Elucidating the Risk of Colorectal Cancer for Variants in Hereditary Colorectal Cancer Genes.

"Conflicts of interest: These authors disclose the following: After the completion of the submitted work, Xiaoliang Wang has been employed by Flatiron Health, Inc, and reports being a stockholder in Roche. After the completion of the submitted work, Stephanie A. Bien is employed by and has stocks in Adaptive Biotechnologies. Heather Hampel has served on the scientific advisory board for Invitae Genetics, Genome Medical, and Promega and holds stock/stock options in Genome Medical and GI OnDemand. Anshul Kundaje has been a paid consultant with Illumina Inc, served on the scientific advisory board of Open Targets (GSK), and is the scientific cofounder of Ravel Biotechnology Inc. Victor Moreno reports research projects with Aniling. Rish K. Pai has received consulting fees from Alimentiv Inc, Allergan, and Verily. Zsofia K. Stadler’s immediate family member serves as a consultant for Alcon, Adverum, Neurogene, Gyroscope, and RegenexBio. Stephen B. Gruber is the cofounder of Brogent International LLC, unrelated to present work. The remaining authors disclose no conflicts."

"Funding This work was funded by the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute (NCI), National Institutes of Health (NIH), and US Department of Health and Human Services (R01 CA059045, U01 CA164930, R01201407, R01CA248857, R01 CA206279, R01 CA244588, and R21 CA230486). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Scientific Computing Infrastructure at Fred Hutchinson Cancer Center funded by Office of Research Infrastructure Programs (ORIP) grant S10OD028685. ASTERISK: a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). The ATBC Study is supported by the Intramural Research Program of the NCI, NIH, and US Department of Health and Human Services. BWHS is funded by NIH U01CA164974. CLUE II funding was from the NCI (U01 CA86308, Early Detection Research Network; P30 CA006973), National Institute on Aging (U01 AG18033), and the American Institute for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Maryland Cancer Registry Cancer data were provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, and Maryland Department of Health, with funding from the State of Maryland and the Maryland Cigarette Restitution Fund. The collection and availability of cancer registry data are also supported by Cooperative Agreement NU58DP006333, funded by the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the US Department of Health and Human Services. ColoCare: This work was supported by the NIH (grant numbers R01 CA189184 [Christopher Li and Cornelia M. Ulrich], U01 CA206110 [Cornelia M. Ulrich, Christopher Li, Erin Siegel, Jane C. Figueiredo, and Graham Colditz], R01 CA207371 [Cornelia M. Ulrich and Christopher Li]), the Matthias LackasFoundation, the German Consortium for Translational Cancer Research, and the European Union TRANSCAN initiative. The Colon Cancer Family Registry (CCFR) (https://www.coloncfr.org) is supported in part by funding from the NCI, NIH (award U01 CA167551). Support for case ascertainment was provided in part from the Surveillance, Epidemiology, and End Results (SEER) Program; the following US state cancer registries: Arizona, Colorado, Minnesota, North Carolina, and New Hampshire; and the Victoria Cancer Registry (Australia) and Ontario Cancer Registry (Canada). The CCFR Set-1 (Illumina 1M/1M-Duo) and Set-2 (Illumina Omni1-Quad) scans were supported by NIH awards U01 CA122839 and R01 CA143237 (to Graham Casey). The CCFR Set-3 (Affymetrix Axiom CORECT Set array) was supported by NIH award U19 CA148107 and R01 CA81488 (to Stephen B. Gruber). The CCFR Set-4 (Illumina OncoArray 600K SNP array) was supported by NIH award U19 CA148107 (to Stephen B. Gruber) and by the Center for Inherited Disease Research, which is funded by the NIH to Johns Hopkins University, contract number HHSN268201200008I. Additional funding for the OFCCR/ARCTIC was through a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society (to Steven Gallinger), and through generous support from the Ontario Ministry of Research and Innovation. The SFCCR Illumina HumanCytoSNP array was supported in part through NCI/NIH awards U01/U24 CA074794 and R01 CA076366 (to Polly A. Newcomb). The content of this manuscript does not necessarily reflect the views or policies of the NCI, NIH, or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government, any cancer registry, or the CCFR. COLON: The COLON study is sponsored by Wereld Kanker Onderzoek Fonds, including funds from grant 2014/1179 as part of the World Cancer Research Fund International Regular Grant Programme, by Alpe d’Huzes and the Dutch Cancer Society (UM 2012–5653, UW 2013–5927, UW2015–7946), by TRANSCAN (JTC2012-MetaboCCC, JTC2013-FOCUS) and by RegioDeal Foodvalley (grant number 162135). The Nqplus study is sponsored by a ZorgOnderzoek Nederland/Medical Sciences (ZonMW) investment grant (98–10030); by the Prevention of Diabetes Through Lifestyle Intervention and Population Studies in Europe and Around the World (PREVIEW) project, which received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant number 312057; by funds from Top Institute Food and Nutrition (cardiovascular health theme), a public–private partnership on precompetitive research in food and nutrition; and by FOODBALL, the Food Biomarker Alliance, a project from Joint Program Initiative Healthy Diet for a Healthy Life. COLO2&3: NIH (R01 CA60987). Colorectal Cancer Transdisciplinary (CORECT) study: The CORECT study was supported by the NCI/NIH, US Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350, P01 CA196569, R01 CA201407, U19 CA148107, R01 CA242218) and National Institutes of Environmental Health Sciences, NIH (grant number T32 ES013678). CORSA: The CORSA study was funded by Austrian Research Funding Agency BRIDGE (grant 829675, to Andrea Gsur) and the “Herzfelder’sche Familienstiftung” (grant to Andrea Gsur) and was supported by European Cooperation in Science and Technology (COST) Action BM1206. Cancer Prevention Study-II (CPS-II): The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. This study was conducted with institutional review board approval. Colorectal Cancer Genetics & Genomics (CRCGEN): Colorectal Cancer Genetics and Genomics, Spanish study was supported by Instituto de Salud Carlos III, cofunded by European Regional Development Fund (FEDER) funds—A Way to Build Europe (grants PI14–613 and PI09–1286), the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723), Junta de Castilla y León (grant LE22A10–2), and Spanish Association Against Cancer Scientific Foundation grants POSTD037OBON and GCTRA18022MORE. Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncología de Catalunya, Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. Czech Republic CCS: This work was supported by the Grant Agency of the Czech Republic (20–03997S), by the grants AZV NV18/03/00199, and by Charles University grants Unce/Med/006 and Progress Q28/LF1. DACHS: This work was supported by the German Research Council (BR 1704/6–1, BR 1704/6–3, BR 1704/6–4, CH 117/1–1, HO 5117/2–1, HE 5998/2–1, KL 2354/3–1, RO 2270/8–1, and BR 1704/17–1); the Interdisciplinary Research Program of the National Center for Tumor Diseases, Germany; and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). DALS: NIH (R01 CA48998 to Martha L. Slattery). EDRN: This work is funded and supported by the NCI, EDRN grant U01 CA152753. EPIC: The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the National Institute for Health and Care Research (NIHR) Imperial Biomedical Research Center. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare, and Sports; Netherlands Cancer Registry; LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund; and Statistics Netherlands (Netherlands); Health Research Fund–Instituto de Salud Carlos III; Regional Governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra; and the Catalan Institute of Oncology (ICO), Spain; Swedish Cancer Society, Swedish Research Council, Region Skåne, and Region Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford) and Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPICOLON: This work was supported by grants from Fondo de Investigación Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, P111/00219, PI11/ 00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, PI20/00113, PI20/00226, Acción Transversal de Cáncer), Xunta de Galicia (PGIDIT07PXIB9101209PR), Ministerio de Economia y Competitividad (SAF07–64873, SAF 2010–19273, SAF2014–54453R), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), Beca Grupo de Trabajo “Oncología” (Asociación Española de Gastroenterología), Fundación Privada Olga Torres, FP7 CHIBCHA Consortium, Agència de Gestió d’Ajuts Universitaris i de Recerca (Generalitat de Catalunya, 2014SGR135, 2014SGR255, 2017SGR21, 2017SGR653), Catalan Tumour Bank Network (Pla Director d’Oncologia, Generalitat de Catalunya), PERIS (SLT002/16/00398, Genera"