Endocrine Abstracts

Introduction: Familial non-medullary thyroid cancer(FNMTC) represents 3–9% of thyroid cancer cases. Although the susceptibility genes for syndromic FNMTC are known, most cases of FNMTC are nonsyndromic and the genetic causes are unknown.

Patients and methods: We conducted a multicenter study to identify a candidate susceptibility gene for nonsyndromic FNTMC. We collected blood specimens, clinical and pathological data from 38 kindreds with FNMTC (32 with two affected members, six with ≥3 affected members). Genomic DNA was extracted from peripheral blood samples and Whole-Exome sequencing (WES) was performed in 10 affected individuals from four kindreds with at least three cases of FNMTC in each kindred. We filtered and identified the germline SNPs and INDELs using Haplotype Caller using the GATK package. We identified and validated the likely pathogenic variants (LPV) by Sanger sequencing in 38 kindreds and in our own control group (50 healthy subjects).

Results: Sixty-eight percent were women, with a mean age at diagnosis of 42.6±13.6 years. 90.4% had classic papillary thyroid cancer, 26% were bilateral and 46% were multifocal. Among genes with LPV and population frequency of <5%, we identified two novel germline heterozygous mutations in kinesin family member1B gene (KIF1B) in two kindreds. In the first family, five of five affected members presented a mutation c.2680G>A (p.V894M) in exon 24 and three of four affected members in the other family had a c.2480C>T (p.T827I) mutation in exon 23. We believe that the remaining member could be a phenocopy considering the high prevalence of thyroid cancer. Both LPVs are described in ExAc database with population frequencies of <0.2%. Importantly, we didn’t find the V894M KIF1B variant in our control group. We didn’t test T827I variant in control group as it was already described as a very rare variant (not present among 270 controls of diverse ethnic backgrounds). KIF1B is in the chromosomal region 1p36.22 and encodes a motor protein that transports mitochondria and synaptic vesicle precursors. Several studies suggested KIF1B as a potential tumor suppressor gene particularly in neuroblastomas.

Conclusions: We identified two families with FNMTC presenting two novel or rare germline variants in KIF1B gene. Further studies are needed to establish the potential pathogenic impact of these genetic changes, as well as its involvement as a possible risk factor to develop FNMTC.

Collaborators: R. Alfayate, S. Martínez, F. Hanzu, S. Chicharro, C. Villabona, J. Otero, A. Simó, M.C. Vilardell, A.M. Gutiérrrez, E. Pizarro, A. Sitges, C. Zafón, A. Ortiz, P. Casano, J.J. Díez, P. Iglesias, J. Biarnés, M. Recasens, R. Casañ.