Abstract
Approximately 5% of all cases of papillary thyroid cancer (PTC) are inherited. However, the susceptibility gene(s) for nonsyndromic familial PTC (FPTC) remain unclear. We performed whole genome sequencing of peripheral blood DNA samples from two affected family members with PTC. CHEK2 transcript expression and the protein levels of CHK2 and p53 were evaluated in the thyroid tissues from two affected members of the kindred and sporadic PTC cases. The entire CHEK2 coding sequence was examined by Sanger sequencing in blood DNA samples from 242 sporadic PTC patients. We identified a novel heterozygous germline mutation in CHEK2 (c.417C→A) that was detected in all available affected members of a kindred with FPTC. This variant was found in only 1 out of 264,200 persons in the Genome Aggregation Database and the NHLBI Trans-Omics for Precision Medicine program. The CHEK2 c.417C→A variant introduces a premature termination codon (Y139X). We found reduced CHK2 protein expression in tumor samples from the two patients who carried the variant as compared with sporadic cases without the variant. The Y139X loss-of-function variant led to reduced p53 phosphorylation and decreased p53 protein level. In addition, two rare missense variants (R180C and H371Y) in CHEK2 were identified in 5 (2%) of 242 patients with sporadic PTC. Our findings suggest that the CHEK2 Y139X variant may be associated with FPTC.