Novel Susceptibility Genes Drive Familial Non-Medullary Thyroid Cancer in a Large Consanguineous Kindred

Abstract

Familial non-medullary thyroid cancer (FNMTC) is a well-differentiated thyroid cancer (DTC) of follicular cell origin in two or more first-degree relatives. Patients typically demonstrate an autosomal dominant inheritance pattern with incomplete penetrance. While known genes and chromosomal loci account for some FNMTC, the molecular basis for most FNMTC remains elusive. To identify the variation(s) causing FNMTC in an extended consanguineous family consisting of 16 papillary thyroid carcinoma (PTC) cases, we performed whole exome sequence (WES) analysis of six family patients. We demonstrated an association of ARHGEF28, FBXW10, and SLC47A1 genes with FNMTC. The variations in these genes may affect the structures of their encoded proteins and, thus, their function. The most promising causative gene is ARHGEF28, which has high expression in the thyroid, and its protein-protein interactions (PPIs) suggest predisposition of PTC through ARHGEF28-SQSTM1-TP53 or ARHGEF28-PTCSC2-FOXE1-TP53 associations. Using DNA from a patient's thyroid malignant tissue, we analyzed the possible cooperation of somatic variations with these genes. We revealed two somatic heterozygote variations in XRCC1 and HRAS genes known to implicate thyroid cancer. Thus, the predisposition by the germline variations and a second hit by somatic variations could lead to the progression to PTC.

Keywords: ARHGEF28; FBXW10; HRAS; SLC47A1; XRCC1; familial non-medullary thyroid cancer (FNMTC); papillary thyroid carcinoma (PTC); protein–protein interactions (PPIs); whole exome sequence (WES).

Figure 1

Simplified pedigree of the Bedouin kindred. The two left branches are our current focus. Black symbols denote FNMTC; grey symbols denote MNG. * Available DNA, ** whole exome sequence available. : top—patient’s code; bottom—patient’s age at diagnosis. : number of individuals.

Figure 2

Evolutionary conservation and 3D structure of ARHGEF28, FBXW10, and SLC47A1 proteins. (A) The evolutionary conservation in the region of the proteins containing the variations. An * (asterisk) indicates a fully conserved residue. A : (colon) indicates conservation between groups of strongly similar properties. A . (period) indicates conservation between groups of weakly similar properties. (B) The predicted 3D structure of the proteins. Part 1—ARHGEF28, the left side represents residues 1–285 of the overall 3D structure of the ARHGEF28 protein, based on the alpha fold model (accession code—Q8N1W1). The right side presents a zoomed-in view of the site of the affected amino acid, Asn108, and its hydrogen bonds (dashed lines) connecting it to the Ser154 and Arg163 amino acids. Part 2—FBXW10, the left side represents the propellor domain, residues 339–693 of the overall 3D structure of the FBXW10 protein, based on the alpha fold model (accession code—Q5XX13). The right side presents a zoomed-in view of the site of the affected amino acid, Ile440, and its hydrogen bonds connecting it to the Asp438 and Lys443 amino acids. Part 3—SLC47A1, zoomed-in view of the site of the affected amino acid, Gly288 of the SLC47A1 protein, based on the alpha fold model (accession code—Q96FL8).