Germline MET T1010I can play a Role in the Pathogenesis of Hereditary Medullary Thyroid Cancer Negative for any Germline RET Mutation

  • Background: Virtually all familial cases of Medullary Thyroid Cancer (MTC) harbor germline RET mutations. However, oncogenesis of some familial MTCs still needs to be clarified. MET proto-oncogene was found mutated in many cancers and may have a role in MTC oncogenesis.

    Methods: We studied a family characterized by 2 brothers with MTC and 14 negative controls. We performed Sanger sequencing (SS) to identify germline mutations of RET and ESR2, Whole Exome Sequencing (WES) (Illumina) to identify other germline mutations, and Target Sequencing (Ion Torrent) to identify somatic mutations of most relevant thyroid cancer oncogenes.

    Results: The 2 MTC patients did not harbor RET and ESR2 germline mutations, according to SS analysis. We performed WES in blood samples of MTC patients and 2 negative controls and we identified 22 potential germline variants. According to SS, intriguingly, one specific MET mutation (MET-T1010I) was present in the two MTC brothers and in the apparently unaffected mother, but not in the other relatives. Furthermore, we performed Target Sequencing of the MTC tissue samples of the two brothers and we identified the MET-T1010I mutation in association with a somatic RET-M918T mutation.

    Discussion & conclusion
    We demonstrated by WES that this family is not harboring any RET or ESR2 germline mutations. However, we found a germline MET-T1010I mutation associated with a somatic RET-M918T mutation in both MTC cases. We can hypothesize that MET-T1010I mutation may represent an early driver oncogene mutation, which might predispose to the development of a late mutation such as RET-M918T.

 

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