Molecular pathogenesis and mechanisms of thyroid cancer

Abstract

Thyroid cancer is a common endocrine malignancy. There has been exciting progress in understanding its molecular pathogenesis in recent years, as best exemplified by the elucidation of the fundamental role of several major signalling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these pathways, such as mutation, gene copy-number gain and aberrant gene methylation. Many of these molecular alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for thyroid cancer, which provide unprecedented opportunities for further research and clinical development of novel treatment strategies for this cancer.

An update on molecular biology of thyroid cancers

“…The most common genetic changes in PTC include point mutations of BRAF which are observed in 35-70% of papillary thyroid carcinomas [29,30]. More than 95% of BRAF mutations detected in thyroid cancers are thymine to adenine transversions at position 1799 (T1799A) resulting in the substitution of valine by glutamate at residue 600 (V600E) ( Table 1) [31]. This mutation causes constitutive activation of BRAF kinase and, thus, induction of the MAPK signaling pathway, which is responsible for thyroid tumorigenesis [14,31].…”

“…More than 95% of BRAF mutations detected in thyroid cancers are thymine to adenine transversions at position 1799 (T1799A) resulting in the substitution of valine by glutamate at residue 600 (V600E) ( Table 1) [31]. This mutation causes constitutive activation of BRAF kinase and, thus, induction of the MAPK signaling pathway, which is responsible for thyroid tumorigenesis [14,31]. In small percentages of PTC, K601E point mutation, small deletions or insertion around codon 600 and AKAP9/BRAF rearrangement are also be observed [30].…”

“…The BRAF point mutation is the most common mutation in PTC (35-70%) and has recently been reported to be associated with poor prognostic features like extrathyroidal soft tissue infiltration, lymph node metastasis, disease aggressiveness, tumor recurrence, loss of radioiodine avidity and, thus, resistance to annual therapeutic methods [29][30][31][32][33][34]199,200]. Additionally, the BRAF mutation occurs most commonly in aggressive subtypes of PTC [178,201].…”

Genetic alterations of differentiated thyroid carcinoma in iodine‐rich and iodine‐deficient countries

“…RET is a proto‐oncogene encoding a RTK (receptor tyrosine kinase). There are more than 10 types of RET/PTC rearrangements, and the most common types are RET/PTC1 and RET/PTC3 26.…”

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

“…Notably, the most aggressive form of thyroid cancer, anaplastic thyroid cancer (ATC), has a mortality rate of nearly 100%, with median survival time of 3-5 months, mainly because of local invasion and metastasis to lung, lymph nodes (LNs), and other tissues (2). The mechanisms that mediate metastasis in ATC strongly depend on the activation of genetic mutations, such as V-Raf murine sarcoma viral oncogene homolog B (BRAF), TP53, RAS, PIK3CA, and AKT1 (3). Current treatments for ATC rely on various combinations of surgical resection with adjuvant therapies, such as chemotherapy and radiotherapy, but have shown only limited survival benefits (4).…”