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Molecular pathogenesis and mechanisms of thyroid cancer

Nature Reviews Cancer volume 13, pages 184–199 (2013)Cite this article

Subjects

Key Points

  • Thyroid cancer is a common endocrine malignancy, and exciting progress has occurred in recent years in understanding its molecular pathogenesis.

  • Genetic and epigenetic alterations are the driving forces of thyroid cancer. Examples of these alterations include mutations in BRAF (BRAFV600E), RAS, PIK3CA, PTEN, TP53, β-catenin (CTNNB1), anaplastic lymphoma kinase (ALK) and isocitrate dehydrogenase 1 (IDH1), translocations (RET–PTC and paired box 8 (PAX8)–peroxisome proliferator-activated receptor-γ (PPARG)) and aberrant gene methylation.

  • At the core of the molecular pathogenesis of thyroid cancer is the uncontrolled activity of various signalling pathways, including the MAPK, PI3K–AKT, nuclear factor-κB (NF-κB), RASSF1–mammalian STE20-like protein kinase 1 (MST1)–forkhead box O3 (FOXO3), WNT–β-catenin, hypoxia-inducible factor 1α (HIF1α) and thyroid-stimulating hormone (TSH)–TSH receptor (TSHR) pathways.

  • The progression of thyroid cancer is a process of accumulation of genetic and epigenetic alterations with corresponding progressive derangements of signalling pathways. These are accompanied by numerous secondary molecular alterations, both in the cell and in the tumour microenvironment, which, acting in cooperation, amplify and synergize their impacts on thyroid tumorigenesis.

  • Aberrant silencing of thyroid iodide-handling genes and consequent loss of radioiodine avidity of thyroid cancer promoted by BRAF-V600E is a unique molecular pathological process in thyroid cancer, which causes the failure of radioiodine treatment.

  • The recent molecular findings provide unprecedented opportunities for further research and clinical development of novel molecular-based treatment strategies for 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.

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Figure 1: The MAPK and related pathways in thyroid cancer.
Figure 2: The PI3K–AKT and related pathways in thyroid cancer.
Figure 3: Model of the progression of thyroid tumorigenesis driven by the MAPK and PI3K–AKT pathways.
Figure 4: Iodide-handling machinery in the thyroid cell and its silencing by BRAF-V600E.

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Acknowledgements

This work is supported by the US National Institutes of Health (NIH) R01 grants CA113507 and CA134225 to the author. The author thanks A. K. Murugan, Y. Trink and D. Liu for their help in preparing the figures and references. The author also thanks the numerous colleagues and investigators in this field whose outstanding work made it an extremely enjoyable experience to write this Review. The author wishes to apologize to those whose work is not cited owing to space limitations.

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  1. Division of Endocrinology and Metabolism, Laboratory for Cellular and Molecular Thyroid Research, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, 21287, Maryland, USA

    Mingzhao Xing

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  1. Mingzhao Xing
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Correspondence to Mingzhao Xing.

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M.X. receives royalty payments as co-holder of the United States of America patent on the initial discovery and clinical characterization of BRAFV600E mutation in thyroid cancer.

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Glossary

Differentiated thyroid cancer

(DTC). Collectively includes both papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), which are histologically differentiated, by comparison with poorly differentiated thyroid cancer (PDTC) and undifferentiated anaplastic thyroid cancer (ATC).

Radioiodine treatment

A classical treatment for patients with thyroid cancer. It is used after total thyroidectomy and consists of treating patients with the radioiodine isotope 131I, which emits high-energy β-particles and takes advantage of the unique function of thyroid follicular cells to accumulate iodide as a substrate for the synthesis of thyroid hormone.

MAPK pathway

This pathway has a fundamental role in the regulation of cell growth, proliferation, apoptosis and metabolic activities, through regulating the expression of various genes.

PI3K–AKT pathway

This pathway also has a fundamental role in the regulation of cell growth, proliferation, apoptosis and metabolic activities, through regulating the expression of various genes.

Pten

A tumour suppressor gene, the protein product of which converts phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol (4,5)-trisphosphate (PIP2), counteracting the conversion of PIP2 to PIP3 by PI3K and thus terminating PI3K–AKT signalling.

Cowden's syndrome

Also known as Cowden's disease or multiple hamartoma syndrome. A rare, autosomally inherited disorder that is caused by mutations or defects in the tumour suppressor gene PTEN and is characterized by multiple tumour-like growths called hamartomas and an increased risk of certain cancers, such as breast cancer and follicular thyroid cancer.

Copy-number gain

A genetic abnormality in which the copy number of a chromosomal region or gene is more than the normal two copies (one paternal allele and one maternal allele), which occurs through the amplification of a local region of DNA within a chromosome, or through aneuploidy, in which multiple copies or fragments of identical chromosomes are present.

Receptor tyrosine kinases

(RTKs). These are typically growth-promoting transmembrane receptors that transduce extracellular signalling into intracellular signalling through the activation of their cytoplasmic kinase domain in response to extracellular signals such as ligand-binding.

Gene translocation

A genetic rearrangement in which a chromosomal fragment is translocated to another chromosome where it is not normally located, which may create a recombinant gene product with new function or uncontrolled function (compared with the original gene product).

Follicular thyroid tumours

Collectively includes follicular thyroid adenoma (FTA), follicular thyroid cancer (FTC) and follicular variant papillary thyroid cancer (FVPTC); they share common dense follicular cell architectures.

Gene methylation

An epigenetic covalent addition of a methyl group to the fifth carbon of the cytosine residue in a CpG dinucleotide, typically in CpG islands (that is, CpG-rich regions) in the 5′-flanking promoter regions of genes. Such methylation is usually closely associated with chromatin remodelling and silencing of the corresponding genes.

Capsular invasiveness

A phenomenon in which thyroid cancer invades the connective tissue capsule that surrounds the tumour, which is a defining feature of progression to malignancy from a benign thyroid tumour.

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Xing, M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 13, 184–199 (2013). https://doi.org/10.1038/nrc3431

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