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Article Dans Une Revue Clinical Cancer Research Année : 2019

A constitutional activating MET mutation makes the genetic link between malignancies and chronic inflammatory diseases

Résumé

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: Using ONCOSCAN technology, we identified a constitutional pR988C, c2962C>T mutation of MET. Using CRISPR-Cas9 technology, we established pR988C MET-mutated transgenic mice which reproduced the auto-immune 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. CONCLUSIONS: 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.

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Cancer
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Dates et versions

inserm-02124688 , version 1 (09-05-2019)

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El Bouchtaoui Morad, Marcio Do Cruzeiro, Christophe Leboeuf, Irmine Loisel-Ferreira, Carèle Fédronie, et al.. A constitutional activating MET mutation makes the genetic link between malignancies and chronic inflammatory diseases. Clinical Cancer Research, 2019, 25 (14), pp.4504-15. ⟨10.1158/1078-0432.CCR-18-3261⟩. ⟨inserm-02124688⟩
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