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Mechanisms of Disease: hydrogen peroxide, DNA damage and mutagenesis in the development of thyroid tumors

Abstract

Somatic mutations can be identified in two-thirds of papillary and follicular thyroid carcinomas and 'hot' thyroid nodules, whereas equivalent mutations relevant for benign 'cold' thyroid nodules are unknown. This Review summarizes current knowledge about early molecular conditions for nodular and tumor transformation in the thyroid gland. We reconstruct a line of events that could explain the predominant neoplastic character (i.e. originating from a single mutated cell) of thyroid nodular lesions. This process might be triggered by the oxidative nature of thyroid hormone synthesis or additional oxidative stress caused by iodine deficiency or smoking. If the antioxidant defense is not effective, this oxidative stress can cause DNA damage followed by an increase in the spontaneous mutation rate, which is a platform for tumor genesis. The hallmark of thyroid physiology—H2O2 production during hormone synthesis—is therefore very likely to be the ultimate cause of frequent mutagenesis in the thyroid gland. DNA damage and mutagenesis could provide the basis for the frequent nodular transformation of endemic goiters.

Key Points

  • Histologically, thyroid nodules can be hyperplastic nodules or true tumors; both can be classified as hypofunctional, normofunctional or hyperfunctional, and the latter include carcinomas

  • The high frequency of thyroid tumors despite a slow proliferation rate of thyroid epithelial cells suggests a high mutation rate and/or a susceptibility to aberrant growth stimulation

  • H2O2 is crucial for the generation of thyroid hormones but is a potential source of reactive oxygen intermediates, which can lead to DNA damage if antioxidant defenses are inadequate

  • Iodine deficiency, selenium deficiency or tobacco smoking can increase levels of H2O2 and decrease antioxidant defenses

  • Conditions such as iodine deficiency, pregnancy and goitrogens can increase thyroid cell proliferation and contribute to the high rates of thyroid tumors

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Figure 1: The classification of thyroid nodules on the basis of results from clonality studies.
Figure 2: The two concepts of thyroid nodular transformation.
Figure 3: Mechanisms that might cause mutagenesis in the thyroid gland.
Figure 4: Factors that might contribute to the development of thyroid tumors.

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Correspondence to Ralf Paschke.

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Supplementary information

Supplementary Table 1

Supplementary information, in the form of a table listing the known oxidative DNA-base modifications and their consequences for mutations, is available on the Nature Clinical Practice Endocrinology & Metabolism website. (DOC 241 kb)

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Krohn, K., Maier, J. & Paschke, R. Mechanisms of Disease: hydrogen peroxide, DNA damage and mutagenesis in the development of thyroid tumors. Nat Rev Endocrinol 3, 713–720 (2007). https://doi.org/10.1038/ncpendmet0621

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