Background: HABP2 is an extra-cellular matrix protein involved in cell proliferation. Recently, HABP2 was proposed as responsible for the familial clustering of Differentiated Thyroid Carcinoma (FDTC). However, its involvement was questioned by subsequent studies revealing high prevalence HAPB2 polymorphisms (SNPs) in the general population, leaving its pathogenic role uncertain.
Objective and hypotheses: To identify genetic HABP2 variants/mutations and investigate their involvement in FDTC.
Patients and methods: HABP2 was sequenced in four index patients with FDTC. Variants identified were investigated in the rest of family members, and segregation analyses performed in affected and healthy individuals. Germline mutations were screened in lymphocyte DNA using PCR amplification and Sanger sequencing. HABP2 SNP prevalence in Spanish population was determined from 178 control alleles. Public SNP databases served to estimate variant prevalence in Caucasian populations. BRAF hotspot mutations were studied in the paraffin-embedded tissue from index patient by PCR and Sanger Sequencing.
Results: Two germline heterozygous HABP2 variants (p.Glu393Gln and p.Gly534Glu) in exons 10 and 13, were respectively identified in individuals from 1 family with 2 affected (index patient, mother) and 5 additional healthy members of the kindred. Both variants are present in SNP databases (rs11575688, rs7080536) with Minor Alleles Frequencies (MAF) between 0.82-2.79% and 0.32-1.34%, respectively. In Spanish control alleles, p.Gly534Glu prevalence is 5.1%. However, pathogenicity programs predict they are possibly damaging. 3/7 individuals in the pedigree harboured both variants but their presence does not co-segregate with the phenotype. The index patient presented the most prevalent somatic mutation of BRAF (V600E) in PTC.
Conclusion: HABP2 G534E and E393Q variants are prevalent in the normal Spanish population and they do not co-segregate with the FDTC phenotype. Our findings do not support a relevant role of HAPB2 in the pathogenesis of FDTC. Other germline defects different from HAPB2 must be investigated to explain the familial susceptibility in DTC.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology