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

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.

Prevalence of Malignancy in MNG: Final Histopathology Perspective

Objective: To determine the malignancy in multinodular goiter by doing final histopathology of specimen. Study Design: This is an observational study. Setting: Study carried out in the department of ENT, Head & Neck Surgery of Khairpur Medical College Hospital Khairpur, from August 2016 to July 2019. Materials and Methods: All those patients with MNG with or without thyrotoxicosis were selected and advised for Thyroid function tests, ultrasound thyroid and serum calcium level. FNAC was performed only in cases with suspicious nodule. All the patients under went total/near total thyroidectomy after all base line routine investigations along with thyroid function tests. Histopathological evaluation was also conducted. Results: Out of total 70 patients with MNG, 17 (24.3%) cases were suspected of malignancy. Out of 17 suspicious cases, FNAc showed colloid goiter in 8 (47%), follicular in 7 (41%) cases and papillary in 2 (12%) cases. Final histopathology showed total 5 (29%) cases as malignant and remaining 12 (71%) cases were benign. Out of 5 malignant cases, 4 (80%) cases were papillary and 1 (20%) cases were Follicular cell carcinoma. While other 53 (75.7%) cases under went for near total thyroidectomy and specimens sent for histopathology, among these only 1 (2%) case found as Papillary cell Carcinoma. Total 6 cases were malignant out of which in which 5 cases were Papillary cell Carcinoma and one was Follicular cell Carcinoma. Conclusion: We conclude that multinodular goiter is the most prevalent thyroid disease found in female. Follicular thyroid carcinoma is the most frequent cancer seen in this study.

Familial thyroid follicular cell carcinomas in a large number of Dutch German longhaired pointers

Thyroid carcinomas originating from follicular cells of the thyroid gland occur in both humans and dogs and they have highly similar histomorphologic patterns. In dogs, thyroid carcinomas have not been extensively investigated, especially concerning the familial origin of thyroid carcinomas. Here we report familial thyroid follicular cell carcinomas confirmed by histology in 54 Dutch origin German longhaired pointers. From the pedigree, 45 of 54 histopathologically confirmed cases are closely related to a pair of first-half cousins in the past, indicating a familial disease. In addition, genetics contributed more to the thyroid follicular cell carcinoma than other factors by an estimated heritability of 0.62 based on pedigree. The age of diagnosis ranged between 4.5 and 13.5 years, and 76% of cases were diagnosed before 10 years of age, implying an early onset of disease. We observed a significant higher pedigree-based inbreeding coefficient in the affected dogs (mean F 0.23) compared to unaffected dogs (mean F 0.14), suggesting the contribution of inbreeding to tumour development. The unique occurrence of familial thyroid follicular cell carcinoma in this dog population and the large number of affected dogs make this population an important model to identify the genetic basis of familial thyroid follicular cell carcinoma in this breed and may contribute to the research into pathogenesis, prevention and treatment in humans.