In recent years,the incidence of thyroid cancer has been rapidly increasing globally at a rateof approximately 20% per year, making it one of the top ten malignant tumors.The incidence rate among women is among the top five, with a male-to-femaleratio of 1: (2-4). It can occur at any age, but it is more common in young andmiddle-aged adults.

Figure 1 Big Data Analysis of Global Thyroid Cancer in2020

Thyroid cancer is the most common malignant endocrinetumor. According to the origin and differentiation, it can be divided intodifferentiated thyroid cancer (DTC), medullary thyroid cancer (MTC), poorlydifferentiated thyroid cancer (PDTC), and undifferentiated thyroid cancer(ATC). Among them, DTC can be further divided into papillary thyroid cancer(PTC) and follicular thyroid cancer (FTC) (see Figure 2). With the deepening ofresearch, the molecular mechanisms of thyroid cancer occurrence are graduallyelucidated. Abnormal activation of intracellular signaling pathways (such asMAPK, PI3K-AKT, WNT-beta, NF-κB, etc.) is an important factor in the occurrenceand development of thyroid cancer.

Figure 2 Classification and Prognosis of Thyroid Cancer

Figure 2 Classification and Prognosis of ThyroidCancer

The abnormal activation of the MAPK signaling pathway(Ras→Raf→MEK→ERK/MAP) is the major driving event in the formation of thyroidcancer (especially PTC), with molecular-level changes in this pathway caused bymutations in genes such as BRAF, RAS, RET, etc. Similarly, the PI3K-Aktsignaling pathway also influences the occurrence and development of thyroidcancer (especially FTC), with molecular-level changes in this pathway caused bymutations in genes such as RAS, PTEN, PIK3CA, AKT, etc. (Figure 3). It can beseen that the RAS gene participates in both the MAPK and PI3K-AKT signalingpathways. Mutated RAS genes can simultaneously activate these two pathways,thereby affecting processes such as cell growth, differentiation, andapoptosis, ultimately leading to carcinogenesis.

Figure 3 MAPK and PI3K-Akt Signaling Pathways inThyroid Cancer

The RAS gene family members include HRAS, KRAS, andNRAS, located at chromosome 11p15.1~p15.3、12p1.1~pter and 1p22~p32[4],respectively. They have similar structures, each containing 4 exons. Theencoded RAS proteins consist of 198 amino acids with a molecular weight ofapproximately 21 kD, also known as p21 protein[5]. RAS protein is a GTP/GDPbinding protein located on the inner side of the cell membrane. When activated,RAS protein binds to GTPase activating protein, effectively hydrolyzing thebound GTP into GDP, thus converting into an inactive form of RAS protein. Itthen transmits cell growth signals downstream through the MAPK and PI3K-Aktpathways, thereby controlling processes such as cell growth, differentiation,and apoptosis (Figure 4).[5]

Figure 4 Mechanism of Action of RAS Proteins

In thyroid cancer, mutations in the RAS gene mainlyoccur at codons 12, 13, and 61, with the most common being mutations at codon61 of the NRAS gene. Mutations at codons 12 and 13 of the RAS gene enhance theaffinity of RAS protein for GTP, while mutations at codon 61 inhibit the GTPaseactivity of RAS protein. Both situations result in the inability of GTP boundto RAS protein to be converted, leading to sustained activation and subsequentactivation of the MAPK and PI3K-AKT signaling pathways, inducing carcinogenesis.However, in follicular thyroid carcinoma (FTC), mutated RAS protein seems topreferentially activate the PI3K-AKT pathway, while in papillary thyroidcarcinoma (PTC) and anaplastic thyroid carcinoma (ATC), mutated RAS protein ismostly present in the follicular variant subtype. This indicates that thefrequency of RAS gene mutations varies among different subtypes of thyroidcancer, with frequencies of 40% to 50% in FTC and 10% to 20% in PTC and ATC.

1. RAS Gene Mutations and the Diagnosis of ThyroidNodule Malignancy

Thyroid nodules are common in the population, andcurrently, the preferred method for distinguishing between benign and malignantnodules is ultrasound-guided fine-needle aspiration (US-FNA). However, thisdiagnostic technique yields uncertain cytological results in approximately 30%of cases, posing challenges for the determination of nodule malignancy. Withtechnological advancements, molecular testing has provided a new approach fordiagnosing nodule malignancy, assessing it at the genetic level to avoiddiagnostic surgeries to rule out malignant tumors and to prevent complicationsfrom overtreatment. However, the presence of RAS gene mutations may limit thediagnosis of thyroid nodule malignancy because RAS gene mutations have alsobeen found in benign follicular adenomas (FA). Nevertheless, RAS gene mutationsmostly occur in tumors of follicular cell origin (FA, FTC, follicular variantof papillary thyroid carcinoma (FVPTC)), and these subtypes are difficult todifferentiate as benign or malignant based solely on cytological diagnosis,highlighting the importance of RAS gene mutation detection. Although RAS genemutations cannot predict cancer with 100% certainty, they highly suggest FTC orFVPTC. The presence of RAS gene mutations significantly increases the risk ofcancer (~85%); even RAS-positive FA may increase the risk of malignancy.Therefore, RAS gene mutations can guide subsequent treatment.

2. RAS Gene Mutations and Thyroid Cancer Prognosis

Although there is currently no high-quality clinicalevidence supporting the notion that RAS gene mutations indicate a poorprognosis for thyroid cancer patients, some studies suggest that RAS genemutations are associated with dedifferentiation of thyroid cancer, distantmetastasis, and shortened survival, indicating a poorer prognosis. In addition,some studies have found that ATC may arise from PTC and FTC through gradualdedifferentiation, a process possibly promoted by RAS gene mutations. Some evidencesupporting this theory comes from in vitro findings that mutated RAS canpromote chromosomal instability.[8,10] Tumors with lower differentiation haveworse prognoses. Consensus among Chinese experts also suggests that whenBRAF/RAS mutations are combined with TERT, PIK3CA, TP53, and other genemutations, it indicates high invasiveness of the tumor, and more aggressivetreatment options should be considered under appropriate clinical conditions.[9]

RAS gene mutations are the second most common geneticalteration in thyroid cancer. They are mainly found in follicular thyroidcarcinoma, and increasing evidence suggests that the status of RAS genemutations has significant diagnostic value when used concurrently with US-FNA.This is particularly true for cases with cytological diagnoses that areuncertain, as it can assist in evaluating the malignancy of nodules and guidesubsequent treatment strategies.

3.SpaceGen Thyroid Cancer GeneDetection

SpaceGen Thyroid Cancer Gene Mutation Detection helpsscientifically and accurately assess the risk of individual thyroid cancer, andformulate personalized management plans.

References:

[1] IARC 2020 Global Cancer Burden Data.

[2] Thyroid Cancer Diagnosis and Treatment Guidelines(2022 Edition).

[3] Critical Reviews in Oncology Hematology, 2014,90(3).

[4] Thyroid, 2010, 20:697-706.

[5] Nature Reviews Endocrinology, 2011, 7:569-580.

[6] Treatment Research, 2004, 122:131-148.

[7] Nature Reviews Cancer, 2013, 13(3):184-199.

[8] Head & Neck, 2022, 44(6):1277-1300.

[9] Expert Consensus on Thyroid Cancer Gene Testingand Clinical Application in Guangdong (2020 Edition).

[10] The Oncologist, 2013, 18(8):926-932.

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