title: BRAFV600Ecooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis.
abstract: While 20-30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8-10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from 'serrated' versus 'conventional adenoma' precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss orBRAFmutations in ~60% of cases and often together (p=0.04). CDX2Null/BRAFV600Eexpression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAFV600Epotently interacted with CDX2 silencing to alter gene expression. Like human serrated lesions, CDX2Null/BRAFV600E-mutant epithelium expressed gastric markers. Organoids from CDX2Null/BRAFV600E-mutant colon epithelium showed serrated features, and partially recapitulated the gene expression pattern in mouse colon tissues. We present a novel mouse tumor model based on signature defects seen in many human serrated CRCs - CDX2 loss and BRAFV600E. The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, United States.|Department of Molecular Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, United States.
authors.forename: Carmine
authors.initials: C
authors.lastname: Stolfi
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, United States.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kurosu
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, United States.
authors.forename: Maranne
authors.initials: M
authors.lastname: Green
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, United States.
authors.forename: Jeffry
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, United States.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Green
authors.affiliation: Department of Molecular Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sentani
authors.affiliation: Department of Molecular Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.affiliation: Department of Dermatology, University of Utah Medical School, Salt Lake City, United States.|Huntsman Cancer Institute, University of Utah Medical School, Salt Lake City, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, United States.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Hardiman
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, United States.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States.
authors.forename: Jason R
authors.identifier: 0000-0001-7869-3992
authors.initials: JR
authors.lastname: Spence
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Nobukatsu
authors.initials: N
authors.lastname: Horita
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, United States.
authors.forename: Joel K
authors.initials: JK
authors.lastname: Greenson
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, United States.
authors.forename: Rork
authors.initials: R
authors.lastname: Kuick
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, United States.|Department of Pathology, University of Michigan, Ann Arbor, United States.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, United States.|Department of Pathology, University of Michigan, Ann Arbor, United States.|Department of Human Genetics, University of Michigan, Ann Arbor, United States.
authors.forename: Eric R
authors.identifier: 0000-0003-2867-3971
authors.initials: ER
authors.lastname: Fearon
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D007413:Intestinal Mucosa / Q000473:pathology; D051379:Mice; D009940:Organoids; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse; C482119:BRAF protein, human; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf
keywords: cancer biology; cancer diagnosis; colorectal cancer; homeobox gene; human; human biology; intestinal differentiation; medicine; mouse; oncogene; tumor suppressor gene