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Identification of crucial genes involved in thyroid cancer development



A malignancy of the endocrine system, one of the most common types, is thyroid cancer. It is proven that children who receive radiation treatment for leukemia or lymphoma are at a heightened risk of thyroid cancer due to low-dose radiation exposure throughout childhood. Several factors can increase the risk of thyroid cancer (ThyCa), such as chromosomal and genetic mutations, iodine intake, TSH levels, autoimmune thyroid disorders, estrogen, obesity, lifestyle changes, and environmental contaminants.


The study aimed to identify a specific gene as an essential candidate for thyroid cancer progression. We might be able to focus on developing a better understanding of how thyroid cancer is inherited.


The review article uses electronic databases such as PubMed, Google Scholar, Ovid MEDLINE, Embase, and Cochrane Central. The most frequently associated genes with thyroid cancer found on PubMed were BAX, XRCC1, XRCC3, XPO5, IL-10, BRAF, RET, and K-RAS. To perform an electronic literature search, genes derived from DisGeNET: a database of gene-disease associations, including PRKAR1A, BRAF, RET, NRAS, and KRAS, are used.


Examining the genetics of thyroid cancer explicitly emphasizes the primary genes associated with the pathophysiology of young and older people with thyroid cancer. Developing such gene investigations at the beginning of the thyroid cancer development process can identify better outcomes and the most aggressive thyroid cancers.


Thyroid cancer (ThyCa) develops in the thyroid gland (TG), a component of the endocrine system that controls hormone production in the body by collecting iodine from the circulation and converting it into thyroid hormones, which regulate metabolism. In the USA, we primarily see it in female patients, making up 3.1% of newly diagnosed malignancies. Every year in the USA, there are around 53,990 newly diagnosed ThyCa cases and 2060 fatalities. They found ThyCa in 14.3 people per 100,000 [1,2,3]. It was shown that radiation exposure increased the incidence of thyroid cancer by double [4] after the World War II atomic bombs of Hiroshima and Nagasaki. There is evidence that low-dose radiation exposure throughout childhood, such as in patients undergoing therapeutic radiation for leukemia or lymphoma, is linked to an elevated risk of ThyCa [5]. There is additional evidence that children treated with low-voltage radiation for acne have an increased risk of ThyCa. Although ThyCa is more common after radiation exposure, the biological activity of the illness is identical in radiation-exposed and non-radiation-induced thyroid cancers. The concept that different types of genomic instability might lead to distinct molecular carcinogenic pathways is now widely accepted [6]. The metabolic pathways of cancer cells are also changed to provide a constant supply of components essential for synthesizing membranes and expressing genes and proteins [7]. As a result, whereas radiation exposure appears to be significant in initiating the disease, there is no evidence that it is related to cancer aggressiveness [8]. Papillary carcinoma (accounting for more than 85% of cases), followed by follicular carcinoma (5 to 15% of cases), medullary carcinoma (5% of cases), anaplastic (undifferentiated) carcinoma (< 5% of cases) [9]. Both incidence and mortality (Fig. 1) estimates were presented by country and aggregated across the 20 UN-defined world regions and according to the UN’s four-tier Human Development Index (ie, low, medium, high, and very high) in 2020 [10].

Fig. 1
figure 1

Incidence and mortality rate of thyroid cancer

Thyroid carcinoma: molecular pathogenesis

Carcinogenesis is a multistage process with at least three phases or stages: initiation, promotion, and progression [11]. Several pathological factors associated with functional dedifferentiation led to thyroid cancer cells having lower iodide capacities and inadequate iodine absorption. Thyroid-stimulating hormones in thyroid cancer can increase iodine absorption. Iodine metabolism is abnormally affected by thyroglobulin synthesis defects, leading to malignant thyroid cell development. Iodoproteins are also produced and released into the bloodstream by thyroid tumors [12].

Over 90% of ThyCa patients have one or more genetic abnormalities [13]. Two distinct signaling cascades are involved in most of the targeted genes: Phosphatidylinositol 3-kinase (PI3K) and extracellular regulated kinase (ERK) play similar roles [14]. In eukaryotes, the ERK pathway is a numerous mitogen-activated protein kinase (MAPK) control module [15]. When a growth factor is activated, it attaches to the corresponding membrane receptor, which has tyrosine kinase catalytic activity (RTK). As a result, the RTK’s kinase activity is activated, followed by the conscription of guanine nucleotide exchange factors (GEF) that facilitates the packing of RAS small GTPases with GTP nucleotides. Besides being recruited to GTP-bound RAS, ARAF, BRAF, and CRAF, serine/threonine RAF kinases are triggered by phosphorylation and dimerization of MEK proteins, as illustrated in Fig. 2. MEKs are dual-activity kinases that phosphorylate the ERKs p44 and p42, which are serine/threonine kinases. Finally, active ERKs target a range of transcription factors directly or indirectly through other downstream kinases like p90RSK to significantly impact cellular transcriptional output [16]. RTKs or RAS, like the MAPK system, instantly activate PI3K [14]. The PIP3 trisphosphate is a phosphorylated form of phosphatidylinositol (3, 4, 5) and is the second intracellular messenger produced in PI3K. PIP3 activates the enzyme PDK1, which phosphorylates the serine/threonine kinase AKT/threonine PKB’s 308 residues.

Fig. 2
figure 2

Pathogenesis of thyroid carcinoma

By hydrolyzing PIP3, and PTEN (phosphatase and tensin homolog), phosphatase acts as a gatekeeper. Through inhibiting the tuberous sclerosis complex 2 (TSC2) by active AKT, mTOR rapamycin activates mTORC1’s mammalian target, initiating the Rheb small GTPase. mTOR promotes in a cell in which protein synthesis takes place and proliferation. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) is phosphorylated by p70-S6 kinase, which phosphorylates the ribosomal protein S6. Genetic mutations target several PI3K signaling pathway components in ThyCa [17, 18].

Thyroid tumor genesis and aging processes

Women are two to three times as likely as men to be affected by papillary thyroid cancer (PTC). The female-to-male ratio appears to be declining with age [19]. Notably, the elderly have a greater death risk from PTC. This is probably due to the higher mitotic activity of these tumors and the possibility of distant metastases [20]. Patients with aggressive PTC variations are more likely to gain metastatic disease in the general population identified [21]. The second most prevalent thyroid cancer is follicular thyroid carcinoma (FTC). Compared to PTC, this cancer has a poorer prognosis since it is more prone to hematogenous spread to distant areas. Up to 5% of thyroid malignancies are medullary thyroid carcinomas (MTC), which develop from the thyroid gland's parafollicular cells (C cells). Its sporadic form is more common than familial MTC and affects older adults more frequently. Anaplastic (undifferentiated) thyroid cancer (ATC) that proliferates and is often highly aggressive is uncommon; it should be emphasized, however, that elderly individuals are more likely to have it than younger ones. Most individuals have extensive local invasion and distant metastases by diagnosis. ATC’s poor prognosis appears to be strongly correlated with age [22].

Younger and older age population in thyroid carcinoma

Most cases in the 20- to 39-year-old age group are differentiated thyroid carcinoma (DTC), with PTC being the most common, accounting for around 85% of thyroid malignancies. Among young adults, the age group of 35 to 39 years old has the highest frequency of DTC. It is substantially more prevalent in females than males, and young adults, like the overall population, have seen a considerable increase in thyroid cancer incidence [23]. Thyroid cancer comprises various subtypes, but MTC is a rare subtype representing approximately 5% of all thyroid cancers [24]. Only around one-third of MTC cases involve people under 40, with a median age of diagnosis of 50.

Young individuals aged 20 to 24 have an annual incidence rate of 0.6 cases per million, whereas those aged 35 to 39 have a yearly incidence rate of 1.5 cases per million. In contrast to DTC, the young adult population shows no overt gender preference, with an average of 1.6 males for every female [25]. One in three young people, in addition to familial MTC, there is a familial multi-endocrine neoplasia type 2a or type 2b which are inherited tumor syndromes that cause familial MTC, are impacted (FMTC). Besides MTC, pheochromocytomas and hyperparathyroidism can develop in up to 20% of MEN2A patients and 50% of MEN2A and MEN2B patients. Additional symptoms include Hirschsprung’s disease, PTC, and cutaneous lichen amyloidosis [26]. Younger thyroid cancer patients outlived older patients overall and in cancer-specific survival, but they may receive more aggressive treatment [27]. Although many aging-related illnesses appear considerably more frequently in both age groups, there is a higher risk of thyroid cancer for thyroid cancer survivors diagnosed before the age of 40 [28]. We believe that one of the best indicators of prognosis is the age at which diagnosed anaplastic thyroid carcinoma is. Kim et al. investigated one hundred twenty-one patients with anaplastic thyroid carcinoma. In a multivariate analysis, age under 60, tumor size under 7 cm, and disease severity were independent predictors of a decline in cause-specific mortality [29]. Female MTC patients under 45 with thyroid involvement had the best overall prognosis of 100% survival after 10 years [30]. With a mean diagnosis of about 47 years, the sporadic variation of medullary carcinoma is more common in older people than the genetic variant in younger people. It can pass the hereditary form down through families. This condition occurs either as a genetic condition or as an expression of type 2A or type 2B multiple endocrine neoplasia syndrome [31].

Age and thyroid cancer staging: implications for prognosis

Risk stratification is one of the essential aspects of DTC treatment. Upon diagnosis, the clinicopathologic features of the tumor and the patient’s age are used to determine the prognosis. They associated a lower chance of survival in older patients with their age at diagnosis. The American Joint Committee on Cancer staging approach has the age in it DTC as the sole human malignancy. The patient’s age is a reliable indicator of ThyCa mortality, albeit the reason is unknown. The occurrence of the connection suggests that either the disease or the treatment has an age-dependent component [32, 33]. Research has shown that differences in the sodium–iodide symporter expression, essential for radioiodine absorption, correlate with patient age [34,35,36]. Age seems to affect how well a patient responds to therapy. Shah et al. examined death and recurrence rates in high-risk groups by American Thyroid Association (ATA), a risk assessment organization [37]. Patients over 55 had less chance of benefiting from therapy than younger patients. The disease-specific survival was lower in older patients with a partial response to treatment in the ATA-high-risk category. It has been found that tumor volume, type, penetrating vascular, extrathyroidal tumor extension, metastatic infection, and neck examination performance were all independent predictors of partial treatment response.

A molecular study has clarified the relevance of numerous tumor mutations, especially in the DTC oncogenesis, and the relationship with prognosis and age, BRAF, and TERT is essential [38,39,40,41,42]. The BRAF mutation has been traditionally about 45% of PTC patients in the USA have this condition, which is connected to reduced thyroid differentiation indicators such as thyroglobulin, thyroid peroxidase, and sodium/iodide symporter. Mutations in a PTC tumor are more likely to exist [43,44,45]. Although the BRAF mutation is a diagnostic marker for PTC, it is not a reliable sign of PTC mortality or recurrence [46, 47]. It has proven TERT promoter mutations reliable indicators of cancer-related mortality and DTC recurrence [48, 49]. Among the men and women living in the United States, there is a gender disparity in thyroid cancer incidence primarily confined to small subclinical PTCs detected. As a result of this trend, women have been affected more than men: during the period 1975 to 2017, PTC incidence increased by 13.3 cases per 100,000 women (from 4.6 to 17.9 cases, or 389%), while it decreased by 4.3 cases per 100,000 men (from 2.2 to 6.5 cases, or 295%). Several factors, including hormonal and reproductive factors, have been suggested to increase the likelihood of women developing thyroid cancer over men. There have been suggestions that thyroid cancer may be linked to a recent pregnancy, infertility, abnormal menstruation cycles, and breast cancer [50].

Genes associated with thyroid carcinoma

Different thyroid cancer types have been associated with changes in some genes and pathways, as shown in Fig. 3. This review summarises the most relevant ones (Table 1). DNA repair genes can be affected by gene polymorphisms that result in amino acid substitutions, resulting in different capacities to repair DNA damage due to genetic polymorphisms associated with amino acid substitutions. There have been several studies that have shown that certain types of environmental pollution are associated with genetic instability and the development of cancer. There have been several types of DNA repair mechanisms, including base excision repair (BER), nucleotide excision repair (NER), double-strand break repair (DSBR), mismatch repair (MR), and homologous recombination repair (HRR) that have been identified in mammalian cells. Ionizing radiation or oxidative damage in combination with methylation, oxidation, or reduction of non-bulky base adducts serves as the trigger for the BER pathway to eliminate them. As part of maintaining genomic integrity, several DNA repair pathways are regulated carefully, as well as modulating the repair capability in response to DNA damage to modulate TC susceptibility [51].

Fig. 3
figure 3

Genetic basis of thyroid carcinoma

Table 1 Candidate gene associated with thyroid carcinoma

A wide variety of diseases are associated with aberrant miRNA expressions, including cancer, according to a recent study that suggests that miRNA expressions may be related to a wide range of diseases. Several previous studies have demonstrated that the dysregulation of miRNAs in TC significantly affects the expression. The most important biological processes are imperative for survival are proliferation, metastasis, invasion, and apoptosis. When overexpression of XPO5 is observed, it is believed that the activity of miRNAs will be increased, whereas a decrease in XPO5 expression is thought this compound inhibits Pre-miRNA export; as a result, the increase in miRNA activity. The study of miRNA activity and quantity has demonstrated that even a slight alteration can adversely affect target mRNAs and cellular functions, so miRNA-related single-nucleotide polymorphisms have been identified in recent years as potential and valuable biomarkers for cancer prediction and prognosis [61].

It is critical the understanding the tumor microenvironment to be aware of how cancer occurs and develops. Several components, such as immune cells, stromal cells, cytokines, and chemokines, are involved in the immune system that can influence tumor growth positively or negatively. T lymphocytes, monocytes, macrophages, and endothelial cells are significant sources of interleukin production. Interleukin is a small protein signaling molecule in the cytokine family most commonly produced by these cells. Several studies have demonstrated that interleukins, such as IL-1 and IL-38, play a significant role in developing various types of cancer, such as breast, hepatocellular, and thyroid cancers [57]. Gene changes result from genetic modifications that encode cell signaling pathways contributing to tumor transformation by causing imbalances in the relationship between proliferation and apoptosis in cells. Specific gene mutations have been linked to metastatic lymph node spread due to increased tumor aggressiveness, a tendency to dedifferentiate, and reduced efficiency of radioiodine treatments. We selected these genes for this study based on this concept.

BCL-2 associated X

A crucial member of the Bcl-2 family of antiapoptotic proteins is B cell lymphoma 2 (Bcl-2), linked with protein X. The BAX gene is located at position 19q13.33. and contains seven exons, which are primarily found in the cytoplasm. The apoptotic factor cytochrome C may also be produced by BAX proteins, enhancing the susceptibility of the mitochondrial membrane and starting the apoptosis cascade reaction. There is an antiapoptotic protein called Bcl-2 present in most thyroid tumors, including follicular neoplasms (FN), papillary carcinomas (PTC), and medullary carcinomas (MTC), but not in most undifferentiated thyroid tumors. It is the overexpression of Bcl-2 which is associated with poor prognosis. It has been shown that Bcl-2 plays a role in thyroid cancer. A decrease in Bcl-2 was associated with a loss of differentiation ability in thyroid tumors [62]. BAX is thus required for regulating the mitochondrial apoptosis signaling pathway [63]. Polymorphisms in the BAX gene and cancer depend on the patient’s prognosis and the prevalence of the disease. It is a decreased amount of specific protein produced and thought to be caused by the (248 G > A) polymorphism, while it connected this to the transcriptional activity of the BAX gene being negatively regulated. This increases the Bcl-2 to BAX proportion and could inhibit apoptosis in tumor cells [64]. Over 70% of differentiated carcinomas have molecular markers for thyroid cancer, and knowledge of its many molecular pathways opens up new avenues for its detection and therapy [52]. The genetic variants, which are molecular changes in at least 1% of the population and they refer to as SNPs when they occur in only one nucleotide, are among the different molecular markers known as SNPs (single nucleotide polymorphisms). The BAX SNP (248 G > A) (rs4645878) genotype and allele frequencies are to be linked to a greater risk of PTC [65].

X-ray repair cross-complementing group 1

Chromosome 19q13.31 has the 17 exon XRCC1 gene. In the BER pathway, this protein collaborates with DNA ligase III, DNA polymerase, and PARP to repair single-strand DNA breaks [66, 67]. Base excision repair (BER) and single-strand break repair (SSBR) depend significantly on them. In the presence of reactive oxygen species produced by the body, ionizing radiation or alkylating agents [68, 69]. BER predominantly removes it based on base adducts that are not bulky and are created by methylation, oxidation, and reduction [53]. A recent study has clarified the biological importance of frequent XRCC1 polymorphisms (rs25487, rs25489, and rs1799782). However, genetic investigations are still unclear in this area [70]. As previously shown by research [71, 72], There may be a link between DTC risk and XRCC1-rs1799782 in the Chinese population. Other investigations have found that the XRCC1-rs1799782 polymorphism has little effect on DTC susceptibility in different ethnic groups [73]. The SNP rs25489 has, however, been linked positively to DTC risk in the Caucasian population [74]. To coordinate the rate and sequence of enzymatic activities and prevent the release of harmful DNA intermediates into the cellular environment, XRCC1 interacts with various enzymes and DNA intermediates in different DNA repair pathways [66].

X-ray repair cross-complementing group 3

The RAD51 gene encodes a protein belonging to the RecA/Rad51 family. To preserve chromosomal integrity and repair DNA damage brought on by endogenous and exogenous sources, and is structurally and functionally connected to the XRCC3 gene on chromosome 14q32.3 [75, 76]. One of the most crucial proteins in the homologous recombination repair process (HRR). It interacts with and stabilizes RAD51, contributing to HRR for DNA double-strand breaks (DSBs) and cross-link repairs in eukaryotic cells [77]. According to earlier research, the XRCC3-rs861539 polymorphism impacts DNA repair capacity, which is linked to the risk of developing cancer [54, 78]. According to an earlier study, the XRCC3-rs861539 polymorphism affects DNA repair capacity and may be linked to cancer risk. Future research is still needed to fully understand the relationship between DTC risk and the four XRCC3 SNPs (rs861539, rs1799794, rs56377012, and rs1799796), though [79].

Exportin 5

The nucleocytoplasmic transport protein exportin (XPO5) and members of the importin-b family on chromosome 6p21.1 are well-known regulators of siRNA and miRNA nuclear export. Because XPO5 is a Ran-guanosine triphosphate (GTP)-dependent dsRNA-binding protein, the pre-miRNAs are delivered into the cytoplasm through a GTP-dependent mechanism. The pre-miRNAs mature in the cell after export before becoming functional miRNAs [55, 80]. Researchers have also discovered that XPO5 (rs11077) may protect pre-miRNAs from nuclear degradation [81]. The decreased expression of miRNAs that results from XPO5 deletion may contribute to cancer development, progression, and metastasis. According to Jing and colleagues’ research, XPO5 expression varies across healthy and tumor tissues and decreases in malignancies. ThyCa may have been formed because XPO5 inhibits the growth of tumors in ThyCa cells. Tests also confirmed their findings on hepatocellular carcinoma and colorectal cancer cells [61, 82].


The Interleukin-10 genes are found at 1q31 to 1q32 on chromosome 1 and comprise five exons. It is an anti-inflammatory cytokine. As a growth factor, it stimulates the humoral immune response by activating T and B cells, monocytes, and thymocytes. Many of the pathogenic properties of thyroid cancer can be attributed to the production of IL-10 by thyroid cancer cells. IL-10 promotes the survival and proliferation of thyroid cancer cells [83]. Studies have linked SNPs in the promoter region–174 to prostate, colorectal, and pancreatic cancers [84], and other studies have found conflicting results [85]. The genetic risk factor for PTC is thought to be the IL-10- 1082 polymorphism [56]. The IL-10–1082 G allele and the GG genotype, connected with increased IL-10 production, were more common in PTC patients. Once age, sex, and smoking status are controlled, beings with the IL-10–1082 GG genotype are twice as likely to develop thyroid cancer as those with the AA genotype [83]. Finally, they assert that PTC may be linked to the IL-10–1082 G allele. The IL-10 gene variant may significantly impact the pathophysiology of PTC, which may also lead to the development of new medicinal techniques. When it is discovered, high-risk individuals may be subjected to more rigorous examinations to diagnose minor PTC. A high-risk group for PTC can also be designed with personalized treatment and preventive strategies [84]. IL-10 might promote thyroid cancer aggressiveness by suppressing the immune system and promoting immune escape from thyroid cancer cells [57].

B-Raf proto-oncogene

In addition to being a proto-oncogene, BRAF plays a crucial role in regulating cell proliferation, differentiation, and programmed cell death [86]. Most thyroid carcinomas are caused by point mutations (BRAF V600E) occurring at codon 600 of the 15th exon of the BRAF gene [87]. This mutation permanently activates the BRAF protein. Several genes are impacted by the mutant BRAF protein, including those for thyroglobulin, thyroperoxidase, and others. The NIS (natriumiodide symporter) gene expression is reduced, as are the genes for thyroglobulin and thyroperoxidase [88, 89]. As a result of this mutation, several studies have linked this mutation to a worse prognosis, a higher likelihood of recurrence, and an increase. There is evidence of decreased iodine transport into the cells, increased tumor aggressiveness, extrathyroidal spread, and local and distant lymph node metastases [90]. As a result of having the BRAF V600E mutation, there is a nearly 100% chance that you will develop cancer in the future [58]. The oncogenic BRAFV600E activates the MAPK pathway independently of extracellular stimuli. As a result, there is no negative regulation from ERK to RAF dimerization, leading to strong activation of the pathway (Fig. 4) [91].

Fig. 4
figure 4

BRAFV600E signaling in thyroid carcinoma

Ret proto-oncogene

A transmembrane tyrosine kinase receptor encoded by the RET proto-oncogene is critical to cell proliferation, differentiation, and survival. RET gene mutations are commonly found in medullary carcinomas (MTCs) due to point mutations in the gene [92]. More than 95% of the patients with MEN2A and MEN2B were found to have genetic alterations, compared with 50% of the patients who had known MTC and over 95% with sporadic MTC [93]. Family members of patients with a detectable germline mutation in the RET gene are recommended to undergo genetic testing [41]. There is a significant risk of MTC associated with an inherited RET mutation. Therefore, a complete preventative thyroidectomy is recommended for patients with an inherited RET mutation [52, 59]. As a result of the genotype–phenotype correlations that have been found, individual recommendations are created, particularly regarding scheduling a complete preventive thyroidectomy in childhood to prevent thyroiditis from developing [60]. In thyroid cancers, there is a rearrangement of the tyrosine kinase receptor. MAPK and PI3K downstream pathways are activated by binding RET, NTRK, and ALK agonists in normal thyroid tissue [91].

K-RAS proto-oncogene gene

In addition to acting as signal transducers between transmembrane tyrosine kinase receptors and the nucleus, these proteins contribute to cell growth and differentiation via the MAPK or PI3K-AKT pathways (Fig. 5). A proto-oncogene can transform into an oncogene when a point mutation occurs in one of these genes. Oncogenes stimulate cell proliferation while inhibiting differentiation. A common mutation in thyroid tumors results in modifications in the HRAS, KRAS, and NRAS genes, and it is still unclear what their significance is. Both benign and malignant thyroid tumors can contain mutations in these genes. A mutation in the RAS gene may play a role in the progression of a benign tumor to carcinoma in the future [92, 94]. PTCs arising from follicular variants are found to have RAS mutations in approximately 20% of cases [86, 95]. The thyroid biopsy is most commonly used to detect these genetic changes and BRAF mutations in the human body. ETA recommends performing less radical surgery when pathogenic mutations in RAS genes are detected (e.g., hemithyroidectomy) while considering the patient's clinical and anamnestic history [96].

Fig. 5
figure 5

Impact of RAS mutations in thyuroid carcinomas


As we age, our endocrine system, including the thyroid gland, changes how it regulates biological functions. Establishing a physiological norm for thyroid hormone levels is challenging due to the increasing resetting of the hypothalamic-pituitary-thyroid axis with age. This results in elevated levels of TSH. Thyroid carcinoma is more common among older adults, and men are more prone than women to developing these tumors aggressively. The mortality risk of thyroid carcinoma increases significantly with age from the ages of 40 to 45. Thyrocytes and follicular cells, the gland’s epithelial components, are where ThyCa originate. ThyCa is divided into two types based on clinical characteristics and appearance: differentiated (which includes medullary, follicular, and papillary carcinoma) and anaplastic (which does not include medullary, follicular, or papillary carcinoma). Proliferation, survival, and tumorigenesis are all regulated by the MAPK pathway. This pathway significantly contributes to thyroid tumorigenesis, particularly in PTC. MAPK pathway activators are responsible for driving thyroid cancer. This review highlights that although the link between age and thyroid cancer is still not obvious, generation continues to be a significant predictive factor for thyroid cancer. They were identifying these critical genes as potential biomarkers improves thyroid cancer patients’ early diagnosis and survival. By developing such gene investigations at the beginning of the thyroid cancer development process, we can achieve better outcomes and identify the most aggressive forms of thyroid cancer. Finally, altered thyroid function may significantly influence lifetime control via several pathways. Reduced thyroid function, in particular, may contribute to an increased lifespan.

Availability of data and materials

Not applicable.



Thyroid cancer


Thyroid-stimulating hormone


Autoimmune thyroid disease


Thyroid gland


Extracellular regulated kinase


Phosphatidylinositol 3-kinase


Mitogen-activated protein kinase


Tyrosine kinase catalytic activity


Guanine nucleotide exchange factors


Papillary thyroid cancer


Follicular thyroid cancer


Medullary thyroid cancer


Anaplastic thyroid cancer


Differentiated thyroid cancer


Protein kinase cAMP-dependent type I regulatory subunit alpha


B-Raf proto-oncogene; serine/threonine kinase


Ret proto-oncogene


NRAS proto-oncogene; GTPase


  1. McDow AD, Pitt SC. Extent of surgery for low-risk differentiated thyroid cancer. Surg Clin. 2019;99(4):599–610.

    Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.

  3. Henley SJ, Ward EM, Scott S, Ma J, Anderson RN, Firth AU, Thomas CC, Islami F, Weir HK, Lewis DR, Sherman RL, Wu M, Benard VB, Richardson LC, Jemal A, Cronin K, Kohler BA. Annual report to the nation on the status of cancer, part I: National cancer statistics. Cancer. 2020;126(10):2225–49.

    Article  PubMed  Google Scholar 

  4. Furukawa K, Preston D, Funamoto S, Yonehara S, Ito M, Tokuoka S, Sugiyama H, Soda M, Ozasa K, Mabuchi K. Long-term trend of thyroid cancer risk among Japanese atomic-bomb survivors: 60 years after exposure. Int J Cancer. 2013;132(5):1222–6.

    Article  CAS  PubMed  Google Scholar 

  5. Bhatti P, Veiga LH, Ronckers CM, Sigurdson AJ, Stovall M, Smith SA, Weathers R, Leisenring W, Mertens AC, Hammond S, Friedman DL. Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat Res. 2010;174(6a):741–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sushmitha S, Murugesan R, Saraswathi S, Rathiusha K, Madhumala G, Jose S, Laura B, Antara B, Francesco M, Surajit P. A review on role of ATM gene in hereditary transfer of colorectal cancer. Acta Bio Med. 2018;89(4):463.

    Google Scholar 

  7. Sharma U, Jagannathan NR. Magnetic resonance imaging (MRI) and MR spectroscopic methods in understanding breast cancer biology and metabolism. Metabolites. 2022;12(4):295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shah JP. Thyroid carcinoma: epidemiology, histology, and diagnosis. Clin Adv Hematol Oncol. 2015;13(4 Suppl 4):3.

    PubMed  PubMed Central  Google Scholar 

  9. Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran pathologic basis of disease, professional edition ebook. Elsevier health sciences. 2014.

  10. Pizzato M, Li M, Vignat J, Laversanne M, Singh D, La Vecchia C, Vaccarella S. The epidemiological landscape of thyroid cancer worldwide: GLOBOCAN estimates for incidence and mortality rates in 2020. Lancet Diabetes Endocrinol. 2022;10(4):264–72.

    Article  PubMed  Google Scholar 

  11. Srivastava KC, Austin RD, Shrivastava D, Sethupathy S, Rajesh S. A case control study to evaluate oxidative stress in plasma samples of oral malignancy. Contemp Clin Dent. 2012;3(3):271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bílek R, Dvořáková M, Grimmichová T, Jiskra J. Iodine, thyroglobulin and thyroid gland. Physiol Res. 2020;69(Suppl 2):S225–36.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hsiao SJ, Nikiforov YE. Molecular approaches to thyroid cancer diagnosis. Endocr Relat Cancer. 2014;21(5):T301.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36(6):320–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Soares-Silva M, Diniz FF, Gomes GN, Bahia D. The mitogen-activated protein kinase (MAPK) pathway: role in immune evasion by trypanosomatids. Front Microbiol. 2016;7:183.

    Article  PubMed  PubMed Central  Google Scholar 

  16. López-Camarillo C, Ocampo EA, Casamichana ML, Pérez-Plasencia C, Alvarez-Sánchez E, Marchat LA. Protein kinases and transcription factors activation in response to UV-radiation of skin: implications for carcinogenesis. Int J Mol Sci. 2012;13(1):142–72.

    Article  PubMed  Google Scholar 

  17. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–45.

    Article  CAS  PubMed  Google Scholar 

  18. Moritz A, Li Y, Guo A, Villén J, Wang Y, MacNeill J, Kornhauser J, Sprott K, Zhou J, Possemato A, Ren JM. Akt–RSK–S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases. Sci Signal. 2010;3(136):ra64.

  19. Kilfoy BA, Devesa SS, Ward MH, Zhang Y, Rosenberg PS, Holford TR, Anderson WF. Gender is an age-specific effect modifier for papillary cancers of the thyroid gland. Cancer Epidemiol Biomark Prev. 2009;18(4):1092–100.

    Article  Google Scholar 

  20. Toniato A, Bernardi C, Piotto A, Rubello D, Pelizzo MR. Features of papillary thyroid carcinoma in patients older than 75 years. Updat Surg. 2011;63:115–8.

    Article  Google Scholar 

  21. Chrisoulidou A, Boudina M, Tzemailas A, Doumala E, Iliadou PK, Patakiouta F, Pazaitou-Panayiotou K. Histological subtype is the most important determinant of survival in metastatic papillary thyroid cancer. Thyroid Res. 2011;4(1):1–5.

    Article  Google Scholar 

  22. Gesing A, Lewiński A, Karbownik-Lewińska M. The thyroid gland and the process of aging; what is new? Thyroid Res. 2012;5(1):1–5.

    Article  Google Scholar 

  23. Ries LA, Melbert D, Krapcho M, Stinchcomb DG, Howlader N, Horner MJ, Mariotto A, Miller BA, Feuer EJ, Altekruse SF, Lewis DR. SEER cancer statistics review, 1975–2005. Bethesda: National Cancer Institute; 2008. online.

    Google Scholar 

  24. Lee K, Anastasopoulou C, Chandran C, Cassaro S. Thyroid cancer. InStatPearls: StatPearls Publishing; 2021.

    Google Scholar 

  25. Waguespack S, Wells S, Ross J, Bleyer A, et al. Thyroid cancer. In: Bleyer A, O’Leary M, Barr R, et al., editors. Cancer epidemiology in older adolescents and young adults 15 to 29 years of age, including SEER incidence and survival 1975–2000. Bethesda: National Cancer Institute; 2006. p. 143–54.

    Google Scholar 

  26. Kosary C. Cancer of the Thyroid, in Ries LAG YJ, Keel GE, Eisner MP, Lin YD, Horner MJ (eds): SEER survival monograph: cancer survival among adults: U.S. SEER PROGRAM, 1988–2001, patient and tumor characteristics. Bethesda: National Cancer Institute, 2007, pp 217–226.

  27. Blackburn BE, Ganz PA, Rowe K, Snyder J, Wan Y, Deshmukh V, Newman M, Fraser A, Smith K, Herget K, Kim J. Aging-related disease risks among young thyroid cancer survivorsaging-related disease risks among thyroid cancer survivors. Cancer Epidemiol Biomark Prev. 2017;26(12):1695–704.

    Article  Google Scholar 

  28. Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer. 2006;107(9):2134–42.

  29. Kim TY, Kim KW, Jung TS, Kim JM, Kim SW, Chung KW, Kim EY, Gong G, Oh YL, Cho SY, Yi KH. Prognostic factors for Korean patients with anaplastic thyroid carcinoma. Head Neck. 2007;29(8):765–72.

    Article  PubMed  Google Scholar 

  30. Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer. 2000;88(5):1139–48.

    Article  CAS  PubMed  Google Scholar 

  31. Rukhman N, Silverberg A. Thyroid cancer in older men. Aging Male. 2011;14(2):91–8.

    Article  PubMed  Google Scholar 

  32. Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM. Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA. 2017;317(13):1338–48.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Haymart MR. Understanding the relationship between age and thyroid cancer. Oncologist. 2009;14(3):216–21.

    Article  PubMed  Google Scholar 

  34. Faggiano A, Coulot J, Bellon N, Talbot M, Caillou B, Ricard M, Bidart JM, Schlumberger M. Age-dependent variation of follicular size and expression of iodine transporters in human thyroid tissue. J Nucl Med. 2004;45(2):232–7.

    CAS  PubMed  Google Scholar 

  35. Iglesias ML, Schmidt A, Ghuzlan AA, Lacroix L, Vathaire FD, Chevillard S, Schlumberger M. Radiation exposure and thyroid cancer: a review. Arch Endocrinol Metab. 2017;61:180–7.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Mihailovic J, Nikoletic K, Srbovan D. Recurrent disease in juvenile differentiated thyroid carcinoma: prognostic factors, treatments, and outcomes. J Nucl Med. 2014;55(5):710–7.

    Article  PubMed  Google Scholar 

  37. Shah S, Boucai L. Effect of age on response to therapy and mortality in patients with thyroid cancer at high risk of recurrence. J Clin Endocrinol Metab. 2018;103(2):689–97.

    Article  PubMed  Google Scholar 

  38. Liu R, Bishop J, Zhu G, Zhang T, Ladenson PW, Xing M. Mortality risk stratification by combining BRAF V600E and TERT promoter mutations in papillary thyroid cancer: genetic duet of BRAF and TERT promoter mutations in thyroid cancer mortality. JAMA Oncol. 2017;3(2):202–8.

    Article  PubMed  Google Scholar 

  39. Shen X, Zhu G, Liu R, Viola D, Elisei R, Puxeddu E, Fugazzola L, Colombo C, Jarzab B, Czarniecka A, Lam AK. Patient age–associated mortality risk is differentiated by BRAF V600E status in papillary thyroid cancer. J Clin Oncol. 2018;36(5):438.

    Article  CAS  PubMed  Google Scholar 

  40. Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, Celestino R, Almeida A, Salgado C, Eloy C, Castro P. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab. 2014;99(5):E754–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nikiforov YE. Role of molecular markers in thyroid nodule management: then and now. Endocr Pract. 2017;23(8):979–89.

    Article  PubMed  Google Scholar 

  42. Haymart MR. Is BRAF V600E mutation the explanation for age-associated mortality risk in patients with papillary thyroid cancer? J Clin Oncol. 2017;36(5):433–4.

    Article  PubMed  Google Scholar 

  43. Silver JA, Bogatchenko M, Pusztaszeri M, Forest VI, Hier MP, Yang JW, Tamilia M, Payne RJ. BRAF V600E mutation is associated with aggressive features in papillary thyroid carcinomas≤ 1.5 cm. J Otolaryngol Head Neck Surg. 2021;50:1–8.

  44. Song YS, Jung CK, Jung KC, Park YJ, Won JK. Rare manifestations of anaplastic thyroid carcinoma: the role of BRAF mutation analysis. J Korean Med Sci. 2017;32(10):1721–6.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Liu C, Chen T, Liu Z. Associations between BRAFV600E and prognostic factors and poor outcomes in papillary thyroid carcinoma: a meta-analysis. World J Surg Oncol. 2016;14(1):1–2.

    Article  CAS  Google Scholar 

  46. Fnais N, Soobiah C, Khalid AQ, Hamid JS, Perrier L, Straus SE, Tricco AC. Diagnostic value of fine needle aspiration BRAFV600E mutation analysis in papillary thyroid cancer: a systematic review and meta-analysis. Hum Pathol. 2015;46(10):1443–54.

    Article  CAS  PubMed  Google Scholar 

  47. DiLorenzo MM, Miller JL, Tuluc M, Wang ZX, Savarese VW, Pribitkin EA. False-positive FNA due to highly sensitive BRAF assay. Endocr Pract. 2014;20(1):e8-10.

    Article  PubMed  Google Scholar 

  48. Landa I, Ganly I, Chan TA, Mitsutake N, Matsuse M, Ibrahimpasic T, Ghossein RA, Fagin JA. Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J Clin Endocrinol Metab. 2013;98(9):E1562–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu X, Bishop J, Shan Y, Pai S, Liu D, Murugan AK, Sun H, El-Naggar AK, Xing M. Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer. 2013;20(4):603.

    Article  PubMed  PubMed Central  Google Scholar 

  50. LeClair K, Bell KJ, Furuya-Kanamori L, Doi SA, Francis DO, Davies L. Evaluation of gender inequity in thyroid cancer diagnosis: differences by sex in US thyroid cancer incidence compared with a meta-analysis of subclinical thyroid cancer rates at autopsy. JAMA Intern Med. 2021;181(10):1351–8.

  51. Wang X, Zhang K, Liu X, Liu B, Wang Z. Association between XRCC1 and XRCC3 gene polymorphisms and risk of thyroid cancer. Int J Clin Exp Pathol. 2015;8(3):3160.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1–33.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Duarte MC, Colombo J, Rossit AR, Caetano A, Borim AA, Wornrath D, Silva AE. Polymorphisms of DNA repair genes XRCC1 and XRCC3, interaction with environmental exposure and risk of chronic gastritis and gastric cancer. World J Gastroenterol. 2005;11(42):6593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Santos LS, Gomes BC, Bastos HN, Gil OM, Azevedo AP, Ferreira TC, Limbert E, Silva SN, Rueff J. Thyroid cancer: the quest for genetic susceptibility involving DNA repair genes. Genes. 2019;10(8):586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang X, Liu F, Yang F, Meng Z, Zeng Y. Selectivity of Exportin 5 binding to human precursor microRNAs. RNA Biol. 2021;18(sup2):730–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhou Y, Hu W, Zhuang W, Wu X. Interleukin-10− 1082 promoter polymorphism and gastric cancer risk in a Chinese Han population. Mol Cell Biochem. 2011;347:89–93.

    Article  CAS  PubMed  Google Scholar 

  57. Xi C, Zhang GQ, Sun ZK, Song HJ, Shen CT, Chen XY, Sun JW, Qiu ZL, Luo QY. Interleukins in thyroid cancer: from basic researches to applications in clinical practice. Front Immunol. 2020;11:1124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Safaee Ardekani G, Jafarnejad SM, Tan L, Saeedi A, Li G. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS ONE. 2012;7(10): e47054.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Filetti S, Durante C, Hartl D, Leboulleux S, Locati LD, Newbold K, Papotti MG, Berruti A. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(12):1856–83.

    Article  CAS  PubMed  Google Scholar 

  60. Machens A, Dralle H. Long-term outcome after DNA-based prophylactic neck surgery in children at risk of hereditary medullary thyroid cancer. Best Pract Res Clin Endocrinol Metab. 2019;33(4): 101274.

    Article  PubMed  Google Scholar 

  61. Wen J, Gao Q, Wang N, Zhang W, Cao K, Zhang Q, Chen S, Shi L. Association of microRNA-related gene XPO5 rs11077 polymorphism with susceptibility to thyroid cancer. Medicine. 2017;96(14).

  62. Gupta A, Jain S, Khurana N, Kakar AK. Expression of p63 and Bcl-2 in malignant thyroid tumors and their correlation with other diagnostic immunocytochemical markers. J Clin Diagnostic Res. 2016;10(7):EC04.

  63. Uhliarova B, Hajtman A. Hashimoto’s thyroiditis-an independent risk factor for papillary carcinoma. Braz J Otorhinolaryngol. 2018;84:729–35.

    Article  PubMed  Google Scholar 

  64. Sun L, Wei L, Wei L, Li D. Correlation between Bax gene polymorphisms and esophagus cancer. Oncol Lett. 2018;16(6):7097–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Romero-Sánchez C, Gómez-Gutierrez A, Gómez PE, Casas-Gomez MC, Briceño I. C677t (rs1801133) MTFHR gene polymorphism frequency in a colombian population. Colombia Med. 2015;46(2):75–9.

    Article  Google Scholar 

  66. Campalans A, Moritz E, Kortulewski T, Biard D, Epe B, Radicella JP. Interaction with OGG1 is required for efficient recruitment of XRCC1 to base excision repair and maintenance of genetic stability after exposure to oxidative stress. Mol Cell Biol. 2015;35(9):1648–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wu F, Zhang J, Liu Y, Zheng Y, Hu N. HIF1α genetic variants and protein expressions determine the response to platinum based chemotherapy and clinical outcome in patients with advanced NSCLC. Cell Physiol Biochem. 2013;32(6):1566–76.

    Article  CAS  PubMed  Google Scholar 

  68. Duell EJ, Millikan RC, Pittman GS, Winkel S, Lunn RM, Tse CK, Eaton A, Mohrenweiser HW, Newman B, Bell DA. Polymorphisms in the DNA repair gene XRCC1 and breast cancer. Cancer Epidemiol Biomark Prev. 2001;10(3):217–22.

    CAS  Google Scholar 

  69. Thompson LH, West MG. XRCC1 keeps DNA from getting stranded. Mutat Res. 2000;459(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  70. Wang C, Ai Z. Association of XRCC1 polymorphisms with thyroid cancer risk. Tumor Biology. 2014;35:4791–7.

    Article  CAS  PubMed  Google Scholar 

  71. Bao Y, Jiang L, Zhou JY, Zou JJ, Zheng JY, Chen XF, Liu ZM, Shi YQ. XRCC1 gene polymorphisms and the risk of differentiated thyroid carcinoma (DTC): a meta-analysis of case-control studies. PLoS ONE. 2013;8(5): e64851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ho T, Li G, Lu J, Zhao C, Wei Q, Sturgis EM. Association of XRCC1 polymorphisms and risk of differentiated thyroid carcinoma: a case–control analysis. Thyroid. 2009;19(2):129–35.

    Article  CAS  PubMed  Google Scholar 

  73. Li C, Xiang X, Zhou Y. No association between XRCC1 genetic polymorphisms and differentiated thyroid carcinoma risk: a meta-analysis. Mol Biol Rep. 2014;41:7613–21.

    Article  CAS  PubMed  Google Scholar 

  74. Hu Z, Hu X, Long J, Su L, Wei B. XRCC1 polymorphisms and differentiated thyroid carcinoma risk: a meta analysis. Gene. 2013;528:67–73.

    Article  CAS  PubMed  Google Scholar 

  75. Howlader NR, Rahman MM, Hossain MA, Sultana R, Hossain SM, Mazid MA, Rahman MM. Genetic polymorphisms in DNA repair genes XRCC1 and 3 are associated with increased risk of breast cancer in Bangladeshi population. Breast Cancer Res Treat. 2020;182:739–50.

    Article  CAS  PubMed  Google Scholar 

  76. Pasqualetti F, Gonnelli A, Orlandi P, Palladino E, Giannini N, Gadducci G, Mattioni R, Montrone S, Calistri E, Mazzanti CM, Franceschi S. Association of XRCC3 rs1799794 polymorphism with survival of glioblastoma multiforme patients treated with combined radio-chemotherapy. Invest New Drugs. 2021;39:1159–65.

    Article  CAS  PubMed  Google Scholar 

  77. Kurumizaka H, Ikawa S, Nakada M, Eda K, Kagawa W, Takata M, Takeda S, Yokoyama S, Shibata T. Homologous-pairing activity of the human DNA-repair proteins Xrcc3 Rad51C. Proc Natl Acad Sci. 2001;98(10):5538–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yuan K, Huo M, Sun Y, Wu H, Chen H, Wang Y, Fu R. Association between x-ray repair cross-complementing group 3 (XRCC3) genetic polymorphisms and papillary thyroid cancer susceptibility in a Chinese Han population. Tumor Biol. 2016;37:979–87.

    Article  CAS  Google Scholar 

  79. Yan L, Li Q, Li X, Ji H, Zhang L. Association studies between XRCC1, XRCC2, XRCC3 polymorphisms and differentiated thyroid carcinoma. Cell Physiol Biochem. 2016;38(3):1075–84.

    Article  CAS  PubMed  Google Scholar 

  80. Wu K, He J, Pu W, Peng Y. The role of exportin-5 in microRNA biogenesis and cancer. Genomics Proteomics Bioinformatics. 2018;16(2):120–6.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Melo SA, Esteller M. A precursor microRNA in a cancer cell nucleus: get me out of here! Cell Cycle. 2011;10(6):922–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Li Y, Wang X, He B, Cai H, Gao Y. Downregulation and tumor-suppressive role of XPO5 in hepatocellular carcinoma. Mol Cell Biochem. 2016;415:197–205.

    Article  CAS  PubMed  Google Scholar 

  83. Cunha LL, Tincani AJ, da Assumpçao LV, Soares FA, Vassallo J, Ward LS. Interleukin-10 but not interleukin-18 may be associated with the immune response against well-differentiated thyroid cancer. Clinics. 2011;66(7):1203–8.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Çil E, Kumral A, Kanmaz-Özer M, Vural P, Doğru-Abbasoğlu S, Altuntaş Y, Uysal M. Interleukin-10-1082 gene polymorphism is associated with papillary thyroid cancer. Mol Biol Rep. 2014;41(5):3091–7.

    Article  PubMed  Google Scholar 

  85. Shao N, Xu B, Mi YY, Hua LX. IL-10 polymorphisms and prostate cancer risk: a meta-analysis. Prostate Cancer Prostatic Dis. 2011;14(2):129–35.

    Article  CAS  PubMed  Google Scholar 

  86. Prete A, Borges de Souza P, Censi S, Muzza M, Nucci N, Sponziello M. Update on fundamental mechanisms of thyroid cancer. Front Endocrinol. 2020;11:102.

  87. Pekova B, Dvorakova S, Sykorova V, Vacinova G, Vaclavikova E, Moravcova J, Katra R, Vlcek P, Sykorova P, Kodetova D, Vcelak J. Somatic genetic alterations in a large cohort of pediatric thyroid nodules. Endocr Connect. 2019;8(6):796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B, Yip L, Mian C, Vianello F, Tuttle RM, Robenshtok E. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013;309(14):1493–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Song JY, Sun SR, Dong F, Huang T, Wu B, Zhou J. Predictive value of BRAFV600E mutation for lymph node metastasis in papillary thyroid cancer: a meta-analysis. Curr Med Sci. 2018;38(5):785–97.

    Article  CAS  PubMed  Google Scholar 

  90. Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D, Elisei R, Bendlová B, Yip L, Mian C, Vianello F. Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol. 2015;33(1):42.

    Article  PubMed  Google Scholar 

  91. Zaballos MA, Santisteban P. Key signaling pathways in thyroid cancer. J Endocrinol. 2017;235(2):R43-61.

    Article  CAS  PubMed  Google Scholar 

  92. Nikiforov YE. Molecular diagnostics of thyroid tumors. Arch Pathol Lab Med. 2011;135(5):569–77.

    Article  CAS  PubMed  Google Scholar 

  93. Laha D, Nilubol N, Boufraqech M. New therapies for advanced thyroid cancer. Front Endocrinol. 2020;11:82.

    Article  Google Scholar 

  94. Paulson VA, Shivdasani P, Angell TE, Cibas ES, Krane JF, Lindeman NI, Alexander EK, Barletta JA. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features accounts for more than half of “carcinomas” harboring RAS mutations. Thyroid. 2017;27(4):506–11.

    Article  CAS  PubMed  Google Scholar 

  95. Xing M. Clinical utility of RAS mutations in thyroid cancer: a blurred picture now emerging clearer. BMC Med. 2016;14:1–4.

    Article  Google Scholar 

  96. Paschke R, Cantara S, Crescenzi A, Jarzab B, Musholt TJ, Simoes MS. European thyroid association guidelines regarding thyroid nodule molecular fine-needle aspiration cytology diagnostics. Eur Thyroid J. 2017;6(3):115–29.

    Article  PubMed  PubMed Central  Google Scholar 

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The authors thank the Chettinad Academy of Research and Education for their constant support and encouragement.



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IBK and GS have written the contents, edited the figures and tables of this manuscript. RV designed the study and approved the manuscript for submission. All authors have read and approved the final manuscript.

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Kalarani, I.B., Sivamani, G. & Veerabathiran, R. Identification of crucial genes involved in thyroid cancer development. J Egypt Natl Canc Inst 35, 15 (2023).

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