Somatic ephrin receptor mutations are associated with metastasis in primary colorectal cancer

The contribution of somatic mutations to metastasis of colorectal cancers (CRC) is currently unknown. To find mutations involved in the CRC metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II-IV primary CRC, of which half had metastasized. The mutation prevalence in the ephrin (Eph) family of tyrosine kinase receptors was ten-fold higher in primary tumors of metastatic CRC than in non-metastatic cases and preferentially occurred in stage III and IV tumours. Mutational analyses in situ confirmed expression of mutant Eph receptors. To enable functional studies of EphB1 mutations, we demonstrated that DLD-1 CRC cells expressing EphB1 form aggregates upon co-culture with ephrin-B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EphB1 were compared to wild-type EphB1 in DLD-1 CRC cells, they decreased ephrin-B1 induced compartmentalization. These observations provide a mechanistic link between EphB receptor mutations and metastasis in CRC.

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