Met Modifier Genes Identified by Genomic Analysis of a Mouse CC Model, Serves as a Predictors of Survival in Breast Cancer Patients

It was shown that different types of tumors are derived from the same driver genes. The exact molecular mechanism of this phenomenon is not fully understood. Met tyrosine kinase is the receptor for hepatocyte growth factor/scatter factor (HGF/SF). Met is essential for normal embryonic development and plays a major role in pathological processes such as tumorigenesis and metastasis in carcinoma, sarcoma, lymphoma and leukemia. Met constitutive activation and mutations have profound effects on the promotion of tumor growth and metastases. Met is involved in tumor progression in a variety of human cancers and its inhibitors are approved for therapy by the FDA. We hypothesis that the molecular mechanisms of different type tumor development induced by Met activation is dictated by inherited driver modifier genes (IDMGs). We combined two model systems: 1) Knock-In FVB/NM1248T/L1193V Met mutated mice that were shown to develop tumors. 2) Collaborative-Cross (CC) mice tool. We have created a novel mice model in which 20 CC lines with different genetic background overexpresses the mutated Met receptor. CT imaging and H&E staining analyses follow-up revealed that the mutated Met CC lines showed wider diversity regarding tumor types (carcinoma, lymphoma, and sarcoma). Met modifiers can enhance and promote tumor development or delay and reduce tumor progression. QTL and computational bioinformatics analyses (SNP’s, ANAT and Human cBioPortal Datsbase) together with qPCR and immunofluresence staining, enabled the selection of 9 candidate genes that demonstrate alteration by modulation of Met signaling. These novel identified Met-IDMGs may be associated with Met, alter the Met signaling pathway and change the tumor profile. Elucidating the molecular mechanisms of mutated Met induced tumorigenicity is important for basic science and these novel genes may be novel targets for combined anti Met therapy.