the newly eligible 2021 population included 5833 individuals (31.5%) aged 50 to 54 years, a larger proportion of women (52.0% [n = 9631]), and more racial or ethnic minority groups. The relative increases in the proportion of newly eligible individuals were 60.6% for Asian, Native Hawaiian, or Pacific Islander; 67.4% for Hispanic; 69.7% for non-Hispanic Black; and 49.0% for non-Hispanic White groups. The relative increase for women was 13.8% higher than for men (61.2% vs 47.4%), and those with a lower comorbidity burden and lower SES had higher relative increases (eg, 68.7% for a Charlson Comorbidity Index score of 0; 61.1% for lowest SES). The 2021 recommendations were associated with an estimated 30% increase in incident lung cancer diagnoses compared with the 2013 recommendations. Conclusions and relevance This cohort study suggests that, in diverse health care systems, adopting the 2021 USPSTF recommendations will increase the number of women, racial and ethnic minority groups, and individuals with lower SES who are eligible for lung cancer screening, thus helping to minimize the barriers to screening access for individuals with high risk for lung cancer.
Published: 2021

228. DEMOGRAPHIC, CLINICAL, AND BEHAVIORAL FACTORS ASSOCIATED WITH E-CIGARETTE USE IN A LARGE COHORT IN THE UNITED STATES

Author: Morgan Clennin, Heather Spencer Feigelson, Andrea N. Burnett-Hartman, Mark Gray, John H. Powers, Jason Lyons, and Shauna Goldberg Scott
Subjects: Pulmonary and Respiratory Medicine, business.industry, Environmental health, Medicine, Cigarette use, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine, business, Large cohort
Published: 2021

229. Prediagnostic non-steroidal anti-inflammatory drug use and survival after diagnosis of colorectal cancer

Author: Coghill, Anna E, Newcomb, Polly A, Campbell, Peter T, Burnett-Hartman, Andrea N, Adams, Scott V, Poole, Elizabeth M, Potter, John D, and Ulrich, Cornelia M
Published: 2011
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230. Hemochromatosis risk genotype is not associated with colorectal cancer or age at its diagnosis

Author: Jarvik, Gail P., primary, Wang, Xiaoliang, additional, Fontanillas, Pierre, additional, Kim, Esther, additional, Chanprasert, Sirisak, additional, Gordon, Adam S., additional, Bastarache, Lisa, additional, Kowdley, Kris V., additional, Harrison, Tabitha, additional, Rosenthal, Elisabeth A., additional, Stanaway, Ian B., additional, Bézieau, Stéphane, additional, Weinstein, Stephanie J., additional, Newcomb, Polly A., additional, Casey, Graham, additional, Platz, Elizabeth A., additional, Visvanathan, Kala, additional, Le Marchand, Loic, additional, Ulrich, Cornelia M., additional, Hardikar, Sheetal, additional, Li, Christopher I., additional, van Duijnhoven, Franzel J.B., additional, Gsur, Andrea, additional, Campbell, Peter T., additional, Moreno, Victor, additional, Vodička, Pavel, additional, Brenner, Hermann, additional, Chang-Claude, Jenny, additional, Hoffmeister, Michael, additional, Slattery, Martha L., additional, Gunter, Marc J., additional, Aglago, Elom K., additional, Castellví-Bel, Sergi, additional, Kweon, Sun-Seog, additional, Chan, Andrew T., additional, Li, Li, additional, Zheng, Wei, additional, Bishop, D. Timothy, additional, Giles, Graham G., additional, Rennert, Gad, additional, Offit, Kenneth, additional, Keku, Temitope O., additional, Woods, Michael O., additional, Hampe, Jochen, additional, Van Guelpen, Bethan, additional, Gallinger, Steven J., additional, de la Chapelle, Albert, additional, Hampel, Heather, additional, Berndt, Sonja I., additional, Tangen, Catherine M., additional, Lindblom, Annika, additional, Wolk, Alicja, additional, Burnett-Hartman, Andrea, additional, Wu, Anna H., additional, White, Emily, additional, Gruber, Stephen B., additional, Jenkins, Mark A., additional, Mountain, Joanna, additional, Peters, Ulrike, additional, and Crosslin, David R., additional
Published: 2020
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231. Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk

Author: Thomas, Minta, primary, Sakoda, Lori C., additional, Hoffmeister, Michael, additional, Rosenthal, Elisabeth A., additional, Lee, Jeffrey K., additional, van Duijnhoven, Franzel J.B., additional, Platz, Elizabeth A., additional, Wu, Anna H., additional, Dampier, Christopher H., additional, de la Chapelle, Albert, additional, Wolk, Alicja, additional, Joshi, Amit D., additional, Burnett-Hartman, Andrea, additional, Gsur, Andrea, additional, Lindblom, Annika, additional, Castells, Antoni, additional, Win, Aung Ko, additional, Namjou, Bahram, additional, Van Guelpen, Bethany, additional, Tangen, Catherine M., additional, He, Qianchuan, additional, Li, Christopher I., additional, Schafmayer, Clemens, additional, Joshu, Corinne E., additional, Ulrich, Cornelia M., additional, Bishop, D. Timothy, additional, Buchanan, Daniel D., additional, Schaid, Daniel, additional, Drew, David A., additional, Muller, David C., additional, Duggan, David, additional, Crosslin, David R., additional, Albanes, Demetrius, additional, Giovannucci, Edward L., additional, Larson, Eric, additional, Qu, Flora, additional, Mentch, Frank, additional, Giles, Graham G., additional, Hakonarson, Hakon, additional, Hampel, Heather, additional, Stanaway, Ian B., additional, Figueiredo, Jane C., additional, Huyghe, Jeroen R., additional, Minnier, Jessica, additional, Chang-Claude, Jenny, additional, Hampe, Jochen, additional, Harley, John B., additional, Visvanathan, Kala, additional, Curtis, Keith R., additional, Offit, Kenneth, additional, Li, Li, additional, Le Marchand, Loic, additional, Vodickova, Ludmila, additional, Gunter, Marc J., additional, Jenkins, Mark A., additional, Slattery, Martha L., additional, Lemire, Mathieu, additional, Woods, Michael O., additional, Song, Mingyang, additional, Murphy, Neil, additional, Lindor, Noralane M., additional, Dikilitas, Ozan, additional, Pharoah, Paul D.P., additional, Campbell, Peter T., additional, Newcomb, Polly A., additional, Milne, Roger L., additional, MacInnis, Robert J., additional, Castellví-Bel, Sergi, additional, Ogino, Shuji, additional, Berndt, Sonja I., additional, Bézieau, Stéphane, additional, Thibodeau, Stephen N., additional, Gallinger, Steven J., additional, Zaidi, Syed H., additional, Harrison, Tabitha A., additional, Keku, Temitope O., additional, Hudson, Thomas J., additional, Vymetalkova, Veronika, additional, Moreno, Victor, additional, Martín, Vicente, additional, Arndt, Volker, additional, Wei, Wei-Qi, additional, Chung, Wendy, additional, Su, Yu-Ru, additional, Hayes, Richard B., additional, White, Emily, additional, Vodicka, Pavel, additional, Casey, Graham, additional, Gruber, Stephen B., additional, Schoen, Robert E., additional, Chan, Andrew T., additional, Potter, John D., additional, Brenner, Hermann, additional, Jarvik, Gail P., additional, Corley, Douglas A., additional, Peters, Ulrike, additional, and Hsu, Li, additional
Published: 2020
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232. Abstract LB-161: A comparison of dietary factors between early-onset and late-onset colorectal cancer patients

Author: Burnett-Hartman, Andrea N., primary, Ton, Mimi (Trucmai), additional, He, Chad (Qianchuan), additional, Malen, Rachel C., additional, Phipps, Amanda I., additional, Labadie, Julia D., additional, Feigelson, Heather Spencer, additional, and Newcomb, Polly A., additional
Published: 2020
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233. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, Jeroen R, primary, Harrison, Tabitha A, additional, Bien, Stephanie A, additional, Hampel, Heather, additional, Figueiredo, Jane C, additional, Schmit, Stephanie L, additional, Conti, David V, additional, Chen, Sai, additional, Qu, Conghui, additional, Lin, Yi, additional, Barfield, Richard, additional, Baron, John A, additional, Cross, Amanda J, additional, Diergaarde, Brenda, additional, Duggan, David, additional, Harlid, Sophia, additional, Imaz, Liher, additional, Kang, Hyun Min, additional, Levine, David M, additional, Perduca, Vittorio, additional, Perez-Cornago, Aurora, additional, Sakoda, Lori C, additional, Schumacher, Fredrick R, additional, Slattery, Martha L, additional, Toland, Amanda E, additional, van Duijnhoven, Franzel JB, additional, Van Guelpen, Bethany, additional, Arndt, Volker, additional, Agudo, Antonio, additional, Albanes, Demetrius, additional, Alonso, M Henar, additional, Anderson, Kristin, additional, Arnau-Collell, Coral, additional, Banbury, Barbara, additional, Bassik, Michael C, additional, Berndt, Sonja I, additional, Bézieau, Stéphane, additional, Bishop, D Timothy, additional, Boehm, Juergen, additional, Boeing, Heiner, additional, Boutron-Ruault, Marie-Christine, additional, Brenner, Hermann, additional, Brezina, Stefanie, additional, Buch, Stephan, additional, Buchanan, Daniel D, additional, Burnett-Hartman, Andrea, additional, Caan, Bette J, additional, Campbell, Peter T, additional, Carr, Prudence, additional, Castells, Antoni, additional, Castellví-Bel, Sergi, additional, Chan, Andrew T, additional, Chang-Claude, Jenny, additional, Chanock, Stephen J, additional, Curtis, Keith R, additional, de la Chapelle, Albert, additional, Easton, Douglas F, additional, English, Dallas R, additional, Feskens, Edith JM, additional, Gala, Manish, additional, Gallinger, Steven J, additional, Gauderman, W James, additional, Giles, Graham G, additional, Goodman, Phyllis J, additional, Grady, William M, additional, Grove, John S, additional, Gsur, Andrea, additional, Gunter, Marc J, additional, Haile, Robert W, additional, Hampe, Jochen, additional, Hoffmeister, Michael, additional, Hopper, John L, additional, Hsu, Wan-Ling, additional, Huang, Wen-Yi, additional, Hudson, Thomas J, additional, Jenab, Mazda, additional, Jenkins, Mark A, additional, Joshi, Amit D, additional, Keku, Temitope O, additional, Kooperberg, Charles, additional, Kuhn, Tilman, additional, Küry, Sébastien, additional, Le Marchand, Loic, additional, Lejbkowicz, Flavio, additional, Li, Christopher I, additional, Li, Li, additional, Lieb, Wolfgang, additional, Lindblom, Annika, additional, Lindor, Noralane M, additional, Männistö, Satu, additional, Markowitz, Sanford D, additional, Milne, Roger L, additional, Moreno, Lorena, additional, Murphy, Neil, additional, Nassir, Rami, additional, Offit, Kenneth, additional, Ogino, Shuji, additional, Panico, Salvatore, additional, Parfrey, Patrick S, additional, Pearlman, Rachel, additional, Pharoah, Paul D P, additional, Phipps, Amanda I, additional, Platz, Elizabeth A, additional, Potter, John D, additional, Prentice, Ross L, additional, Qi, Lihong, additional, Raskin, Leon, additional, Rennert, Gad, additional, Rennert, Hedy S, additional, Riboli, Elio, additional, Schafmayer, Clemens, additional, Schoen, Robert E, additional, Seminara, Daniela, additional, Song, Mingyang, additional, Su, Yu-Ru, additional, Tangen, Catherine M, additional, Thibodeau, Stephen N, additional, Thomas, Duncan C, additional, Trichopoulou, Antonia, additional, Ulrich, Cornelia M, additional, Visvanathan, Kala, additional, Vodicka, Pavel, additional, Vodickova, Ludmila, additional, Vymetalkova, Veronika, additional, Weigl, Korbinian, additional, Weinstein, Stephanie J, additional, White, Emily, additional, Wolk, Alicja, additional, Woods, Michael O, additional, Wu, Anna H, additional, Abecasis, Goncalo R, additional, Nickerson, Deborah A, additional, Scacheri, Peter C, additional, Kundaje, Anshul, additional, Casey, Graham, additional, Gruber, Stephen B, additional, Hsu, Li, additional, Moreno, Victor, additional, Hayes, Richard B, additional, Newcomb, Polly A, additional, and Peters, Ulrike, additional
Published: 2020
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234. A population-based survey to assess the association between cannabis and quality of life among colorectal cancer survivors

Author: Calcaterra, Susan L., primary, Burnett-Hartman, Andrea N., additional, Powers, J. David, additional, Corley, Douglas A., additional, McMullen, Carmit M., additional, Pawloski, Pamala A., additional, and Feigelson, Heather Spencer, additional
Published: 2020
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235. Associations between molecular characteristics of colorectal serrated polyps and subsequent advanced colorectal neoplasia

Author: Hua, Xinwei, primary, Newcomb, Polly A., additional, Chubak, Jessica, additional, Malen, Rachel C., additional, Ziebell, Rebecca, additional, Kamineni, Aruna, additional, Zhu, Lee-Ching, additional, Upton, Melissa P., additional, Wurscher, Michelle A., additional, Thomas, Sushma S., additional, Newman, Hana, additional, Hardikar, Sheetal, additional, and Burnett-Hartman, Andrea N., additional
Published: 2020
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236. A Population-Based Survey to Assess the Association between Cannabis and Quality of Life among Colorectal Cancer Survivors

Author: Calcaterra, Susan, primary, Burnett-Hartman, Andrea N., additional, Powers, J. David, additional, Corley, Douglas A, additional, McMullen, Carmit M, additional, Pawloski, Pamala A., additional, and Feigelson, Heather Spencer, additional
Published: 2020
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237. Lessons Learned to Promote Lung Cancer Screening and Preempt Worsening Lung Cancer Disparities

Author: Burnett-Hartman, Andrea N., primary and Wiener, Renda Soylemez, additional
Published: 2020
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238. Cumulative Burden of Colorectal Cancer–Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer

Author: Archambault, Alexi N., primary, Su, Yu-Ru, additional, Jeon, Jihyoun, additional, Thomas, Minta, additional, Lin, Yi, additional, Conti, David V., additional, Win, Aung Ko, additional, Sakoda, Lori C., additional, Lansdorp-Vogelaar, Iris, additional, Peterse, Elisabeth F.P., additional, Zauber, Ann G., additional, Duggan, David, additional, Holowatyj, Andreana N., additional, Huyghe, Jeroen R., additional, Brenner, Hermann, additional, Cotterchio, Michelle, additional, Bézieau, Stéphane, additional, Schmit, Stephanie L., additional, Edlund, Christopher K., additional, Southey, Melissa C., additional, MacInnis, Robert J., additional, Campbell, Peter T., additional, Chang-Claude, Jenny, additional, Slattery, Martha L., additional, Chan, Andrew T., additional, Joshi, Amit D., additional, Song, Mingyang, additional, Cao, Yin, additional, Woods, Michael O., additional, White, Emily, additional, Weinstein, Stephanie J., additional, Ulrich, Cornelia M., additional, Hoffmeister, Michael, additional, Bien, Stephanie A., additional, Harrison, Tabitha A., additional, Hampe, Jochen, additional, Li, Christopher I., additional, Schafmayer, Clemens, additional, Offit, Kenneth, additional, Pharoah, Paul D., additional, Moreno, Victor, additional, Lindblom, Annika, additional, Wolk, Alicja, additional, Wu, Anna H., additional, Li, Li, additional, Gunter, Marc J., additional, Gsur, Andrea, additional, Keku, Temitope O., additional, Pearlman, Rachel, additional, Bishop, D. Timothy, additional, Castellví-Bel, Sergi, additional, Moreira, Leticia, additional, Vodicka, Pavel, additional, Kampman, Ellen, additional, Giles, Graham G., additional, Albanes, Demetrius, additional, Baron, John A., additional, Berndt, Sonja I., additional, Brezina, Stefanie, additional, Buch, Stephan, additional, Buchanan, Daniel D., additional, Trichopoulou, Antonia, additional, Severi, Gianluca, additional, Chirlaque, María-Dolores, additional, Sánchez, Maria-José, additional, Palli, Domenico, additional, Kühn, Tilman, additional, Murphy, Neil, additional, Cross, Amanda J., additional, Burnett-Hartman, Andrea N., additional, Chanock, Stephen J., additional, de la Chapelle, Albert, additional, Easton, Douglas F., additional, Elliott, Faye, additional, English, Dallas R., additional, Feskens, Edith J.M., additional, FitzGerald, Liesel M., additional, Goodman, Phyllis J., additional, Hopper, John L., additional, Hudson, Thomas J., additional, Hunter, David J., additional, Jacobs, Eric J., additional, Joshu, Corinne E., additional, Küry, Sébastien, additional, Markowitz, Sanford D., additional, Milne, Roger L., additional, Platz, Elizabeth A., additional, Rennert, Gad, additional, Rennert, Hedy S., additional, Schumacher, Fredrick R., additional, Sandler, Robert S., additional, Seminara, Daniela, additional, Tangen, Catherine M., additional, Thibodeau, Stephen N., additional, Toland, Amanda E., additional, van Duijnhoven, Franzel J.B., additional, Visvanathan, Kala, additional, Vodickova, Ludmila, additional, Potter, John D., additional, Männistö, Satu, additional, Weigl, Korbinian, additional, Figueiredo, Jane, additional, Martín, Vicente, additional, Larsson, Susanna C., additional, Parfrey, Patrick S., additional, Huang, Wen-Yi, additional, Lenz, Heinz-Josef, additional, Castelao, Jose E., additional, Gago-Dominguez, Manuela, additional, Muñoz-Garzón, Victor, additional, Mancao, Christoph, additional, Haiman, Christopher A., additional, Wilkens, Lynne R., additional, Siegel, Erin, additional, Barry, Elizabeth, additional, Younghusband, Ban, additional, Van Guelpen, Bethany, additional, Harlid, Sophia, additional, Zeleniuch-Jacquotte, Anne, additional, Liang, Peter S., additional, Du, Mengmeng, additional, Casey, Graham, additional, Lindor, Noralane M., additional, Le Marchand, Loic, additional, Gallinger, Steven J., additional, Jenkins, Mark A., additional, Newcomb, Polly A., additional, Gruber, Stephen B., additional, Schoen, Robert E., additional, Hampel, Heather, additional, Corley, Douglas A., additional, Hsu, Li, additional, Peters, Ulrike, additional, and Hayes, Richard B., additional
Published: 2020
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239. 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, Neil, primary, Carreras-Torres, Robert, additional, Song, Mingyang, additional, Chan, Andrew T., additional, Martin, Richard M., additional, Papadimitriou, Nikos, additional, Dimou, Niki, additional, Tsilidis, Konstantinos K., additional, Banbury, Barbara, additional, Bradbury, Kathryn E., additional, Besevic, Jelena, additional, Rinaldi, Sabina, additional, Riboli, Elio, additional, Cross, Amanda J., additional, Travis, Ruth C., additional, Agnoli, Claudia, additional, Albanes, Demetrius, additional, Berndt, Sonja I., additional, Bézieau, Stéphane, additional, Bishop, D. Timothy, additional, Brenner, Hermann, additional, Buchanan, Daniel D., additional, Onland-Moret, N. Charlotte, additional, Burnett-Hartman, Andrea, additional, Campbell, Peter T., additional, Casey, Graham, additional, Castellví-Bel, Sergi, additional, Chang-Claude, Jenny, additional, Chirlaque, María-Dolores, additional, de la Chapelle, Albert, additional, English, Dallas, additional, Figueiredo, Jane C., additional, Gallinger, Steven J., additional, Giles, Graham G., additional, Gruber, Stephen B., additional, Gsur, Andrea, additional, Hampe, Jochen, additional, Hampel, Heather, additional, Harrison, Tabitha A., additional, Hoffmeister, Michael, additional, Hsu, Li, additional, Huang, Wen-Yi, additional, Huyghe, Jeroen R., additional, Jenkins, Mark A., additional, Keku, Temitope O., additional, Kühn, Tilman, additional, Kweon, Sun-Seog, additional, Le Marchand, Loic, additional, Li, Christopher I., additional, Li, Li, additional, Lindblom, Annika, additional, Martín, Vicente, additional, Milne, Roger L., additional, Moreno, Victor, additional, Newcomb, Polly A., additional, Offit, Kenneth, additional, Ogino, Shuji, additional, Ose, Jennifer, additional, Perduca, Vittorio, additional, Phipps, Amanda I., additional, Platz, Elizabeth A., additional, Potter, John D., additional, Qu, Conghui, additional, Rennert, Gad, additional, Sakoda, Lori C., additional, Schafmayer, Clemens, additional, Schoen, Robert E., additional, Slattery, Martha L., additional, Tangen, Catherine M., additional, Ulrich, Cornelia M., additional, van Duijnhoven, Franzel J.B., additional, Van Guelpen, Bethany, additional, Visvanathan, Kala, additional, Vodicka, Pavel, additional, Vodickova, Ludmila, additional, Vymetalkova, Veronika, additional, Wang, Hansong, additional, White, Emily, additional, Wolk, Alicja, additional, Woods, Michael O., additional, Wu, Anna H., additional, Zheng, Wei, additional, Peters, Ulrike, additional, and Gunter, Marc J., additional
Published: 2020
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240. Evaluating Lung Cancer Screening Across Diverse Healthcare Systems: A Process Model from the Lung PROSPR Consortium

Author: Rendle, Katharine A., primary, Burnett-Hartman, Andrea N., additional, Neslund-Dudas, Christine, additional, Greenlee, Robert T., additional, Honda, Stacey, additional, Elston Lafata, Jennifer, additional, Marcus, Pamela M., additional, Cooley, Mary E., additional, Vachani, Anil, additional, Meza, Rafael, additional, Oshiro, Caryn, additional, Simoff, Michael J., additional, Schnall, Mitchell D., additional, Beaber, Elisabeth F., additional, Doria-Rose, V. Paul, additional, Doubeni, Chyke A., additional, and Ritzwoller, Debra P., additional
Published: 2020
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241. Real-world Clinical Implementation of Lung Cancer Screening—Evaluating Processes to Improve Screening Guidelines-Concordance

Author: Carroll, Nikki M., primary, Burnett-Hartman, Andrea N., additional, Joyce, Caroline A., additional, Kinnard, William, additional, Harker, Eric J., additional, Hall, Virginia, additional, Steiner, Julie S., additional, Blum-Barnett, Erica, additional, and Ritzwoller, Debra P., additional
Published: 2020
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242. A Population-Based Survey to Assess Cannabis on Quality of Life among Colorectal Cancer Survivors

Author: Calcaterra, Susan, primary, Burnett-Hartman, Andrea N., additional, Powers, J. David, additional, Corley, Douglas A, additional, McMullen, Carmit M, additional, Pawloski, Pamala A., additional, and Feigelson, Heather Spencer, additional
Published: 2020
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243. Return of Research-Related Genetic Test Results and Genetic Discrimination Concerns: Facilitators and Barriers of Genetic Research Participation in Diverse Groups

Author: Burnett-Hartman, Andrea N., primary, Blum-Barnett, Erica, additional, Carroll, Nikki M., additional, Madrid, Sarah D., additional, Jonas, Cabell, additional, Janes, Kristen, additional, Alvarado, Monica, additional, Bedoy, Ruth, additional, Paolino, Valerie, additional, Aziz, Nazneen, additional, and McGlynn, Elizabeth A., additional
Published: 2020
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244. Challenges With Colorectal Cancer Family History Assessment—Motivation to Translate Polygenic Risk Scores Into Practice

Author: Burnett-Hartman, Andrea N., primary, Newcomb, Polly A., additional, and Peters, Ulrike, additional
Published: 2020
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245. Clinical Molecular Marker Testing Data Capture to Promote Precision Medicine Research Within the Cancer Research Network

Author: Burnett-Hartman, Andrea N., primary, Udaltsova, Natalia, additional, Kushi, Lawrence H., additional, Neslund-Dudas, Christine, additional, Rahm, Alanna Kulchak, additional, Pawloski, Pamala A., additional, Corley, Douglas A., additional, Knerr, Sarah, additional, Feigelson, Heather Spencer, additional, Hunter, Jessica Ezzell, additional, Tabano, David C., additional, Epstein, Mara M., additional, Honda, Stacey A., additional, Ter-Minassian, Monica, additional, Lynch, Julie A., additional, and Lu, Christine Y., additional
Published: 2019
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246. Abstract 881: Benchmarking genome-wide polygenic risk score development techniques in colorectal cancer risk prediction

Author: Robert E. Schoen, Heather Hampel, Graham Casey, Douglas A. Corley, Lori C. Sakoda, Victor Moreno, Mark A. Jenkins, Hermann Brenner, Tabitha A. Harrison, Jenny Chang-Claude, Polly A. Newcomb, Andrea N. Burnett-Hartman, Minta Thomas, Stephen B. Gruber, Marc J. Gunter, Jeffrey Lee, Elisabeth A. Rosenthal, Andrew T. Chan, Richard B. Hayes, Steven Gallinger, Gail P. Jarvik, Ulrike Peters, and Li Hsu
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, business.industry, Internal medicine, medicine, Polygenic risk score, Benchmarking, medicine.disease, business, Genome
Abstract: Colorectal cancer (CRC) is a leading cause of cancer death, yet many CRC deaths are preventable via CRC screening. Currently only age and family history are used to define screening eligibility. However, CRC risk varies substantially in the population. In recent years polygenic risk scores (PRS) have gained attention as powerful risk prediction tool to personalize interventions. PRS provides a quantitative measure of an individual's inherited risk based on the cumulative effect of many genetic risk variants. Here, we benchmark several genome wide PRS techniques to select the best performing models in CRC risk prediction. We built CRC risk prediction models that incorporate genome-wide genotype data from large-scale research studies (55,105 cases and 65,079 controls, European ancestries) with the imputed genetic data on over 40 million variants. The risk prediction models were externally evaluated in the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, including 101,987 genotyped individuals within the Kaiser Permanente Northern California (KPNC) integrated healthcare delivery system. We built genome-wide PRS using various methods including known CRC risk variants, thresholding and pruning followed by machine learning approaches (ML), LDpred, improved LDpred2, SBayesR, PRS-CS, Lassosum and empirical Bayes. Among 55,033 individuals of European ancestry in the GERA cohort, we evaluated the performance of models in terms of the age and sex-adjusted AUC. We showed that LDpred, LDpred2, LDpred2-sparse, SBayesR and PRS-CS perform equally well in terms of discriminatory accuracy (AUC=0.65). In addition, the PRS developed using the above-mentioned techniques identified the top 30% of the GERA European population has a hazard ratio estimate of ~2.2 on CRC risk, which is comparable to that for having an affected first-degree relative. The developed CRC PRSs will provide way for risk-stratified CRC screening and other targeted interventions. PRS derivation methodsNo. of variantsAUC(1,311 cases and 53,722 controls)Hazard ratio estimates (CI)Top 30% of population vs. remainingKnown variants1400.631.92 (1.75-2.23)PT Clumping + ML (Ridge)10,0000.631.94 (1.72-2.19)LDpred1.2M0.652.20 (1.94-2.47)LDPred21.2M0.652.20 (1.93-2.45)LDpred2 Sparse530K0.652.20 (1.90-2.41)SBayesR1.2M0.652.20 (1.88-2.38)PRS-CS1.2M0.652.20 (1.91-2.43)Lassosum1.2M0.621.76 (1.56-2.58)EBPRS1.2M0.621.81 (1.66-2.11)AUC based on family history in GERA cohort is 0.54 Citation Format: Minta Thomas, Lori C Sakoda, Jeffrey K Lee, Mark A Jenkins, Andrea Burnett-Hartman, Heather Hampel, Elisabeth A Rosenthal, Hermann Brenner, Jenny Chang-Claude, Marc J Gunter, Polly A Newcomb, Steven Gallinger, Tabitha A Harrison, Graham Casey, Victor Moreno, Gail P Jarvik, Stephen B Gruber, Robert E Schoen, Andrew T Chan, Richard B Hayes, Douglas A Corley, Ulrike Peters, Li Hsu. Benchmarking genome-wide polygenic risk score development techniques in colorectal cancer risk prediction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 881.
Published: 2021

247. Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival

Author: Dennis J. Ahnen, Polly A. Newcomb, Stacey A. Cohen, Andrea N. Burnett-Hartman, Noralane M. Lindor, Amanda I. Phipps, John A. Baron, Sheetal Hardikar, Xinwei Hua, Jonathan M. Kocarnik, and Scott V. Adams
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Population, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Biomarkers, Tumor, medicine, Humans, Registries, education, Survival rate, Aged, Proportional Hazards Models, education.field_of_study, Aspirin, Proportional hazards model, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Hazard ratio, Cancer, Microsatellite instability, ORIGINAL REPORTS, Middle Aged, medicine.disease, digestive system diseases, Surgery, Survival Rate, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, Colorectal Neoplasms, business, medicine.drug
Abstract: Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia. Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up. Survival outcomes were completed through linkage to national death registries. BRAF- and KRAS-mutation status, microsatellite instability, and CpG island methylator phenotype were also evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for overall survival (OS) and CRC-specific survival. Results After a median of 10.8 years of follow-up since diagnosis, 381 deaths (100 as a result of CRC) were observed. Compared with nonusers, postdiagnostic aspirin-only users had more favorable OS (HR, 0.75; 95% CI, 0.59 to 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 to 0.71), especially among those who initiated aspirin use (OS: HR, 0.64; 95% CI, 0.47 to 0.86; CRC-specific survival: HR, 0.40; 95% CI, 0.20 to 0.80). The association between any NSAID use after diagnosis and OS differed significantly by KRAS-mutation status ( Pinteraction = .01). Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 to 0.80) but not among those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 to 1.96). Conclusion Among long-term CRC survivors, regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors.
Published: 2017

248. Lessons Learned to Promote Lung Cancer Screening and Preempt Worsening Lung Cancer Disparities

Author: Renda Soylemez Wiener and Andrea N Burnett-Hartman
Subjects: Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, Extramural, business.industry, Editorials, MEDLINE, Critical Care and Intensive Care Medicine, medicine.disease, Internal medicine, medicine, Lung cancer, business, Mass screening, Lung cancer screening
Published: 2020

249. The Kaiser Permanente Research Bank Cancer Cohort: a collaborative resource to improve cancer care and survivorship.

Author: Feigelson, Heather Spencer, Clarke, Christina L., Van Den Eeden, Stephen K., Weinmann, Sheila, Burnett-Hartman, Andrea N., Rowell, Sarah, Scott, Shauna Goldberg, White, Larissa L., Ter-Minassian, Monica, Honda, Stacey A. A., Young, Deborah R., Kamineni, Aruna, Chinn, Terrence, Lituev, Alexander, Bauck, Alan, and McGlynn, Elizabeth A.
Subjects: CANCER treatment, ELECTRONIC health records, SURVIVAL rate, CANCER research, SURVIVAL analysis (Biometry)
Abstract: Background: The Kaiser Permanente Research Bank (KPRB) is collecting biospecimens and surveys linked to electronic health records (EHR) from approximately 400,000 adult KP members. Within the KPRB, we developed a Cancer Cohort to address issues related to cancer survival, and to understand how genetic, lifestyle and environmental factors impact cancer treatment, treatment sequelae, and prognosis. We describe the Cancer Cohort design and implementation, describe cohort characteristics after 5 years of enrollment, and discuss future directions.Methods: Cancer cases are identified using rapid case ascertainment algorithms, linkage to regional or central tumor registries, and direct outreach to KP members with a history of cancer. Enrollment is primarily through email invitation. Participants complete a consent form, survey, and donate a blood or saliva sample. All cancer types are included.Results: As of December 31, 2020, the cohort included 65,225 cases (56% female, 44% male) verified in tumor registries. The largest group was diagnosed between 60 and 69 years of age (31%) and are non-Hispanic White (83%); however, 10,076 (16%) were diagnosed at ages 18-49 years, 4208 (7%) are Hispanic, 3393 (5%) are Asian, and 2389 (4%) are Black. The median survival time is 14 years. Biospecimens are available on 98% of the cohort.Conclusions: The KPRB Cancer Cohort is designed to improve our understanding of treatment efficacy and factors that contribute to long-term cancer survival. The cohort's diversity - with respect to age, race/ethnicity and geographic location - will facilitate research on factors that contribute to cancer survival disparities. [ABSTRACT FROM AUTHOR]
Published: 2022
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250. The association of bowel function, participation in life activities, and quality of life in rectal cancer survivors.

Author: Bulkley, Joanna E., McMullen, Carmit K., Rawlings, Andreea M., Krouse, Robert S., Francisco, Melanie C., Sterrett, Andrew T., Burnett-Hartman, Andrea N., Pawloski, Pamala A., Corley, Douglas A., Colwell, Janice C., and Feigelson, Heather Spencer
Subjects: RECTAL cancer, CANCER survivors, FINANCIAL stress, ELECTRONIC health records, PARTICIPATION
Abstract: Purpose: To evaluate whether limited participation in life activities is associated with quality of life (QOL) in rectal cancer survivors, and if so, whether this association is independent of bowel function difficulties. Methods: We surveyed rectal cancer survivors from four healthcare systems about their QOL, bowel function, and participation in life activities. Additional demographic and clinical variables were extracted from the electronic health record. We examined independent associations between bowel function, participation in life activities, and QOL, controlling for potential confounders. We also identified factors, including ostomy status, that correlate with participation in life activities. Results: Of the 527 respondents, 52% were male, 80% were non-Hispanic white, and the mean age was 63. In fully adjusted models for all rectal cancer survivors, participation in life activities was positively associated with QOL, while bowel function was not. Bowel function retained an independent association with QOL for those who previously had an ostomy and were therefore more likely to have a low rectal anastomosis. Lower participation in life activities was correlated with lower self-reported physical and cognitive function, younger age, financial difficulty, and being non-Hispanic white. Conclusions: Rectal cancer survivors' participation in life activities was strongly associated with QOL, even when controlling for numerous confounders, including bowel function. Identifying ways to improve participation in life activities may be critical to developing rehabilitative and other supportive interventions that optimize QOL among rectal cancer survivors. [ABSTRACT FROM AUTHOR]
Published: 2022
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