Molecular classification of thyroid cancer driving precision diagnosis and treatment: translational progress and challenges_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Jianing , LI Jiexiao , TANG Zimei ,  MING Jie

Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, P. R. China;

Corresponding author：

MING Jie, Email: mingjiewh@126.com

Keywords：

thyroid cancer; classification; molecular characteristics; prognosis; WHO classification

DOI：

10.7507/1007-9424.202505073

Video：

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Objective This article aims to summarize the historical evolution of thyroid cancer classification and explore the establishment of a precise classification system based on molecular characteristics and its impact on clinical applications.Methods A literature review was conducted to analyze and organize the recent influences of molecular classification of thyroid cancer on clinical diagnosis and treatment. Results In recent years, the classification of thyroid cancer has introduced molecular features such as BRAF and RAS mutations, highlighting the close association between these molecular characteristics and prognosis. For example, the BRAF V600E mutation is associated with high aggressiveness in papillary thyroid cancer, while RAS mutations suggest malignant potential in follicular tumors. With the advancement of multi-omics research, classification strategies based on multi-omics have shown significant value in the diagnosis, monitoring, treatment, and prognostic assessment of thyroid cancer. Although multi-omics integration has significantly improved the accuracy of prognostic assessments in thyroid cancer, there are still limitations, including imprecise detection of tumor heterogeneity and insufficient sensitivity and specificity of molecular biomarker detection. Conclusions The classification of thyroid cancer is developing towards the integration of molecular features to achieve more precise diagnosis and treatment. To accomplish this goal, it is necessary to overcome the challenges of tumor heterogeneity and the limitations of detection technologies in the future, and to promote the practical application of molecular classification in clinical settings.

1.	殷德涛, 赵乾. 全球及中国甲状腺癌的发病特征及趋势. 中国普外基础与临床杂志, 2025, 32(6): 687-693.
2.	Bai Y, Kakudo K, Jung CK. Updates in the pathologic classification of thyroid neoplasms: a review of the World Health Organization classification. Endocrinol Metab (Seoul), 2020, 35(4): 696-715.
3.	Baloch ZW, Asa SL, Barletta JA, et al. Overview of the 2022 WHO classification of thyroid neoplasms. Endocr Pathol, 2022, 33(1): 27-63.
4.	Basolo F, Macerola E, Poma AM, et al. The 5th edition of WHO classification of tumors of endocrine organs: changes in the diagnosis of follicular-derived thyroid carcinoma. Endocrine, 2023, 80(3): 470-476.
5.	Hernandez-Prera JC, Wenig BM. RAS-mutant follicular thyroid tumors: a continuous challenge for pathologists. Endocr Pathol, 2024, 35(3): 167-184.
6.	Stewardson P, Eszlinger M, Paschke R. Diagnosis of endocrine disease: usefulness of genetic testing of fine-needle aspirations for diagnosis of thyroid cancer. Eur J Endocrinol, 2022, 187(3): R41-R52. doi: 10.1530/EJE-21-1293.
7.	Wang L, Zhang L, Ma R, et al. Semaglutide reprograms macrophages via the GLP-1R/PPARG/ACSL1 pathway to suppress papillary thyroid carcinoma growth. J Clin Endocrinol Metab, 2025, dgaf053. doi: 10.1210/clinem/dgaf053.
8.	Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell, 2014, 159(3): 676-690.
9.	Schumm MA, Shu ML, Hughes EG, et al. Prognostic value of preoperative molecular testing and implications for initial surgical management in thyroid nodules harboring suspected (Bethesda Ⅴ) or known (Bethesda Ⅵ) papillary thyroid cancer. JAMA Otolaryngol Head Neck Surg, 2023, 149(8): 735-742.
10.	Franco AT, Ricarte-Filho JC, Isaza A, et al. Fusion oncogenes are associated with increased metastatic capacity and persistent disease in pediatric thyroid cancers. J Clin Oncol, 2022, 40(10): 1081-1090.
11.	Yang AT, Lai ST, Laetsch TW, et al. Molecular landscape and therapeutic strategies in pediatric differentiated thyroid carcinoma. Endocr Rev, 2025, 46(3): 397-417.
12.	Xu B, Ghossein RA. Advances in thyroid pathology: high grade follicular cell-derived thyroid carcinoma and anaplastic thyroid carcinoma. Adv Anat Pathol, 2023, 30(1): 3-10.
13.	Turchini J, Sioson L, Clarkson A, et al. The presence of typical "BRAFV600E-Like" atypia in papillary thyroid carcinoma is highly specific for the presence of the BRAFV600E mutation. Endocr Pathol, 2023, 34(1): 112-118.
14.	Zhang P, Guan H, Yuan S, et al. Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors. Nat Commun, 2022, 13(1): 1588. doi: 10.1038/s41467-022-29000-5.
15.	Fagin JA, Krishnamoorthy GP, Landa I. Pathogenesis of cancers derived from thyroid follicular cells. Nat Rev Cancer, 2023, 23(9): 631-650.
16.	Soares P, Póvoa AA, Melo M, et al. Molecular pathology of non-familial follicular epithelial-derived thyroid cancer in adults: from RAS/BRAF-like tumor designations to molecular risk stratification. Endocr Pathol, 2021, 32(1): 44-62.
17.	de Sousa MSA, Nunes IN, Christiano YP, et al. Genetic alterations landscape in paediatric thyroid tumours and/or differentiated thyroid cancer: systematic review. Rev Endocr Metab Disord, 2024, 25(1): 35-51.
18.	Bikas A, Ahmadi S, Pappa T, et al. Additional oncogenic alterations in RAS-driven differentiated thyroid cancers associate with worse clinicopathologic outcomes. Clin Cancer Res, 2023, 29(14): 2678-2685.
19.	Dolezal JM, Trzcinska A, Liao CY, et al. Deep learning prediction of BRAF-RAS gene expression signature identifies noninvasive follicular thyroid neoplasms with papillary-like nuclear features. Mod Pathol, 2021, 34(5): 862-874.
20.	Alzumaili BA, Fisch AS, Faquin WC, et al. Detection of RAS p. Q61R by immunohistochemistry in practice: a clinicopathologic study of 217 thyroid nodules with molecular correlates. Endocr Pathol, 2024, 35(3): 219-229.
21.	Pekova B, Sykorova V, Dvorakova S, et al. RET, NTRK, ALK, BRAF, and MET fusions in a large cohort of pediatric papillary thyroid carcinomas. Thyroid, 2020, 30(12): 1771-1780.
22.	Lee YA, Lee H, Im SW, et al. NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. J Clin Invest, 2021, 131(18): e144847. doi: 10.1172/JCI144847.
23.	Stosic A, Fuligni F, Anderson ND, et al. Diverse oncogenic fusions and distinct gene expression patterns define the genomic landscape of pediatric papillary thyroid carcinoma. Cancer Res, 2021, 81(22): 5625-5637.
24.	Yu P, Qu N, Zhu R, et al. TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis. Science advances, 2023, 9(35): eadg7125. doi: 10.1126/sciadv.adg7125.
25.	Liu R, Zhu G, Tan J, et al. Genetic trio of BRAF and TERT alterations and rs2853669TT in papillary thyroid cancer aggressiveness. J Natl Cancer Inst, 2024, 116(5): 694-701.
26.	Canberk S, Gonçalves J, Rios E, et al. The role of 5-hydroxymethylcytosine as a potential epigenetic biomarker in a large series of thyroid neoplasms. Endocr Pathol, 2024, 35(1): 25-39.
27.	Pan Z, Tan Z, Xu N, et al. Integrative proteogenomic characterization reveals therapeutic targets in poorly differentiated and anaplastic thyroid cancers. Nature communications, 2025, 16(1): 3601. doi: 10.1038/s41467-025-58910-3.
28.	Qu N, Chen D, Ma B, et al. Integrated proteogenomic and metabolomic characterization of papillary thyroid cancer with different recurrence risks. Nat Commun, 2024, 15(1): 3175. doi: 10.1038/s41467-024-47581-1.
29.	Kim YH, Yoon SJ, Kim M, et al. Integrative multi-omics analysis reveals different metabolic phenotypes based on molecular characteristics in thyroid cancer. Clin Cancer Res, 2024, 30(4): 883-894.
30.	Hong S, Xie Y, Cheng Z, et al. Distinct molecular subtypes of papillary thyroid carcinoma and gene signature with diagnostic capability. Oncogene, 2022, 41(47): 5121-5132.
31.	Byun H, Lee HS, Song YS, et al. Transcriptome of anaplastic thyroid cancer reveals two molecular subtypes with distinct tumor microenvironment and prognosis. Thyroid, 2025, 35(4): 367-378.
32.	Choi YS, Jeon MJ, Doolittle WKL, et al. Macrophage-induced carboxypeptidase A4 promotes the progression of anaplastic thyroid cancer. Thyroid, 2024, 34(9): 1150-1162.
33.	Xu GJ, Loberg MA, Gallant JN, et al. Molecular signature incorporating the immune microenvironment enhances thyroid cancer outcome prediction. Cell Genom, 2023, 3(10): 100409. doi: 10.1016/j.xgen.2023.100409.
34.	Marczyk VR, Recamonde-Mendoza M, Maia AL, et al. Classification of thyroid tumors based on DNA methylation patterns. Thyroid, 2023, 33(9): 1090-1099.
35.	Cararo Lopes E, Sawant A, Moore D, et al. Integrated metabolic and genetic analysis reveals distinct features of human differentiated thyroid cancer. Clin Transl Med, 2023, 13(6): e1298. doi: 10.1002/ctm2.1298.
36.	Ferraz C. Molecular testing for thyroid nodules: where are we now?. Rev Endocr Metab Disord, 2024, 25(1): 149-159.
37.	de Koster EJ, Morreau H, Bleumink GS, et al. Molecular diagnostics and [18F]FDG-PET/CT in indeterminate thyroid nodules: complementing techniques or waste of valuable resources?. Thyroid, 2024, 34(1): 41-53.
38.	Zou M, BinEssa HA, Al-Malki YH, et al. β-catenin attenuation inhibits tumor growth and promotes differentiation in a BRAFV600E-driven thyroid cancer animal model. Mol Cancer Ther, 2021, 20(9): 1603-1613.
39.	Franco AT, Ricarte-Filho JC, Laetsch TW, et al. Oncogene-specific inhibition in the treatment of advanced pediatric thyroid cancer. J Clin Invest, 2021, 131(18): e152696. doi: 10.1172/JCI152696.
40.	Li Y, Liu C, Zhang X, et al. CCT5 induces epithelial-mesenchymal transition to promote gastric cancer lymph node metastasis by activating the Wnt/β-catenin signalling pathway. Br J Cancer, 2022, 126(12): 1684-1694.
41.	Cao J, Zhu X, Sun Y, et al. The genetic duet of BRAF V600E and TERT promoter mutations predicts the poor curative effect of radioiodine therapy in papillary thyroid cancer. European journal of nuclear medicine and molecular imaging, 2022, 49(10): 3470-3481.
42.	Facchinetti F, Lacroix L, Mezquita L, et al. Molecular mechanisms of resistance to BRAF and MEK inhibitors in BRAFV600E non-small cell lung cancer. Eur J Cancer, 2020, 132: 211-223.
43.	Shimizu Y, Maruyama K, Suzuki M, et al. Acquired resistance to BRAF inhibitors is mediated by BRAF splicing variants in BRAF V600E mutation-positive colorectal neuroendocrine carcinoma. Cancer letters, 2022, 543: 215799. doi: 10.1016/j.canlet.2022.215799.
44.	Ciccone V, Simonis V, Del Gaudio C, et al. ALDH1A1 confers resistance to RAF/MEK inhibitors in melanoma cells by maintaining stemness phenotype and activating PI3K/AKT signaling. Biochem Pharmacol, 2024, 224: 116252. doi: 10.1016/j.bcp.2024.116252.
45.	Schäfer A, Haenig B, Erupathil J, et al. Inhibition of endothelin-B receptor signaling synergizes with MAPK pathway inhibitors in BRAF mutated melanoma. Oncogene, 2021, 40(9): 1659-1673.
46.	Wang B, Zhang W, Zhang G, et al. Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma. Oncogene, 2021, 40(37): 5590-5599.
47.	Pranteda A, Piastra V, Serra M, et al. Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance. Biomed Pharmacother, 2023, 167: 115480. doi: 10.1016/j.biopha.2023.115480.
48.	Ruiz-Saenz A, Atreya CE, Wang C, et al. A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors. Nat Cancer, 2023, 4(2): 240-256.
49.	Garcia-Rendueles MER, Krishnamoorthy G, Saqcena M, et al. Yap governs a lineage-specific neuregulin1 pathway-driven adaptive resistance to RAF kinase inhibitors. Mol Cancer, 2022, 21(1): 213. doi: 10.1186/s12943-022-01676-9.
50.	Nassar KW, Hintzsche JD, Bagby SM, et al. Targeting CDK4/6 represents a therapeutic vulnerability in acquired BRAF/MEK inhibitor-resistant melanoma. Mol Cancer Ther, 2021, 20(10): 2049-2060.
51.	Tahara M, Kiyota N, Imai H, et al. A phase 2 study of encorafenib in combination with binimetinib in patients with metastatic BRAF-mutated thyroid cancer in Japan. Thyroid, 2024, 34(4): 467-476.
52.	Su X, Li P, Han B, et al. Vitamin C sensitizes BRAFV600E thyroid cancer to PLX4032 via inhibiting the feedback activation of MAPK/ERK signal by PLX4032. J Exp Clin Cancer Res, 2021, 40(1): 34. doi: 10.1186/s13046-021-01831-y.
53.	Li L, Cheng L, Sa R, et al. Real-world insights into the efficacy and safety of tyrosine kinase inhibitors against thyroid cancers. Crit Rev Oncol Hematol, 2022, 172: 103624. doi: 10.1016/j.critrevonc.2022.103624.
54.	Zhi J, Yi J, Hou X, et al. Targeting SHP2 sensitizes differentiated thyroid carcinoma to the MEK inhibitor. Am J Cancer Res, 2022, 12(1): 247-264.
55.	Bible KC, Menefee ME, Lin CJ, et al. An international phase 2 study of pazopanib in progressive and metastatic thyroglobulin antibody negative radioactive iodine refractory differentiated thyroid cancer. Thyroid, 2020, 30(9): 1254-1262.
56.	Zaballos MA, Acuña-Ruiz A, Morante M, et al. Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer. Cell Mol Life Sci, 2022, 79(9): 504. doi: 10.1007/s00018-022-04530-9.
57.	Cabanillas M E, Dadu R, Iyer P, et al. Acquired secondary RAS mutation in BRAFV600E-mutated thyroid cancer patients treated with BRAF inhibitors. Thyroid, 2020, 30(9): 1288-1296.
58.	Yeh CN, Lin SF, Wu CL, et al. Genomic landscape and comparative analysis of tissue and liquid-based NGS in Taiwanese anaplastic thyroid carcinoma. NPJ Precis Oncol, 2025, 9(1): 16. doi: 10.1038/s41698-025-00802-2.
59.	Parrish A G, Szulzewsky F. TRKing down drug resistance in NTRK fusion-positive cancers. J Pathol, 2024, 264(2): 129-131.
60.	Chin PD, Zhu CY, Sajed DP, et al. Correlation of ThyroSeq results with surgical histopathology in cytologically indeterminate thyroid nodules. Endocr Pathol, 2020, 31(4): 377-384.
61.	Li Q, Zhang W, Liao T, et al. An artificial intelligence-driven preoperative radiomic subtype for predicting the prognosis and treatment response of patients with papillary thyroid carcinoma. Clin Cancer Res, 2025, 31(1): 139-150.
62.	Ou X, Chen P, Liu BF. Liquid biopsy on microfluidics: from existing endogenous to emerging exogenous biomarkers analysis. Anal Chem, 2025, 97(16): 8625-8640.
63.	Xie Y, Xu X, Wang J, et al. Latest advances and perspectives of liquid biopsy for cancer diagnostics driven by microfluidic on-chip assays. Lab Chip, 2023, 23(13): 2922-2941.
64.	Bandini S, Ulivi P, Rossi T. Extracellular vesicles, circulating tumor cells, and immune checkpoint inhibitors: hints and promises. Cells, 2024, 13(4): 337. doi: 10.3390/cells13040337.
65.	von Felden J, Craig AJ, Garcia-Lezana T, et al. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene, 2021, 40(1): 140-151.
66.	Zabegina L, Nazarova I, Knyazeva M, et al. MiRNA let-7 from TPO(+) extracellular vesicles is a potential marker for a differential diagnosis of follicular thyroid nodules. Cells, 2020, 9(8): 1917. doi: 10.3390/cells9081917.
67.	Casanova-Salas I, Athie A, Boutros PC, et al. Quantitative and qualitative analysis of blood-based liquid biopsies to inform clinical decision-making in prostate Cancer. Eur Urol, 2021, 79(6): 762-771.
68.	Yang Y, Liu H, Chen Y, et al. Liquid biopsy on the horizon in immunotherapy of non-small cell lung cancer: current status, challenges, and perspectives. Cell Death Dis, 2023, 14(3): 230. doi: 10.1038/s41419-023-05757-5.
69.	Song J, Ye X, Xiao H. Liquid biopsy entering clinical practice: past discoveries, current insights, and future innovations. Crit Rev Oncol Hematol, 2025, 207: 104613. doi: 10.1016/j.critrevonc.2025.104613.
70.	Lone SN, Nisar S, Masoodi T, et al. Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments. Mol Cancer, 2022, 21(1): 79. doi: 10.1186/s12943-022-01543-7.

1. 殷德涛, 赵乾. 全球及中国甲状腺癌的发病特征及趋势. 中国普外基础与临床杂志, 2025, 32(6): 687-693.
2. Bai Y, Kakudo K, Jung CK. Updates in the pathologic classification of thyroid neoplasms: a review of the World Health Organization classification. Endocrinol Metab (Seoul), 2020, 35(4): 696-715.
3. Baloch ZW, Asa SL, Barletta JA, et al. Overview of the 2022 WHO classification of thyroid neoplasms. Endocr Pathol, 2022, 33(1): 27-63.
4. Basolo F, Macerola E, Poma AM, et al. The 5th edition of WHO classification of tumors of endocrine organs: changes in the diagnosis of follicular-derived thyroid carcinoma. Endocrine, 2023, 80(3): 470-476.
5. Hernandez-Prera JC, Wenig BM. RAS-mutant follicular thyroid tumors: a continuous challenge for pathologists. Endocr Pathol, 2024, 35(3): 167-184.
6. Stewardson P, Eszlinger M, Paschke R. Diagnosis of endocrine disease: usefulness of genetic testing of fine-needle aspirations for diagnosis of thyroid cancer. Eur J Endocrinol, 2022, 187(3): R41-R52. doi: 10.1530/EJE-21-1293.
7. Wang L, Zhang L, Ma R, et al. Semaglutide reprograms macrophages via the GLP-1R/PPARG/ACSL1 pathway to suppress papillary thyroid carcinoma growth. J Clin Endocrinol Metab, 2025, dgaf053. doi: 10.1210/clinem/dgaf053.
8. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell, 2014, 159(3): 676-690.
9. Schumm MA, Shu ML, Hughes EG, et al. Prognostic value of preoperative molecular testing and implications for initial surgical management in thyroid nodules harboring suspected (Bethesda Ⅴ) or known (Bethesda Ⅵ) papillary thyroid cancer. JAMA Otolaryngol Head Neck Surg, 2023, 149(8): 735-742.
10. Franco AT, Ricarte-Filho JC, Isaza A, et al. Fusion oncogenes are associated with increased metastatic capacity and persistent disease in pediatric thyroid cancers. J Clin Oncol, 2022, 40(10): 1081-1090.
11. Yang AT, Lai ST, Laetsch TW, et al. Molecular landscape and therapeutic strategies in pediatric differentiated thyroid carcinoma. Endocr Rev, 2025, 46(3): 397-417.
12. Xu B, Ghossein RA. Advances in thyroid pathology: high grade follicular cell-derived thyroid carcinoma and anaplastic thyroid carcinoma. Adv Anat Pathol, 2023, 30(1): 3-10.
13. Turchini J, Sioson L, Clarkson A, et al. The presence of typical "BRAFV600E-Like" atypia in papillary thyroid carcinoma is highly specific for the presence of the BRAFV600E mutation. Endocr Pathol, 2023, 34(1): 112-118.
14. Zhang P, Guan H, Yuan S, et al. Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors. Nat Commun, 2022, 13(1): 1588. doi: 10.1038/s41467-022-29000-5.
15. Fagin JA, Krishnamoorthy GP, Landa I. Pathogenesis of cancers derived from thyroid follicular cells. Nat Rev Cancer, 2023, 23(9): 631-650.
16. Soares P, Póvoa AA, Melo M, et al. Molecular pathology of non-familial follicular epithelial-derived thyroid cancer in adults: from RAS/BRAF-like tumor designations to molecular risk stratification. Endocr Pathol, 2021, 32(1): 44-62.
17. de Sousa MSA, Nunes IN, Christiano YP, et al. Genetic alterations landscape in paediatric thyroid tumours and/or differentiated thyroid cancer: systematic review. Rev Endocr Metab Disord, 2024, 25(1): 35-51.
18. Bikas A, Ahmadi S, Pappa T, et al. Additional oncogenic alterations in RAS-driven differentiated thyroid cancers associate with worse clinicopathologic outcomes. Clin Cancer Res, 2023, 29(14): 2678-2685.
19. Dolezal JM, Trzcinska A, Liao CY, et al. Deep learning prediction of BRAF-RAS gene expression signature identifies noninvasive follicular thyroid neoplasms with papillary-like nuclear features. Mod Pathol, 2021, 34(5): 862-874.
20. Alzumaili BA, Fisch AS, Faquin WC, et al. Detection of RAS p. Q61R by immunohistochemistry in practice: a clinicopathologic study of 217 thyroid nodules with molecular correlates. Endocr Pathol, 2024, 35(3): 219-229.
21. Pekova B, Sykorova V, Dvorakova S, et al. RET, NTRK, ALK, BRAF, and MET fusions in a large cohort of pediatric papillary thyroid carcinomas. Thyroid, 2020, 30(12): 1771-1780.
22. Lee YA, Lee H, Im SW, et al. NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. J Clin Invest, 2021, 131(18): e144847. doi: 10.1172/JCI144847.
23. Stosic A, Fuligni F, Anderson ND, et al. Diverse oncogenic fusions and distinct gene expression patterns define the genomic landscape of pediatric papillary thyroid carcinoma. Cancer Res, 2021, 81(22): 5625-5637.
24. Yu P, Qu N, Zhu R, et al. TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis. Science advances, 2023, 9(35): eadg7125. doi: 10.1126/sciadv.adg7125.
25. Liu R, Zhu G, Tan J, et al. Genetic trio of BRAF and TERT alterations and rs2853669TT in papillary thyroid cancer aggressiveness. J Natl Cancer Inst, 2024, 116(5): 694-701.
26. Canberk S, Gonçalves J, Rios E, et al. The role of 5-hydroxymethylcytosine as a potential epigenetic biomarker in a large series of thyroid neoplasms. Endocr Pathol, 2024, 35(1): 25-39.
27. Pan Z, Tan Z, Xu N, et al. Integrative proteogenomic characterization reveals therapeutic targets in poorly differentiated and anaplastic thyroid cancers. Nature communications, 2025, 16(1): 3601. doi: 10.1038/s41467-025-58910-3.
28. Qu N, Chen D, Ma B, et al. Integrated proteogenomic and metabolomic characterization of papillary thyroid cancer with different recurrence risks. Nat Commun, 2024, 15(1): 3175. doi: 10.1038/s41467-024-47581-1.
29. Kim YH, Yoon SJ, Kim M, et al. Integrative multi-omics analysis reveals different metabolic phenotypes based on molecular characteristics in thyroid cancer. Clin Cancer Res, 2024, 30(4): 883-894.
30. Hong S, Xie Y, Cheng Z, et al. Distinct molecular subtypes of papillary thyroid carcinoma and gene signature with diagnostic capability. Oncogene, 2022, 41(47): 5121-5132.
31. Byun H, Lee HS, Song YS, et al. Transcriptome of anaplastic thyroid cancer reveals two molecular subtypes with distinct tumor microenvironment and prognosis. Thyroid, 2025, 35(4): 367-378.
32. Choi YS, Jeon MJ, Doolittle WKL, et al. Macrophage-induced carboxypeptidase A4 promotes the progression of anaplastic thyroid cancer. Thyroid, 2024, 34(9): 1150-1162.
33. Xu GJ, Loberg MA, Gallant JN, et al. Molecular signature incorporating the immune microenvironment enhances thyroid cancer outcome prediction. Cell Genom, 2023, 3(10): 100409. doi: 10.1016/j.xgen.2023.100409.
34. Marczyk VR, Recamonde-Mendoza M, Maia AL, et al. Classification of thyroid tumors based on DNA methylation patterns. Thyroid, 2023, 33(9): 1090-1099.
35. Cararo Lopes E, Sawant A, Moore D, et al. Integrated metabolic and genetic analysis reveals distinct features of human differentiated thyroid cancer. Clin Transl Med, 2023, 13(6): e1298. doi: 10.1002/ctm2.1298.
36. Ferraz C. Molecular testing for thyroid nodules: where are we now?. Rev Endocr Metab Disord, 2024, 25(1): 149-159.
37. de Koster EJ, Morreau H, Bleumink GS, et al. Molecular diagnostics and [18F]FDG-PET/CT in indeterminate thyroid nodules: complementing techniques or waste of valuable resources?. Thyroid, 2024, 34(1): 41-53.
38. Zou M, BinEssa HA, Al-Malki YH, et al. β-catenin attenuation inhibits tumor growth and promotes differentiation in a BRAFV600E-driven thyroid cancer animal model. Mol Cancer Ther, 2021, 20(9): 1603-1613.
39. Franco AT, Ricarte-Filho JC, Laetsch TW, et al. Oncogene-specific inhibition in the treatment of advanced pediatric thyroid cancer. J Clin Invest, 2021, 131(18): e152696. doi: 10.1172/JCI152696.
40. Li Y, Liu C, Zhang X, et al. CCT5 induces epithelial-mesenchymal transition to promote gastric cancer lymph node metastasis by activating the Wnt/β-catenin signalling pathway. Br J Cancer, 2022, 126(12): 1684-1694.
41. Cao J, Zhu X, Sun Y, et al. The genetic duet of BRAF V600E and TERT promoter mutations predicts the poor curative effect of radioiodine therapy in papillary thyroid cancer. European journal of nuclear medicine and molecular imaging, 2022, 49(10): 3470-3481.
42. Facchinetti F, Lacroix L, Mezquita L, et al. Molecular mechanisms of resistance to BRAF and MEK inhibitors in BRAFV600E non-small cell lung cancer. Eur J Cancer, 2020, 132: 211-223.
43. Shimizu Y, Maruyama K, Suzuki M, et al. Acquired resistance to BRAF inhibitors is mediated by BRAF splicing variants in BRAF V600E mutation-positive colorectal neuroendocrine carcinoma. Cancer letters, 2022, 543: 215799. doi: 10.1016/j.canlet.2022.215799.
44. Ciccone V, Simonis V, Del Gaudio C, et al. ALDH1A1 confers resistance to RAF/MEK inhibitors in melanoma cells by maintaining stemness phenotype and activating PI3K/AKT signaling. Biochem Pharmacol, 2024, 224: 116252. doi: 10.1016/j.bcp.2024.116252.
45. Schäfer A, Haenig B, Erupathil J, et al. Inhibition of endothelin-B receptor signaling synergizes with MAPK pathway inhibitors in BRAF mutated melanoma. Oncogene, 2021, 40(9): 1659-1673.
46. Wang B, Zhang W, Zhang G, et al. Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma. Oncogene, 2021, 40(37): 5590-5599.
47. Pranteda A, Piastra V, Serra M, et al. Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance. Biomed Pharmacother, 2023, 167: 115480. doi: 10.1016/j.biopha.2023.115480.
48. Ruiz-Saenz A, Atreya CE, Wang C, et al. A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors. Nat Cancer, 2023, 4(2): 240-256.
49. Garcia-Rendueles MER, Krishnamoorthy G, Saqcena M, et al. Yap governs a lineage-specific neuregulin1 pathway-driven adaptive resistance to RAF kinase inhibitors. Mol Cancer, 2022, 21(1): 213. doi: 10.1186/s12943-022-01676-9.
50. Nassar KW, Hintzsche JD, Bagby SM, et al. Targeting CDK4/6 represents a therapeutic vulnerability in acquired BRAF/MEK inhibitor-resistant melanoma. Mol Cancer Ther, 2021, 20(10): 2049-2060.
51. Tahara M, Kiyota N, Imai H, et al. A phase 2 study of encorafenib in combination with binimetinib in patients with metastatic BRAF-mutated thyroid cancer in Japan. Thyroid, 2024, 34(4): 467-476.
52. Su X, Li P, Han B, et al. Vitamin C sensitizes BRAFV600E thyroid cancer to PLX4032 via inhibiting the feedback activation of MAPK/ERK signal by PLX4032. J Exp Clin Cancer Res, 2021, 40(1): 34. doi: 10.1186/s13046-021-01831-y.
53. Li L, Cheng L, Sa R, et al. Real-world insights into the efficacy and safety of tyrosine kinase inhibitors against thyroid cancers. Crit Rev Oncol Hematol, 2022, 172: 103624. doi: 10.1016/j.critrevonc.2022.103624.
54. Zhi J, Yi J, Hou X, et al. Targeting SHP2 sensitizes differentiated thyroid carcinoma to the MEK inhibitor. Am J Cancer Res, 2022, 12(1): 247-264.
55. Bible KC, Menefee ME, Lin CJ, et al. An international phase 2 study of pazopanib in progressive and metastatic thyroglobulin antibody negative radioactive iodine refractory differentiated thyroid cancer. Thyroid, 2020, 30(9): 1254-1262.
56. Zaballos MA, Acuña-Ruiz A, Morante M, et al. Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer. Cell Mol Life Sci, 2022, 79(9): 504. doi: 10.1007/s00018-022-04530-9.
57. Cabanillas M E, Dadu R, Iyer P, et al. Acquired secondary RAS mutation in BRAFV600E-mutated thyroid cancer patients treated with BRAF inhibitors. Thyroid, 2020, 30(9): 1288-1296.
58. Yeh CN, Lin SF, Wu CL, et al. Genomic landscape and comparative analysis of tissue and liquid-based NGS in Taiwanese anaplastic thyroid carcinoma. NPJ Precis Oncol, 2025, 9(1): 16. doi: 10.1038/s41698-025-00802-2.
59. Parrish A G, Szulzewsky F. TRKing down drug resistance in NTRK fusion-positive cancers. J Pathol, 2024, 264(2): 129-131.
60. Chin PD, Zhu CY, Sajed DP, et al. Correlation of ThyroSeq results with surgical histopathology in cytologically indeterminate thyroid nodules. Endocr Pathol, 2020, 31(4): 377-384.
61. Li Q, Zhang W, Liao T, et al. An artificial intelligence-driven preoperative radiomic subtype for predicting the prognosis and treatment response of patients with papillary thyroid carcinoma. Clin Cancer Res, 2025, 31(1): 139-150.
62. Ou X, Chen P, Liu BF. Liquid biopsy on microfluidics: from existing endogenous to emerging exogenous biomarkers analysis. Anal Chem, 2025, 97(16): 8625-8640.
63. Xie Y, Xu X, Wang J, et al. Latest advances and perspectives of liquid biopsy for cancer diagnostics driven by microfluidic on-chip assays. Lab Chip, 2023, 23(13): 2922-2941.
64. Bandini S, Ulivi P, Rossi T. Extracellular vesicles, circulating tumor cells, and immune checkpoint inhibitors: hints and promises. Cells, 2024, 13(4): 337. doi: 10.3390/cells13040337.
65. von Felden J, Craig AJ, Garcia-Lezana T, et al. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene, 2021, 40(1): 140-151.
66. Zabegina L, Nazarova I, Knyazeva M, et al. MiRNA let-7 from TPO(+) extracellular vesicles is a potential marker for a differential diagnosis of follicular thyroid nodules. Cells, 2020, 9(8): 1917. doi: 10.3390/cells9081917.
67. Casanova-Salas I, Athie A, Boutros PC, et al. Quantitative and qualitative analysis of blood-based liquid biopsies to inform clinical decision-making in prostate Cancer. Eur Urol, 2021, 79(6): 762-771.
68. Yang Y, Liu H, Chen Y, et al. Liquid biopsy on the horizon in immunotherapy of non-small cell lung cancer: current status, challenges, and perspectives. Cell Death Dis, 2023, 14(3): 230. doi: 10.1038/s41419-023-05757-5.
69. Song J, Ye X, Xiao H. Liquid biopsy entering clinical practice: past discoveries, current insights, and future innovations. Crit Rev Oncol Hematol, 2025, 207: 104613. doi: 10.1016/j.critrevonc.2025.104613.
70. Lone SN, Nisar S, Masoodi T, et al. Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments. Mol Cancer, 2022, 21(1): 79. doi: 10.1186/s12943-022-01543-7.

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