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Cancer Res. 2017 Apr 1;77(7):1730-1740. doi: 10.1158/0008-5472.CAN-16-1921. Epub 2017 Jan 20.

Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer.

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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.
Department of Medical Biochemistry and Microbiology, Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, Sweden.
Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden.
Oncology Programme, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Department of Surgical Sciences, Colorectal Surgery, Uppsala University, Sweden.
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.


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 analyses in situ confirmed 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.

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