ArticlemedRxiv : the preprint server for health sciences2026
Integrative screening identifies functional variants and VNTRs underlying GWAS signals at the 5p15.33 multi-cancer susceptibility locus.
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49 authors.
Aidan O'BrienLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0003-2188-4223
Hyunkyung KongLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Harsh PatelLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0002-9860-8254
Michelle HoLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Minal B PatelLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0009-0000-5511-5209
Jun ZhongLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0002-3700-9434
Mai XuLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Brenen W PapenbergLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0003-3734-3018
Katelyn E ConnellyLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0002-1693-5519
Irene CollinsLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Rebecca HennesseyLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0002-5283-6147
Rohit ThakurLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0001-6015-5993
Hayley SowardsLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Karen FunderburkLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Thong LuongLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0001-7534-1289
Oscar Florez-VargasLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0002-4393-2612
Timothy MyersLaboratory of Genetic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0001-8127-3446
Ashley JermusykLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Bryan GormanTrans-Divisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Wen LuoCancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Kristine JonesCancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0003-1584-8920
Sudipto DasCCR Protein and Metabolite Characterization Core (PMCC), Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA.ORCID 0009-0000-8325-0088
Pancreatic Cancer Cohort and Case-Control Consortia (PanScan/PanC4)
Melanoma Meta-Analysis Consortium, International Lung Cancer Consortium (ILCCO)
Qing LanOccupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Nathaniel RothmanOccupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
James D McKayInternational Agency for Research on Cancer, World Health Organization, Lyon, France.ORCID 0000-0002-1787-3874
Rayjean J HungLunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada.ORCID 0000-0002-4486-7496
Christopher I AmosDepartment of Internal Medicine, University of New Mexico, Albuquerque, NM.ORCID 0000-0002-8540-7023
Mark M IlesLeeds Institute for Data Analytics, University of Leeds, Leeds, UK.ORCID 0000-0002-2603-6509
Stella KoutrosOccupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.ORCID 0000-0001-5294-5485
Maria Teresa LandiTrans-Divisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0002-9727-7772
Matthew H LawStatistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD, 4006, Australia.ORCID 0000-0002-4303-8821
Rachael Z Stolzenberg-SolomonMetabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.
Brian M WolpinDepartment of Medical Oncology, Dana-Farber Harvard Cancer Center, USA.
Manal HassanDepartment of Gastrointestinal Medical Oncology, Division of Cancer Prevention and Population Sciences, MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0002-8413-449X
Alison P KleinDepartments of Oncology, Pathology and Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.ORCID 0000-0003-2737-8399
Samuel O AntwiDepartment of Quantitative Health Sciences, Division of Epidemiology,, Mayo Clinic, Jacksonville, FL, USA.
Nick OrrThe Johnston Cancer Research Centre, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.ORCID 0000-0003-2866-942X
Stephen J ChanockDivision of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0002-2324-3393
Sara LindströmDepartment of Epidemiology, University of Washington, Seattle, WA, USA.ORCID 0000-0002-7137-7281
Jason W HoskinsLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0001-6944-1996
Marc-Henri SternInserm U1339 UMR3666, DNA Repair and Uveal Melanoma (D.R.U.M.), Institut Curie, PSL Research University, Paris, France.
Thorkell AndressonCCR Protein and Metabolite Characterization Core (PMCC), Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Jianxin ShiBiostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0001-8606-4707
Ludmila Prokunina-OlssonLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0002-9622-2091
Jiyeon ChoiLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0002-0955-2384
Kevin M BrownLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0002-8558-6711
Laufey T AmundadottirLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.ORCID 0000-0003-1859-8971
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI SELWYN M VICKERS · 1985 to 2026
$347.4MVaccine FacilityP30CA016087 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI MARK Reid PHILIPS · 1985 to 2026
$83.1MSWOG NCORP Research BaseUG1CA189974 · NCI · THE HOPE FOUNDATION · PI CHARLES D. BLANKE, DAWN HERSHMAN · 2014 to 2026
$80.6MStatistical MethodsP01CA087969 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI ELIASSEN, A. HEATHER, TAMIMI, RULLA M · 2000 to 2019
$77.8MTumor Antigens for Individual Signatures and TherapyP50CA062924 · NCI · JOHNS HOPKINS UNIVERSITY · PI THOMPSON, ELIZABETH D · 1993 to 2022
$54.6MWOMEN'S HEALTH INITIATIVE - CLINICAL COORDINATING CENTER: TASK AREA B - LONG LIFE STUDY VISIT 2 LIMITED HOME VISIT75N92021D00001 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI ANDERSON, GARNET L. · 2021 to 2025
$52.0MUnderstanding Population Differences in Cancer: The MEC StudyU01CA164973 · NCI · UNIVERSITY OF HAWAII AT MANOA · PI HAIMAN, CHRISTOPHER ALAN, LE MARCHAND, LOIC · 2015 to 2025
$37.4MWomen's Health Study: Continued Follow-upR01CA047988 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI BURING, JULIE E., LEE, I-MIN · 1991 to 2014
$28.2MRESEARCH IN ENVIRONMENTAL HEALTH SCIENCES (CENTER GRANT)P30ES000260 · NIEHS · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI ZELIKOFF, JUDITH TERRY · 1985 to 2020
$26.1MLong Term Multidisciplinary Study of Cancer in Women: The Nurses Health StudyUM1CA186107 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI ELIASSEN, A. HEATHER, STAMPFER, MEIR · 2014 to 2023
$22.3MPhysicians' Health Study II: Prevention Trial of VitaminsR01CA097193 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI GAZIANO, J. MICHAEL · 2002 to 2011
$15.7MCancer Epidemiology Cohort in Male Health ProfessionalsUM1CA167552 · NCI · HARVARD SCHOOL OF PUBLIC HEALTH · PI WILLETT, WALTER C. · 2012 to 2016
$11.5MNCI NIH HHS P01 CA087969NCI NIH HHS P30 CA008748NCI NIH HHS P30 CA016087NCI NIH HHS P50 CA062924NCI NIH HHS R01 CA034944NCI NIH HHS R01 CA040360NCI NIH HHS R01 CA047988NCI NIH HHS R01 CA049449NCI NIH HHS R01 CA097193NCI NIH HHS R01 CA098380NCI NIH HHS R01 CA098661NCI NIH HHS R01 CA098870NCI NIH HHS R01 CA154823NCI NIH HHS R01 CA297773NCI NIH HHS U01 CA164973NCI NIH HHS U01 CA182883NCI NIH HHS U01 CA182913NCI NIH HHS UG1 CA189974NCI NIH HHS UM1 CA167552NCI NIH HHS UM1 CA182913NCI NIH HHS UM1 CA182934NCI NIH HHS UM1 CA186107NHLBI NIH HHS 75N92021D00001NHLBI NIH HHS 75N92021D00002NHLBI NIH HHS R01 HL026490NHLBI NIH HHS R01 HL034595NHLBI NIH HHS R01 HL043851NHLBI NIH HHS R01 HL080467NHLBI NIH HHS RC1 HL099355NIEHS NIH HHS P30 ES000260WHI NIH HHS 75N92021D00003WHI NIH HHS 75N92021D00004WHI NIH HHS 75N92021D00005
Abstract
Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the
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