Frequent and Rare HABP2 Variants Are Not Associated with Increased Susceptibility to Familial Nonmedullary Thyroid Carcinoma in the Spanish Population

Abstract

Background/Aims: A genomic HABP2 variant was proposed to be responsible for familial nonmedullary thyroid carcinoma (FNMTC). However, its involvement has been questioned in subsequent studies. We aimed to identify genetic HABP2 mutations in a series of FNMTC patients and investigate their involvement in the disease. Methods: HABP2 was sequenced from 6 index patients. Presence of the variants was investigated in all members of one family. Somatic BRAF and RAS “hotspot” mutations were investigated by the Idylla^TM BRAF Mutation Test and/or Sanger sequencing. Results: Two HABP2 variants (p.E393Q and p.G534E) were identified in the index patient from one family with papillary thyroid carcinoma (PTC) (follicular variant). The prevalence of p.E393Q in Spanish control alleles was 0.5% and that of p.G534E was 5.1%. However, neither change cosegregated with the phenotype in 3 affected members and 5 healthy members of the kindred. Interestingly, all 3 members affected by PTC harbored the p.V600E somatic mutation in BRAF. Conclusions: The variant G534E is prevalent in the Spanish population (5.1%); however, p.E393Q is rare (< 1%) and none cosegregated with the FNMTC phenotype. The presence of the noninheritable V600E BRAF mutation in this family supports Knudson’s “double-hit” hypothesis for cancer development and suggests the involvement of more than 1 gene in the clinical expression of FNMTC.

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates

“…Functional studies have shown that HABP2 has a tumor suppressive effect, whereas the G534E variant results in loss of function [62]. However, the role of the HABP2 (10q25.3) gene in NSFNMTC is controversial [88][89][90] because the pathogenicity of HABP2 variants in NSFNMTC could not be confirmed in Chinese, Brazilian and European studies [90][91][92][93][94][95][96][97][98][99][100]. Neither does this variant appear to play a role in sporadic PTC [101].…”

Genetic susceptibility to hereditary non-medullary thyroid cancer

“…The data from various ethnic populations with large sample sizes suggest that this variant is unlikely to be a moderate or high penetrance gene in NMTC patients. Multiple other groups were unable to verify an association between the G534E variant and hereditary thyroid cancer [49][50][51][52][53][54][55][56][57]. Additionally, targeted sequencing of 516 PTC cases failed to identify the G534E variant.…”