title: Characterization of the colorectal cancer-associated enhancer MYC-335 at 8q24: the role of rs67491583.
abstract: Recent genome-wide association studies have identified multiple regions at 8q24 that confer susceptibility to many cancers. In our previous work, we showed that the colorectal cancer (CRC) risk variant rs6983267 at 8q24 resides within a TCF4 binding site at the MYC-335 enhancer, with the risk allele G having a stronger binding capacity and Wnt responsiveness. Here, we searched for other potential functional variants within MYC-335. Genetic variation within MYC-335 was determined in samples from individuals of European, African, and Asian descent, with emphasis on variants in putative transcription factor binding sites. A 2-bp GA deletion rs67491583 was found to affect a growth factor independent (GFI) binding site and was present only in individuals with African ancestry. Chromatin immunoprecipitation performed in heterozygous cells showed that the GA deletion had an ability to reduce binding of the transcriptional repressors GFI1 and GFI1b. Screening of 1,027 African American colorectal cancer cases and 1,773 healthy controls did not reveal evidence for association (odds ratio: 1.17, 95% confidence interval: 0.97-1.41, P = 0.095). In this study, rs67491583 was identified as another functional variant in the CRC-associated enhancer MYC-335, but further studies are needed to establish the role of rs67491583 in the colorectal cancer predisposition of African Americans.
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Tuupanen
authors.affiliation: Institute of Biomedicine, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.|Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Institute of Biomedicine, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Turunen
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Gylfe
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Eevi
authors.initials: E
authors.lastname: Kaasinen
authors.affiliation: Department of Family Medicine and Division of Genetic Epidemiology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Genetics and Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.|Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.|Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|Weiss Center for Hereditary Colon Cancer, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.affiliation: Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Culver
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|Digestive Diseases Institute, Cleveland Clinic, Cleveland, OH, USA.|Weiss Center for Hereditary Colon Cancer, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Kalady
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pennison
authors.affiliation: Division of Hematology/Oncology, Department of Medicine and Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Pasche
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Upender
authors.initials: U
authors.lastname: Manne
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Hampel
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.affiliation: Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI, USA.
authors.forename: Loic Le
authors.initials: LL
authors.lastname: Marchand
authors.affiliation: Computational Systems Biology Laboratory, Institute of Biomedicine and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.affiliation: Department of Medicine and Cancer Center, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Askhtorab
authors.affiliation: Department of Medicine and Cancer Center, Howard University College of Medicine, Washington, DC, USA.|Division of Hematology/Oncology, Department of Medicine and Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Duane
authors.initials: D
authors.lastname: Smoot
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sandler
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Temitope
authors.initials: T
authors.lastname: Keku
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Kupfer
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Ellis
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Institute of Biomedicine, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.|Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics / Q000706:statistics & numerical data; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D002277:Carcinoma / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000208:ethnology / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D016259:Genes, myc / Q000235:genetics* / Q000502:physiology; D005838:Genotype; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data