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Molecular genetics and diagnosis of thyroid cancer

Abstract

Thyroid cancer is a common type of endocrine malignancy, and its incidence has been steadily increasing in many regions of the world. Initiation and progression of thyroid cancer involves multiple genetic and epigenetic alterations, of which mutations leading to the activation of the MAPK and PI3K–AKT signaling pathways are crucial. Common mutations found in thyroid cancer are point mutation of the BRAF and RAS genes as well as RET/PTC and PAX8/PPARγ chromosomal rearrangements. The mutational mechanisms seem to be linked to specific etiologic factors. Chromosomal rearrangements have a strong association with exposure to ionizing radiation and possibly with DNA fragility, whereas point mutations probably arise as a result of chemical mutagenesis. A potential role of dietary iodine excess in the generation of BRAF point mutations has also been proposed. Somatic mutations and other molecular alterations have been recognized as helpful diagnostic and prognostic markers for thyroid cancer and are beginning to be introduced into clinical practice, to offer a valuable tool for the management of patients with thyroid nodules.

Key Points

  • Activation of MAPK and PI3K–AKT signaling pathways is important for thyroid cancer initiation and progression

  • Common mutational mechanisms in thyroid cancer are point mutations, such as those in the RAS and BRAF genes, and chromosomal rearrangements, such as RET/PTC and PAX8/PPARγ

  • RET/PTC and BRAF/AKAP9 chromosomal rearrangements have strong correlation with radiation exposure; RET/PTC can also develop via induction of chromosome fragility

  • Association between BRAF point mutations and high iodine intake or exposure to chemical elements present at high levels in volcanic areas has been proposed

  • Mutational markers can be used to improve cancer diagnosis in fine-needle aspiration samples from thyroid nodules and to aid tumor prognostication

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Figure 1: Scheme of step-wise dedifferentiation of follicular cell-derived thyroid cancer.
Figure 2: The main signaling pathways involved in thyroid carcinogenesis are the MAPK and PI3K–AKT pathways.
Figure 3: Molecular alterations in papillary thyroid cancer and their average prevalence and association with clinical and histopathological features of tumors.
Figure 4: In papillary thyroid cancer, activation of the MAPK signaling pathway occurs via two main mechanisms: chromosomal rearrangement or point mutations, which correlate with distinct etiologic factors.
Figure 5: Potential clinical management of patients with thyroid nodules on the basis of a combination of cytological examination and molecular analysis.

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This work was supported by the NIH grant CA88041.

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Nikiforov, Y., Nikiforova, M. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol 7, 569–580 (2011). https://doi.org/10.1038/nrendo.2011.142

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