Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Thyroid Carcinoma [C73]

OMIM numbers: 188550, 188470, BRAF (164757), HRAS (190020), KRAS (190070), RET (164761)NRAS (164790)

Dipl.-Ing. (FH) Tanja Hinrichsen,
Prof. Dr. med. Barbara Dockhorn-Dworniczak

Scientific Background

Thyroid tumors are the most common endocrine tumors and are responsible for 1-5% of tumors in women and <2% in men. It is a heterogeneous disease that develops from two different epithelial cell types. Most thyroid carcinomas arise from follicular cells. These include papillary thyroid cancer (PTC) (75-85% of cases), follicular thyroid cancer (FTC) (10-15% of cases), Hurthle cell cancer and anaplastic thyroid cancer (ATC). Medullary thyroid cancer (MTC), on the other hand forms from parafollicular calcitonin producing cells and can be part of multiple endocrine neoplasia 2 (MEN2).

PTC and FTC are referred to as differentiated thyroid cancer (DTC) and account for 90-95% of all thyroid carcinomas. In general, these are slow growing tumors associated with an excellent prognosis and a 20-year survival rate of >90% with conventional therapy, which consists of a resection with or without thyroid removal, radioactive iodine therapy and suppressive thyroid hormone therapy. However, a number of patients with DTC have a more aggressive form of disease with recurrent or metastatic progression and an unresponsiveness to radioactive iodine therapy. Molecular markers can help, if necessary, to improve the preoperative diagnosis of thyroid carcinoma and in prognostic stratification.

Tumors with mutations in BRAF are often undifferentiated and associated with more aggressive characteristic such as a poor response to radioactive iodine therapy. The most common mutation in BRAF is the BRAF V600E mutation, which leads to a constitutive activation of the MAPK signaling pathway and to uncontrolled cell growth. It is found in 45-59% of PTCs, primarily in the classic papillary and large cell variants, and in 80% of patients with recurrent or metastatic PTC. In addition, it occurs in 20-40% of poorly differentiated thyroid cancers and 30-40% of ATCs. Combination therapy with BRAF and MEK inhibitors (Dabrafenib and Trametinib) is currently being tested in a phase II study.

Tumors with mutations in NRAS, HRAS and KRAS are often differentiated and associated with follicular growth. RAS mutations are found in 40-50% of FTCs, 10-20% of the follicular variant PTCs, 20-40% of poorly differentiated thyroid carcinomas and ATCs and in 20-40% of benign follicular adenocarcinomas.

MTC accounts for around 3-5% of thyroid carcinomas. Approximately 25% of MTCs are hereditary and show germline mutations in the RET gene. Somatic mutations in RET can also be detected in approximately 50% of sporadic MTCs. In 75-95% of cases a RET M918T mutation, which is associated with aggressive progression, is seen. In 10-45% of sporadic, RET wild type MTCs, mutations in NRAS, HRAS and KRAS are also found. These mutations could possibly have an influence in the future on targeted therapies with the tyrosine kinase inhibitors Vandetanib and Cabozantinib.