Abstract
Major breast cancer predisposition genes, only account for approximately 30% of high-risk breast cancer families and only explain 15% of breast cancer familial relative risk. The HGF growth factor receptor MET is potentially functionally altered due to an uncommon germline single nucleotide polymorphism (SNP), MET-T1010I, in many cancer lineages including breast cancer where the MET-T1010I SNP is present in 2% of patients with metastatic breast cancer. Expression of MET-T1010I in the context of mammary epithelium increases colony formation, cell migration and invasion in-vitro and tumor growth and invasion in-vivo. A selective effect of MET-T1010I as compared to wild type MET on cell invasion both in-vitro and in-vivo suggests that the MET-T1010I SNP may alter tumor pathophysiology and should be considered as a potential biomarker when implementing MET targeted clinical trials.
Highlights
A strong breast cancer family history can signal the presence of inherited risk-modifying genetic events
Based on the odds ratio of 2.0, we decided to assess the functional consequence of MET-T1010I in breast cancer models
We demonstrate that MET germline mutations occur in 7% of patients with metastatic breast cancer with MET
Summary
A strong breast cancer family history can signal the presence of inherited risk-modifying genetic events. Even including the estimated contributions of mutations in high penetrance (BRCA1/2, TP53, CDH1, LKB1, and PTEN), and moderate or low penetrance genes including SNPs associated with breast cancer identified through genomewide association studies (GWAS), 50% of familial breast cancer predisposition still remains unexplained [6]. The hepatocyte growth factor (HGF) and its receptor, the transmembrane tyrosine kinase MET, promote cell proliferation, survival, motility, and invasion, as well as morphogenic changes that can stimulate repair and regeneration in normal tissues. MET over-expression, with or without gene amplification has been reported in a www.impactjournals.com/oncotarget variety of human malignancies [7,8,9,10] where it has been suggested to provide a major resistance mechanism for targeted therapies against multiple receptors [7]. The impact of germline and somatic aberrations remains controversial and is likely context dependent with different effects based on intrinsic lineage expression programs or mutational context in particular cancer lineages
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