title: TFF2-CXCR4 Axis Is Associated with BRAF V600E Colon Cancer.
abstract: Oncogene-induced senescence (OIS), a tumor-suppressive mechanism that is induced by the replicative and metabolic stress of oncogene activation, is a key barrier in the development of BRAF V600E colon cancer. Inhibition of this mechanism has been observed through epigenetic changes observed in sporadic serrated polyps, as well as through the germline mutations associated with those who develop serrated polyposis. We hypothesize that upregulated autocrine factors exist that are specific to the serrated pathway and also promote bypass of oncogene-induced senescence. To identify such autocrine factors, we integrate analyses of microarrays of sessile serrated polyps and two large colon cancer cohorts, the Cancer Genome Atlas (TCGA; n = 153), and French national Cartes d'Identité des Tumeurs (CIT) program (n = 462), with enhanced gene annotation through natural language processing techniques of the existing medical corpus. We reproducibly associate higher expression of the ligand-receptor axis of TFF2 and CXCR4 with BRAF V600E-mutant colon cancer (P = 3.0 × 10(-3) and 0.077, respectively for TCGA; P = 3.0 × 10(-8) and 5.1 × 10(-7) for CIT). Given well-described oncogenic roles of TFF2 and CXCR4 in colon cancer, and availability of CXCR4 inhibitors for other clinical indications, this ligand-receptor axis may represent an actionable target for prevention and treatment of this molecular subtype of colorectal cancer.
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Gala
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: Austin
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. achan@partners.org.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
mesh_terms: D000236:Adenoma; D000465:Algorithms; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D030541:Databases, Genetic; D018450:Disease Progression; D006801:Humans; D009323:Natural Language Processing; D010455:Peptides / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071164:Trefoil Factor-2
chemical_list: C527276:CXCR4 protein, human; D010455:Peptides; D019718:Receptors, CXCR4; C000604007:TFF2 protein, human; D000071164:Trefoil Factor-2; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf