Genetics and epigenetics of sporadic thyroid cancer

Abstract

Thyroid carcinoma is the most common endocrine malignancy, and although the disease generally has an excellent prognosis, therapeutic options are limited for patients not cured by surgery and radioiodine. Thyroid carcinomas commonly contain one of a small number of recurrent genetic mutations. The identification and study of these mutations has led to a deeper understanding of the pathophysiology of this disease and is providing new approaches to diagnosis and therapy. Papillary thyroid carcinomas usually contain an activating mutation in the RAS cascade, most commonly in BRAF and less commonly in RAS itself or through gene fusions that activate RET. A chromosomal translocation that results in production of a PAX8-PPARG fusion protein is found in follicular carcinomas. Anaplastic carcinomas may contain some of the above changes as well as additional mutations. Therapies that are targeted to these mutations are being used in patient care and clinical trials.

Keywords: Anaplastic; BRAF; Follicular; PAX8-PPARG; Papillary; RAS.

Fig. 1

Pie chart showing the most common histological types of thyroid carcinoma and the most common mutations and gene fusions within each type. ATC, anaplastic thyroid carcinoma; FTC, follicular thyroid carcinoma; FVPTC, follicular variant papillary thyroid carcinoma; PPFP, PAX8-PPARG fusion protein; PTC, papillary thyroid carcinoma. Recurring mutations in ATC are not shown.

Fig. 2

Gene mutations and signaling pathways in thyroid carcinomas. Simplified schematic diagrams are shown of the RAS/MAPK and PI3K/AKT pathways. Proteins with reported mutations in thyroid carcinomas are in red. There are many protein targets of these pathways that contribute to oncogenesis, some of which are common to both pathways. A subset of these targets is shown. A question mark appears with the arrow from PAX8-PPARG because the mechanisms by which this fusion protein contributes to oncogenesis are not well understood. Similarly, the arrow from IDH1 has a question mark since the mechanisms by which IDH1 mutations contribute to thyroid cancer are poorly understood. RTK, receptor tyrosine kinase.