Endocrine Abstracts

Introduction: Hereditary medullary thyroid carcinoma (MTC) is associated with only one major cause – germline mutations in the RET proto-oncogene. The most of tested families with MTC is related to specific RET mutation, however, very small number of families left unresolved without the causing inherited mutation. New techniques of next generation sequencing give hope in finding the new candidate genes that could be involved in the pathogenesis of these MTC families.

Methods: We performed RET genetic screening in 870 individuals – 490 patients and 380 at-risk-relatives. The germline RET mutation was detected in 58 families (83% of familial and 7% of apparently sporadic MTCs). No mutation in all RET exons was found in six families with clinically supposed hereditary form of MTC (4 FMTC and 2 MEN2A phenotype). Six index patients of these families were analyzed using Trusight Cancer Sequencing Panel (Illumina) that targeted 94 genes associated with cancer. After exclusion of common single nucleotide polymorphisms, the data were focused on novel or rare non-synonymous variants in coding sequences and tested in silico (SIFT, PolyPhen) for possible damaging effect.

Results: Several promising variants in each patient have been identified in genes involved in key processes for cancer development such as repair genes. Considering SIFT and PolyPhen evaluation, the analysis has discovered very rare variants in genes RHBDF2, XPA, MET and CHEK2. The variants detected in APC and EZH2 were previously investigated in association with other cancers. Three patients have a pathogenic polymorphism in HNF1A.

Conclusion: New candidate genes can represent genetic modifying factors or crucial genes in each family. Although detected alterations are promising, it is necessary to verify them in other affected family members.

Disclosure: This work was supported by the grant projects IGA MH CZ NT13901-4 and MH CZ DRO 00023761.