Deleterious Mutations in the TPO Gene Associated with Familial Thyroid Follicular Cell Carcinoma in Dutch German Longhaired Pointers

Abstract

Familial thyroid cancer originating from follicular cells accounts for 5–15% of all the thyroid carcinoma cases in humans. Previously, we described thyroid follicular cell carcinomas in a large number of the Dutch German longhaired pointers (GLPs) with a likely autosomal recessive inheritance pattern. Here, we investigated the genetic causes of the disease using a combined approach of genome-wide association study and runs of homozygosity (ROH) analysis based on 170k SNP array genotype data and whole-genome sequences. A region 0–5 Mb on chromosome 17 was identified to be associated with the disease. Whole-genome sequencing revealed many mutations fitting the recessive inheritance pattern in this region including two deleterious mutations in the TPO gene, chr17:800788G>A (686F>V) and chr17:805276C>T (845T>M). These two SNP were subsequently genotyped in 186 GLPs (59 affected and 127 unaffected) and confirmed to be highly associated with the disease. The recessive genotypes had higher relative risks of 16.94 and 16.64 compared to homozygous genotypes for the reference alleles, respectively. This study provides novel insight into the genetic causes leading to the familial thyroid follicular cell carcinoma, and we were able to develop a genetic test to screen susceptible dogs.

A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs

“…Five dogs were males and two were females (GLP 36 and 37). All 7 dogs were homozygous for the mutations in the TPO gene associated with the disease identified in our previous study [ 2 ]. The histological subtypes of FCCs include 3 FTCs, 2 FCTCs, 1 CTC, and 1 carcinosarcoma.…”

“…We also performed Sanger sequencing on normal DNA (obtained from blood) of the 7 dogs used in this study and none of them captured the GNAS mutation, confirming that these were somatic mutations. To ensure further that the GNAS p.A204D mutation is generally not present as a germline variant, we checked that this mutation was not present in the whole genome sequences that we previously obtained from blood DNA of 22 GLPs [ 2 ].…”

“…RNA-seq of tumor tissue was obtained and mapped to dog reference genome CanFam3.1, as described previously [ 2 ]. Mapping was performed using HISAT2 [ 44 ].…”

“…The familial FCC was heterogeneous with 5 different histological subtypes: follicular thyroid carcinoma (FTC), papillary thyroid carcinoma (PTC), compact thyroid carcinoma (CTC), follicular-compact thyroid carcinoma (FCTC), and carcinosarcoma. Two homozygous deleterious mutations in the TPO gene were identified to be the germline risk factors of FCC predisposition in these dogs, based on a genome-wide association study (GWAS) and whole-genome sequencing (WGS) analysis [ 2 ]. However, besides the germline risk factors, key somatic mutations (driver mutations) also play an important role.…”

“…In this study, we generated whole genome sequencing data from both the tumor tissue and the matched animal genome. The 7 animals included in this study were closely related and are homozygous for the TPO variants associated with the disease we reported in our previous study [ 2 ]. Somatic single nucleotide variants (SNVs), structural variants (SVs), and copy number alterations (CNAs) were investigated.…”