BRAF is a cytoplasmic protein kinase integral to the MAPK signaling pathway, which is frequently activated in various malignancies [6] . Among the BRAF mutations, the T1799A point mutation is particularly noteworthy; it results in a lysine-to-glutamate substitution at position 600, termed the BRAF V600E mutation. This mutation is commonly found in papillary thyroid carcinoma (PTC), with reported frequencies ranging from 40% to 90% across different populations. The BRAF V600E mutation leads to heightened activation of BRAF kinase within the MAPK pathway [4] , which in turn results in uncontrolled cell proliferation and tumorigenesis. Given its prevalence, this mutation has been the focus of extensive research in recent years. Sancisi et al. found no significant correlation between BRAF V600E mutations and distant metastasis or fatal outcomes in PTC [7] . In contrast, Lai et al. identified a clear association between the presence of BRAF V600E mutations and larger initial tumor size, increased rates of distant metastasis, and advanced stages of disease. Their findings suggest that tumors harboring the BRAF V600E mutation may exhibit greater aggressiveness and a higher propensity for dissemination to distant metastasis [8] . Ye et al. reported that in patients with a positive BRAF V600E mutation, independent risk factors for PTC recurrence included tumor size > 1 cm, extrathyroidal invasion (invasion of adjacent thyroid structures), and lateral regional lymph node metastasis [9] . Wei et al. conducted a literature review and identified several risk factors associated with BRAF V600E positivity in PTC patients, including age (≥ 45 years), male sex, multifocality, lymph node metastasis, vascular invasion, extrathyroidal invasion, and advanced stage [5] . Zhang et al. and Harahap et al. also found significant links between BRAF V600E positivity and extrathyroidal invasion, lymph node metastasis, and clinical stage [10] [11] . However, Wei et al. did not recognize tumor size (> 1 cm) or distant metastasis as risk factors for BRAF V600E mutation positivity in PTC patients [5] . Nechifor-Boila et al. reported that the presence of the BRAF V600E mutation, when combined with multiple risk factors (e.g., male sex, age ≥ 55 years, classic and high cellular variants, extrathyroidal invasion, multifocality, tumor size > 40 mm, and lymph node metastasis), offers a more nuanced prediction of adverse outcomes [12] . Similarly, Du et al. noted a significant correlation between BRAF V600E mutation positivity and an increased risk of lymph node metastasis in the central compartment of PTC patients [13] . Furthermore, studies by Janicki et al. and Cao et al. found that BRAF V600E mutation positivity in PTC patients with Hashimoto’s thyroiditis was associated with multifocal lesions, although these patients exhibited a lower propensity for lymph node metastasis [14] [15] . The incidence of PTC in the context of Hashimoto’s thyroiditis is lower than that of PTC in the general population, and it remains unclear whether Hashimoto’s thyroiditis acts as a protective factor in BRAF V600E-positive PTC patients. Extensive clinical data is required to address this question. Moreover, another study examining the relationship between BRAF V600E mutation positivity and recurrence concluded that the BRAF V600E mutation alone does not serve as an independent predictive factor for PTC. Instead, a multivariate analysis incorporating additional risk factors (such as sex, age, and multifocality) should be utilized [5] [16] [17] . Although the association between BRAF V600E mutations and the invasive behavior of PTC remains a topic of debate, the American Thyroid Association (ATA) guidelines have incorporated the status of the BRAF V600E mutation since 2015 to enhance risk stratification for PTC patients, thereby providing valuable guidance for treatment planning [15] .

Telomerase synthesizes repetitive DNA sequences to preserve telomere length, and research has shown that telomerase shortening is linked to cancer and aging. As telomerase becomes shorter, it can activate telomerase reverse transcriptase (TERT) and induce TERT promoter mutations [18] . TERT functions as the catalytic subunit of telomerase, and its promoter mutations can trigger telomerase activation, leading to tumor initiation [19] . Yang et al. observed a significantly higher frequency of TERT promoter mutations in older tumors, larger tumors, and invasive tissues, suggesting a potential correlation between these mutations, aging, and tumor development [20] . Additional studies indicate that TERT promoter mutations are present in 7% - 22% of patients with papillary thyroid carcinoma (PTC), with a prevalence rate of 11% among Chinese patients diagnosed with PTC [18] . Tanaka et al., Li et al., and Parvathareddy et al. confirmed a significant association between TERT promoter mutations and aggressive clinicopathological features of PTC [21] - [23] . Na et al. and Melo et al. reported a higher frequency of TERT promoter mutations in PTC patients with distant metastasis and recurrence, potentially linked to poorer prognoses and increased disease-specific mortality [24] [25] . Furthermore, numerous studies indicate that the coexistence of BRAF V600E mutations and TERT promoter mutations is closely associated with aggressive clinicopathological features and poor prognosis in PTC, suggesting a possible synergistic effect between these mutations [21] . When both mutations are present, it typically indicates a poor prognosis for PTC patients and may be useful for clinical stratification [26] . Sako et al., Vuong et al., and Liu et al. found that the coexistence of BRAF V600E and TERT promoter mutations significantly enhances the aggressiveness of PTC [27] - [29] . The combined effect of these two oncogenes results in markedly higher specific mortality for PTC compared to individual mutations and conventional clinicopathological risk factors, such as extrathyroidal invasion. The American Thyroid Association (ATA) guidelines from 2015 acknowledged the potential prognostic value of TERT promoter mutations and BRAF V600E mutations, although these factors were not fully endorsed or routinely recommended [30] . The 2023 guidelines for the diagnosis and treatment of thyroid nodules and differentiated thyroid cancer suggested that the coexistence of BRAF V600E and TERT promoter mutations may influence recurrence risk stratification in PTC [31] . Nasirden et al. reported that PTC patients harboring both BRAF V600E and TERT promoter mutations exhibit a poor response to radioiodine therapy (RAI), indicating that these mutations could be predictive of resistance to RAI in late-stage PTC patients, including those with distant metastasis [32] . However, some studies contend that BRAF V600E and TERT promoter mutations are not significantly associated with PTC, and their coexistence does not necessarily correlate with increased aggressiveness or poor prognosis. Further clinical investigation is required to validate the relationship between these mutations and the development of PTC.

RAS proteins, located on the cytoplasmic surface of the cell membrane, function as switch proteins that regulate growth factor receptor signaling [33] . They transmit extracellular signals that promote cell proliferation, differentiation, and survival [34] . The RAS gene family comprises several oncogenes, with KRAS, HRAS, and NRAS being the most prevalent. Mutations in these genes activate RAS proteins, leading to enhanced cell proliferation and inhibited apoptosis. Approximately 30% of human cancers exhibit activation within the RAS-RAF-MEK-ERK pathway [34] [35] . Similar to BRAF mutations, RAS gene mutations can independently drive papillary thyroid carcinoma (PTC) via the MAPK kinase pathway [36] . Studies indicate that RAS mutations are among the most common genetic alterations in thyroid cancer, occurring in about 11.5% to 20% of cases, with a higher prevalence observed in Asian populations [37] [38] . Jung et al. reported a significant increase in RAS mutations after 2000, potentially linked to environmental factors, including exposure to certain chemicals or variations in iodine intake [39] . The relationship between RAS gene mutations and the aggressiveness of thyroid cancer remains contentious. A study by Hara et al. involving 91 PTC patients with a mean follow-up period of 14 years (ranging from 1 to 40 years) found that 33% of PTC cases harbored RAS mutations [40] . However, only 10.5% of patients who survived beyond 35 years had RAS mutations, indicating a complex interplay between RAS mutations and aggressive thyroid cancer behavior. Despite the small sample size and ambiguous conclusions, Yip et al. conducted a retrospective study of 1510 thyroid cancer patients undergoing their first thyroidectomy and genetic testing [41] . Yip concluded that patients with BRAF V600E mutations or RET/PTC fusions (mutations that cause abnormal activation of the RET receptor tyrosine kinase, leading to tumor growth and spread) exhibited more aggressive disease compared to those with RAS mutations. Specifically, RAS mutation patients displayed less aggressive histological characteristics, a lower rate of extrathyroidal extension, and earlier stage disease. Additionally, Marotta et al. found that patients with only RAS mutations did not experience more frequent tumor recurrence or higher mortality, suggesting that RAS mutations alone may not be associated with the invasive behavior of PTC [42] . Riccio et al. also indicated that while RAS gene mutations are linked to an increased risk of malignancy, they are less correlated with PTC invasiveness compared to BRAF V600E mutations [43] . Therefore, more clinical studies are needed to determine whether RAS mutations are an independent risk factor for PTC. Research has also shown that RAS gene mutations are prevalent in follicular papillary thyroid carcinoma, a histological subtype that shares characteristics with follicular thyroid tumors rather than typical papillary carcinoma [44] [45] . This finding suggests that follicular papillary thyroid carcinoma may be biologically intermediate between follicular thyroid carcinoma (FTC) and typical papillary carcinoma [44] . Due to FTC’s distinct pathogenesis, growth characteristics, molecular pathology, and more frequent hematogenous metastasis, it tends to be more invasive than PTC. Fukahori et al. demonstrated that RAS mutations in FTC are associated with poorer overall patient survival [46] . Further research is needed to confirm whether RAS mutations are an independent risk factor for FTC.

Oncoprotein 53 (TP53) is a critical tumor suppressor involved in cell cycle regulation, DNA repair, and apoptosis. The TP53 gene is widely distributed and is susceptible to mutations that may contribute to the development and progression of thyroid cancer [47] . TP53 also regulates miRNA expression, particularly that of the miR-34 family, which plays a key role in tumor suppression by inhibiting genes that promote cell proliferation. As a classic tumor suppressor gene, TP53 is associated with various malignancies, including thyroid cancer [48] . TP53 mutations are found in approximately 3.5% of individuals diagnosed with papillary thyroid carcinoma (PTC) [49] . Some researchers suggest that polymorphisms in TP53 may serve as risk factors for thyroid cancer. Among these, the Arg72Pro polymorphism (Rs1042522) in exon 72, where proline (CCC) replaces arginine (CGC), is the most extensively studied variant. Research indicates that the codon 72 polymorphism (Arg72Pro) is linked to cancer susceptibility [47] [50] [51] . Heidari et al. reported that the G allele polymorphism of Rs1042522 in TP53 correlates with smaller tumor size, a reduced risk of PTC, and a lower incidence of vascular invasion [47] . A study involving 140 cancer patients and 200 controls without cancer found that the TP53 Pro72 polymorphism is strongly associated with thyroid cancer. Specifically, the variant allele (GC + CC) is linked to increased susceptibility to thyroid cancer, particularly among younger individuals, non-smokers, females, and patients with elevated TSH levels. The frequency of the Pro allele mutation is heightened in these groups and is associated with greater thyroid aggressiveness, although further research is needed to validate these findings. Rogounovitch et al. also found, in the adult radiation-associated papillary thyroid carcinoma (PTC) group, that the prevalence of the homozygous Arg genotype decreased [52] . Additionally, other allele combinations of TP53 may elevate the risk of radiation-associated PTC during late childhood, adolescence, or in women. Yu et al. proposed that TP53 mutations, which serve as markers for tumor differentiation, could also function as prognostic indicators for PTC [53] . In patients exhibiting well-differentiated PTC, TP53 mutations occur less frequently but are more common in aggressive cases. Radu et al. and Asa et al. reported similar findings, noting that TP53 mutations are prevalent in poorly differentiated thyroid tumors [54] [55] . Jin et al.’s study also revealed a significantly higher incidence of TP53 mutations in invasive PTC pathology subtypes compared to other subtypes [56] .

In the context of papillary thyroid carcinoma (PTC), four key gene mutations—BRAF V600E, TERT promoter, RAS gene, and TP53—play distinct roles in the initiation, progression, and prognosis of the disease. However, these mutations may not occur in isolation; they may also exhibit interconnections and interactions. Unfortunately, there is currently a scarcity of research exploring the potential associations between these mutations. To enhance our understanding of the occurrence and development of PTC, it is essential to conduct more clinical and basic research to elucidate the interrelationships and mechanisms underlying these mutations.