title: Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer.
abstract: The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analysesin situconfirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.Cancer Res; 77(7); 1730-40. ©2017 AACR.
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Lucy
authors.initials: L
authors.lastname: Mathot
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Snehangshu
authors.initials: S
authors.lastname: Kundu
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Viktor
authors.initials: V
authors.lastname: Ljungström
authors.affiliation: Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Svedlund
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Lotte
authors.initials: L
authors.lastname: Moens
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Tom
authors.initials: T
authors.lastname: Adlerteg
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Elin
authors.initials: E
authors.lastname: Falk-Sörqvist
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Verónica
authors.initials: V
authors.lastname: Rendo
authors.affiliation: Department of Medical Biochemistry and Microbiology, Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bellomo
authors.affiliation: Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Mayrhofer
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Cortina
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Sundström
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Micke
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Botling
authors.affiliation: Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.affiliation: Department of Medical Biochemistry and Microbiology, Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Batlle
authors.affiliation: Department of Surgical Sciences, Colorectal Surgery, Uppsala University, Sweden.
authors.forename: Helgi
authors.initials: H
authors.lastname: Birgisson
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.|Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Nilsson
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden. tobias.sjoblom@igp.uu.se.
authors.forename: Tobias
authors.initials: T
authors.lastname: Sjöblom
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D000071238:Fibronectin Type III Domain / Q000235:genetics; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D036225:Receptor, EphB1 / Q000235:genetics*
chemical_list: D011505:Protein-Tyrosine Kinases; D036225:Receptor, EphB1