Molecular Genetics of Thyroid Cancer: Implications for Diagnosis, Treatment and Prognosis

Marina N Nikiforova; Yuri E Nikiforov

Disclosures

Expert Rev Mol Diagn. 2008;8(1):83-95. 

In This Article

Abstract and Introduction

Thyroid cancer is the most common malignant tumor of the endocrine system and accounts for approximately 1% of all newly diagnosed cancer cases. The most frequent type of thyroid malignancy is papillary carcinoma, which constitutes approximately 80% of all cases. Papillary carcinomas frequently have genetic alterations leading to the activation of the MAPK signal pathway. Those include RET/PTC rearrangement and point mutations of the BRAF and RAS genes. Mutations in these genes are found in over 70% of papillary carcinomas and they rarely overlap in the same tumor. Frequent genetic alterations in follicular carcinomas, the second most common type of thyroid malignancy, include RAS mutations and PAX8-PPARγ rearrangement. RET point mutations are crucial for the development of medullary thyroid carcinomas. Many of these mutations, particularly those leading to the activation of the MAPK pathway, are being actively explored as therapeutic targets for thyroid cancer. Detection of these genetic alterations using molecular techniques is important for preoperative fine-needle aspiration diagnosis, prognosis and treatment of thyroid cancer.

Thyroid cancer is the most common malignant tumor of the endocrine system and accounts for approximately 1% of all newly diagnosed cancer cases. Its incidence has increased significantly in the USA and other countries over the last several decades.[1,2] Most thyroid cancers originate from thyroid follicular cells (Figure 1). The most frequent type of thyroid malignancy is papillary carcinoma, which constitutes approximately 80% of all cases, and this tumor type is primarily responsible for the overall increase in incidence of thyroid cancer.[3] The second most common tumor type is follicular carcinoma, which accounts for approximately 15% of all thyroid malignancies and may be of conventional or oncocytic (Hurthle cell) type.[4] It is likely that follicular carcinomas can develop either from pre-existing benign follicular adenomas or directly, bypassing the stage of adenoma. These follicular cell-derived tumors are well differentiated, in contRASt to poorly differentiated and anaplastic thyroid carcinomas, which can arise de novo or from pre-existing well-differentiated papillary or follicular carcinomas. Anaplastic and poorly differentiated carcinomas are rare (~2% of all thyroid cancer cases) and represent the most aggressive types of thyroid cancer. Thyroid medullary carcinoma originates from parafollicular C cells and accounts for approximately 3% of thyroid cancer.[4]

Schematic representation of thyroid cancer origin and its putative progression. Oncocytic adenoma and carcinoma are currently considered to be variants of follicular adenoma and carcinoma. Papillary carcinoma may be of the classical type or manifests as one of its variants, including oncocytic variant of papillary carcinoma.

Recent years have been marked by significant expansion in the understanding of the molecular basis of thyroid carcinogenesis. It has become apparent that thyroid tumors, especially those of the papillary type, frequently have genetic alterations leading to activation of the MAPK signaling pathway. These include RET/PTC rearrangement and point mutations of the BRAF and RAS genes. In thyroid follicular carcinomas, in addition to RAS mutations and PAX8-PPARγ rearrangement, alterations involving the PI3K/AKT signaling pathway are likely to play a role, particularly in later stages of tumor progression. These alterations, as well as those involving the TP53 and CTNNB1 gene, occur with variable prevalence in poorly differentiated and anaplastic carcinomas. RET point mutations are common in medullary thyroid carcinomas. Many of these mutations are associated with distinct phenotypical features of tumors, and some of them serve as markers of more aggressive tumor behavior. Current molecular techniques allow the detection of these genetic alterations in thyroid fine-needle aspiration (FNA) samples and surgically removed samples, offering useful information for diagnosis and management of patients with thyroid cancer. Many of these mutations, particularly those leading to the activation of the MAPK pathway, are being actively explored for targeted therapy of thyroid cancer.

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