Abstract
Simple SummaryTumor biomarkers are molecules at genetic or protein level, or certain evaluable characteristics. These help in perfecting patient management. Over the past decade, advanced and more sensitive techniques have led to the identification of many new biomarkers in the field of oncology. A knowledge of the recent developments is essential for their application to clinical practice, and furthering research. This review provides a comprehensive account of such various markers identified in thyroid carcinoma, the most common endocrine malignancy. While some of these have been brought into use in routine patient management, others are novel and need more research before clinical application.Thyroid cancer is the most common endocrine malignancy. Recent developments in molecular biological techniques have led to a better understanding of the pathogenesis and clinical behavior of thyroid neoplasms. This has culminated in the updating of thyroid tumor classification, including the re-categorization of existing and introduction of new entities. In this review, we discuss various molecular biomarkers possessing diagnostic, prognostic, predictive and therapeutic roles in thyroid cancer. A comprehensive account of epigenetic dysregulation, including DNA methylation, the function of various microRNAs and long non-coding RNAs, germline mutations determining familial occurrence of medullary and non-medullary thyroid carcinoma, and single nucleotide polymorphisms predisposed to thyroid tumorigenesis has been provided. In addition to novel immunohistochemical markers, including those for neuroendocrine differentiation, and next-generation immunohistochemistry (BRAF V600E, RAS, TRK, and ALK), the relevance of well-established markers, such as Ki-67, in current clinical practice has also been discussed. A tumor microenvironment (PD-L1, CD markers) and its influence in predicting responses to immunotherapy in thyroid cancer and the expanding arena of techniques, including liquid biopsy based on circulating nucleic acids and plasma-derived exosomes as a non-invasive technique for patient management, are also summarized.
Highlights
The most frequent mutation detected in follicular adenoma (FA) and follicular thyroid carcinomas (FTCs) occurs in RAS genes (NRAS, HRAS, and KRAS), followed by mutations of DICER1, EZH1, EIF1AX, PTEN, IDH1, and SPOP, and PPARG gene fusion (Figure 1) [8]
While FTC is one of the major criteria recommended by NCCN for the diagnosis of PTEN hamartoma tumor syndrome, papillary thyroid carcinomas (PTCs) or its follicular variant and other thyroid structural lesions, such as adenoma, and multinodular goiter (MNG) are included among the minor criteria [52]
Hypermethylation can lead to the silencing of tumor suppressor genes, leading to carcinogenesis; common examples in thyroid cancer include Ras association domain family 1; isoform A (RASSF1A); cyclin-dependent kinase inhibitor 2A (CDKN2A or P16INK4A); death-associated protein kinase1 (DAPK); tissue inhibitor of metalloproteinase-3 (TIMP3); SLC5A8; SLC5A5; thyroid stimulating hormone receptor (TSHR); PTEN; retinoic acid receptor β2 (RARβ2); RAP1 GTPase activating protein (RAP1GAP); and fibroblast growth factor receptor (FGFR) 2 [73,74,75,76]
Summary
As thyroid cancers encompass a broad gamut of tumors differing in their molecular, histologic features and clinical behavior, there is a need for identifying robust biomarkers for accurate diagnosis and management. Such markers will be helpful in improving the preoperative categorization of thyroid nodules, 15–30% of which remain diagnostically challenging to fine needle aspiration (FNA) specimens [6]. Recent and continuing developments, including the use of high-throughput technologies, have led to the identification of many new biomarkers in the field of thyroid cancer These aid in accurate and, in some cases, early diagnosis, and provide useful information in guiding clinical decision-making in patients with thyroid cancer. This review provides a comprehensive overview of the recent advances in genetic and epigenetic alterations and protein expression as biomarkers for thyroid neoplasms
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