Familial thyroid carcinoma

Genetic predisposition of thyroid carcinoma

Thyroid carcinoma is the most common endocrine malignancy and papillary thyroid carcinoma (PTC) its most prevalent subtype. PTC represents non-medullary thyroid cancer and accounts for 80-90 % of all thyroid cancers. Up to 15% of PTCs are familial. Apart from a small subset of PTCs belonging to well-defined cancer syndromes such as familial adenomatous polyposis, no high-penetrance susceptibility genes for familial PTC are known. Moreover, no systematic, genome-wide searches for such genes on Finnish PTC families have been performed to date.

This project proposes a comprehensive evaluation of non-syndromic PTC for genetic predisposition (protein coding variants), gene regulatory mechanisms (non-coding variants) and tumorigenesis (somatic gene variants). The experiments will be conducted on Finnish PTC families to be identified through clinical and pathological diagnostics combined with registry-based search. Whole genome sequencing (WGS) will be used to reveal protein-coding and gene regulatory variants from constitutional and tumor tissues, supplemented with relevant functional analyses for variants co-segregating with disease phenotype in the families. Both familial and sporadic PTCs will be utilized for tumorigenesis studies. The role of the familial PTC-associated genes as somatic mutational targets in sporadic PTCs will be assessed in 1500 consecutive PTC samples; collection of paired normal and tumor specimens from the Finnish biobanks is underway. During my Visiting Scholar years (2018-2019) at the Ohio State University (OSU), we made many interesting preliminary observations, including the discovery of putative predisposing and regulatory variants for familial PTC. Results obtained from the Finnish families will be compared with those from the OSU PTC families.

A joint investigation of constitutional predisposition, gene regulation, and tumorigenesis, combined with the possibility to compare familial and sporadic PTCs as well as Finnish and OSU PTC families, constitute important advantages of this investigation. The findings are likely to clarify the complex genetic background of familial PTC, the regulatory circuits, and the signaling pathways required for tumorigenesis. This has the potential to provide new tools for diagnostics, disease classification, and treatment. Therefore, apart from basic science advances anticipated from this research, a significant impact on public health is likely.