A Constitutional Activating <i>MET</i> Mutation Makes the Genetic Link between Malignancies and Chronic Inflammatory Diseases.

Abstract

The genesis of all cancers results from an accumulation of mutations, constitutional and/or acquired when induced by external mutagenic factors. High-speed technologies for genome sequencing have completely changed the study of disease genetics, but with limited knowledge of the functional value of most genetic changes. Here, we proposed an innovative individual approach by studying tissue samples from a young woman with an unusual association of breast cancer, polycythemia vera, and rheumatoid arthritis. We performed genomic analyses for copy number variations and point mutations on laser-microdissected tumor cells from the breast cancer, and on CD34⁺ cells sorted from bone marrow aspiration, to identify gene abnormalities common to these two types of cell populations. Using ONCOSCAN technology, we identified a constitutional pR988C, c2962C>T mutation of <i>MET</i>. Using CRISPR-Cas9 technology, we established pR988C <i>MET</i>-mutated transgenic mice, which reproduced the autoimmune diseases and myeloproliferation found in our index-case; one of the transgenic mice spontaneously developed a skin squamous cell carcinoma. We also showed that additional mutagenic factors were required to induce cancers, including skin squamous cell carcinoma and thyroid cancer. Using an anti-MET drug, cabozantinib, we demonstrated for the first time the functional role of this mutation in the maintenance of myeloproliferation and rheumatoid arthritis, and in cancer genesis. Our study opens a considerable field of application in the domain of constitutional genetics, to establish genetic links between cancers and other very different severe diseases.