WHOLE EXOME SEQUENCING OF MEDULLARY THYROID CARCINOMA CASES IDENTIFIES 86 VARIATIONS IN GENES POSSIBLY INVOLVED IN TUMORAL TRANSFORMATION

Objectives: About 40% of sporadic Medullary Thyroid Carcinomas (MTC) is still orphan of an oncogenic driver. Purpose of this study was to disclose novel genetic alterations leading to the pathogenesis of MTC using Whole Exome Sequencing (WES) of RET+ and RET- cases. Methods: WES analysis was performed on 6 sporadic MTC cases (2 RET+, 4 RET-) using an Illumina platform. After processing and proper filtering, all non-synonymous Single Nucleotide Variations (SNV) shared by the RET- cases were listed. Validation on 135 MTC cases and 189 healthy controls by PCR and enzymatic restriction analysis was performed in one of the genes of interest identified through WES. Results: WES analysis led to the identification of a panel of 86 non-synonymous SNV shared in the 4 RET- cases and possibly involved in tumoral transformation process. Among the 86 SNV identified, the A133S polymorphism of the RASSF1A oncosuppressor appeared to be of interest. We found A133S in 21/135 (15.6%) MTC cases and in 19/189 (10%) healthy controls (P=0.137). The incidence of A133S appeared to be slightly lower in RET mutated MTC [9/64 (14%)] than in not-mutated [12/71 (17%)], although not statistically significant. Conclusions: Through WES analysis we were able to identify 86 non-synonymous SNV shared in RET- MTC cases. This panel represents the first list of variations containing hypothetically novel genetic drivers involved in MTC oncogenesis. The prevalence of the A133S SNP was found to be higher in MTC cases compared to healthy controls (15.6% vs 10%) although not statistically significant. Further validation of other candidate genes is on-going.