Nonmedullary Thyroid Cancer
By whole-exome sequencing followed by Sanger sequencing, Gara et al. (2015) identified a 1601G-A transition in exon 13 of the HABP2 gene resulting in a gly534-to-glu (G534E) amino acid substitution in affected members of a 3-generation family segregating autosomal dominant familial nonmedullary thyroid cancer (NMTC5; 616535). All affected family members were heterozygous for the variant in peripheral blood DNA. This mutation was found with an allele frequency of 0.02223 in the ExAC Browser, and in 4.7% of 423 patients with thyroid cancer reported in TCGA data. The G534E mutation occurs within the serine protease trypsin domain of the HABP2 protein. Homologic modeling showed that the mutation results in a space constraint near the catalytic region, thereby disrupting the active site and surface accessibility of its substrates. Immunohistochemical analysis showed increased HABP2 protein expression in papillary thyroid cancers (PTCs) and follicular adenoma tumors from affected family members, but there was no staining in normal thyroid tissue from the same affected members. In contrast, only 3 of 12 sporadic PTCs had faint HABP2 protein staining. Transient knockdown of wildtype HABP2 in 3 different human cell lines (follicular thyroid cancer, PTC, and embryonic kidney) increased colony formation and cellular migration, suggesting a tumor-suppressive function. Stable overexpression of wildtype HABP2 protein in cell lines reduced colony formation and cellular migration, while overexpression of G534E mutant protein increased colony formation. Foci assays in NIH-3T3 cells demonstrated that the G534E variant induced a significantly higher number of foci and increased cellular migration compared with wildtype. Cotransfection with equal amounts of wildtype and G534E mutant constructs into NIH-3T3 cells resulted in greater foci formation and cellular migration than in wildtype HABP2 overexpression, suggesting a dominant-negative effect of the mutation.
Zhou et al. (2015), Sponziello et al. (2015), and Tomsic et al. (2015) stated that the allele frequency of the G534E variant exceeds the filtering criterion used by Gara et al. (2015) (less than 1% in public databases). Gara et al. (2015) reported an incidence of the G534E variant of 0.7% in the 1000 Genomes Project and HapMap3 databases; Zhou et al. (2015) noted that the frequency in the ExAC database among non-Finnish Europeans is 3.29%. Gara and Kebebew (2015) responded that the ExAC browser includes data from 60,706 persons, 7,601 of whom were patients with cancer that were included in the Cancer Genome Atlas database (12.5%). They also commented that thyroid cancer is a very common condition depending on screening methods used and that the purpose of their study was to report a kindred in whom thyroid cancer segregated with the allele and was very aggressive.
Zhao et al. (2015) noted that the G534E variant was not seen in any Chinese patients with thyroid cancer.
Role in Fibrinolysis
In 24 healthy individuals with normal plasma FSAP levels but reduced pro-urokinase activation, Roemisch et al. (2002) identified heterozygosity for a 1601G-A transition in exon 13 of the HABP2 gene, resulting in a gly534-to-glu (G534E) substitution near the C terminus of the light chain. The authors referred to the mutation as G511E, using the amino acid numbering of the mature protein produced by excision of the 23-amino acid signal peptide.
Willeit et al. (2003) analyzed the Marburg I polymorphism in 810 men and women, aged 40 to 79 years, who had participated in an ultrasound study of atherosclerosis. The Marburg I polymorphism was found in 37 (4.4%) individuals, who showed a prominently reduced in vitro capacity to activate pro-urokinase. No relation was found between the Marburg I polymorphism and early atherogenesis; however, it was a strong and independent risk predictor of incident/progressive carotid stenosis.
Hoppe et al. (2005) found that the frequency of the Marburg I polymorphism was significantly increased in patients with a history of venous thromboembolism (see 188050).
