Endocrine Abstracts

JOINT1254

Background: Papillary thyroid carcinoma (PTC), the most common endocrine cancer, is usually sporadic and little is known about possible genetic determinants. However, we recently identified a truncating pyruvate dehydrogenase phosphatase (PDH) regulatory subunit gene variant segregating with familial PTC in the USA. Our aim was to identify PTC families and search for possible predisposing germline variants in the genetically homogenous Finnish population, an ideal population for the discovery of rare genetic defects of monogenic disorders.

Methods: We identified patients with familial papillary thyroid carcinomas from our University Hospitals and used whole-genome sequencing (WGS) to identify putative pathogenic variants. All patients were clinically characterized, including thyroid antibody measurements and careful histopathological examinations. Only gene variants shared by all PTC patients within the families were considered. Variants were confirmed by Sanger sequencing. Population frequencies were assessed with the gnomAD v.4.1.0 browser. In-silico protein prediction tools and databases were used for further analyses.

Results: We identified 12 families with PTC, 5/12 families have so far undergone WGS. A novel DLD c.100A>G (p.Thr34Ala) variant was found in family 1, and a novel SIRT4 c.755A>C (p.Glu252Ala) variant in family 5. The corresponding allele frequencies in a global control population were 0.00086 and 0.00012, respectively. The DLD c.100 site is predicted to contain GATA4 and SMARCA4 transcription factor binding sites. In family 7, a protein truncating variant c.422-423 del (p.Leu141ProfsTer23), which leads to a premature stop codon in exon 2 in the ZNF197 gene was found. The ZNF197 c.422-423 site contains CTCF, CBX3 and SP1 transcription binding sites.

Conclusion: We have identified 12 Finnish families with PTC and three novel putative underlying gene defects. Two of them, DLD and SIRT4, regulate the pyruvate dehydrogenase complex (PDH) and one, ZNF197, is a VHL-associated KRAB-A domain containing protein, which is overexpressed in some thyroid cancer samples. We hypothesize that the mutations might destroy transcription factor binding sites and impair DLD and ZNF197 gene expression. Further studies are needed to better understand the molecular mechanisms predisposing to PTC in these families.