Multiple HABP2 variants in familial papillary thyroid carcinoma: A case-control study

Objective A heterozygous germline variant in the HABP2 gene (p.G534E), that negatively impacts its tumor suppressive activity in vitro, has been described in 4 to 14% of kindreds of European ancestry with familial papillary thyroid carcinoma (fPTC). But it is also found in ≈4% of Europeans and European Americans from public databases that, however, did not provide information on the thyroid function of the controls. To get unbiased results, we decided to compare genotypes of patients with fPTC with those of “thyroid-checked” controls. Materials and methods We built a control group consisting of 95 European patients who underwent a thyroidectomy for medullary thyroid carcinoma and were devoid of any histologically detectable PTC or follicular-deriving carcinoma. In parallel we recruited 17 patients with fPTC from nine independent European kindreds. The entire coding region of HABP2 was analyzed by Sanger sequencing the germline DNAs of patients. Results Two variants (p.G534E and p.R122 W) were found in 2 and 3 patients at the heterozygous level (minor allele frequency (MAF): 5.55% and 8.33%, respectively). The R122 residue lies in the EGF-3 domain of HABP2 which is important for its activation. In controls, the MAF was either lower for the p.R122 W (1.05%, P Discussion In conclusion, our data do not support the pathogenicity of the HABP2 p.G534E variant but highlight the existence of another variant that should be more extensively searched for in fPTC patients.