https://doi.org/10.4081/jbr.2026.14951
Integrated clinicopathological and molecular profiling of papillary thyroid carcinoma identifies predominant BRAF and TERT promoter mutations: a cross-sectional study
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Published: 7 July 2026
Papillary Thyroid Carcinoma (PTC) exhibits diverse genetic alterations that influence tumor behavior and clinical outcomes. This study aimed to characterize the spectrum of somatic mutations in PTC using targeted Next-Generation Sequencing (NGS) and to evaluate their associations with clinicopathological, metabolic, and stress-related factors. A Prospective study was conducted on 45 patients newly diagnosed with PTC who underwent total thyroidectomy between December 2024 and February 2025. Formalin-Fixed, Paraffin-Embedded (FFPE) tumor tissues were analyzed using a targeted NGS panel encompassing 35 PTC-related genes. Bioinformatics analysis was performed using Genome Analysis Toolkit (GATK) and ANNOtate VARiation (ANNOVAR) for variant detection and annotation. Clinicopathological variables age, sex, Body Mass Index (BMI), tumor size, laterality, thyroid ultrasound findings, Thyroid Imaging Reporting and Data System (TI-RADS) level and stress exposure were statistically correlated with detected mutations using the chi-square test; a p < 0.05 value was considered as significant. All patients exhibited at least one genetic alteration, with 171 somatic mutations identified (average 3.8 per patient). The most frequent mutation was BRAF V600E (73.3%), followed by TERT promoter (28.9%), MET (24.4%), NRAS (22.2%), and DICER1 (20%). BRAF V600E mutations were significantly more common in tumors ≤ 1.2 cm (p = 0.037) and in right-lobe lesions (p = 0.049). RAS mutations correlated with smaller tumor size (p = 0.021), while TERT mutations were associated with stress exposure (p = 0.001). BRAF, RAS, and TERT mutations were also significantly more frequent among overweight and obese patients (p = 0.047, 0.046, and 0.040, respectively). Age-wise, BRAF and RAS mutations predominated in younger patients (≤ 40 years), whereas TERT mutations occurred unexpectedly more often in this group. BRAF V600E and TERT promoter mutations represent the dominant molecular events in PTC and demonstrate significant associations with tumor size, BMI, stress status, and patient age, suggesting that both metabolic and psychosocial factors may influence thyroid tumorigenesis.
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1- Liu J, Li H, Du R, et al. Targeted next-generation sequencing in papillary thyroid carcinoma of Chinese Han population. J Clin Oncol 2019;37:e17574.
2- Bonjoc KJ, Young H, Warner S, et al. Thyroid cancer diagnosis in the era of precision imaging. J Thorac Dis 2020;12:5128. DOI: https://doi.org/10.21037/jtd.2019.08.37
3- Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. DOI: https://doi.org/10.3322/caac.21834
4- Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2024. CA Cancer J Clin 2024;74:7–33. DOI: https://doi.org/10.3322/caac.21820
5- Karwan M, Abdullah OS, Amin AM, et al. Cancer incidence in the Kurdistan region of Iraq: results of a seven-year cancer registration in Erbil and Duhok governorates. Asian Pac J Cancer Prev 2022;23:601. DOI: https://doi.org/10.31557/APJCP.2022.23.2.601
6- Zhang J, Xu S. High aggressiveness of papillary thyroid cancer: from clinical evidence to regulatory cellular networks. Cell Death Discov 2024;10:378. DOI: https://doi.org/10.1038/s41420-024-02157-2
7- Du Y, Zhang S, Zhang G, Hu J, et al. Mutational profiling of Chinese patients with thyroid cancer. Front Endocrinol 2023;14:1156999. DOI: https://doi.org/10.3389/fendo.2023.1156999
8- Shi D, Yao M, Wu D, Jiang M, et al. Detection of genetic mutations in 855 cases of papillary thyroid carcinoma by next generation sequencing and its clinicopathological features. Diagnostic Pathol 2024;19:146. DOI: https://doi.org/10.1186/s13000-024-01573-3
9- Wang Q, Zhao N, Zhang J. Gene mutation analysis in papillary thyroid carcinoma using a multi-gene panel in China. Int J Gen Med 2021;14:5139-48. DOI: https://doi.org/10.2147/IJGM.S327409
10- Mady LJ, Grimes MC, Khan NI, et al. Molecular profile of locally aggressive well differentiated thyroid cancers. Sci Rep 2020;10:8031. DOI: https://doi.org/10.1038/s41598-020-64635-8
11- Zhang BT, Guo M, Yang LR, et al. Mechanistic aspects of inflammation and oxidative stress and their association with thyroid cancer risk. Cancer Med 2025;14:e71030. DOI: https://doi.org/10.1002/cam4.71030
12- Park H, Heo J, Ryu HJ, et al. The association between BMI and BRAFV600E mutation may differ by primary tumor size. Eur Thyroid J 2024;13:e230255. DOI: https://doi.org/10.1530/ETJ-23-0255
13- Jin L, Chen E, Dong S, et al. BRAF and TERT promoter mutations in the aggressiveness of papillary thyroid carcinoma: a study of 653 patients. Oncotarget 2016;7:18346. DOI: https://doi.org/10.18632/oncotarget.7811
14- Akay GG. Telomeres and psychological stress: perspective on psychopathologies. Noro Psikiyatr Ars 2022;59:330.
15- Abdullah HO, Abdalla BA, Kakamad FH, et al. Predatory publishing lists: a review on the ongoing battle against fraudulent actions. BMJ 2024;2:26-30.
16- Adam MA, Thomas S, Hyslop T, et al. Exploring the relationship between patient age and cancer-specific survival in papillary thyroid cancer: rethinking current staging systems. J Clin Oncol 2016;34:4415-20. DOI: https://doi.org/10.1200/JCO.2016.68.9372
17- Huang H, Xu S, Wang X, et al. Patient age is significantly related to distant metastasis of papillary thyroid microcarcinoma. Front Endocrinol 2021;12:748238. DOI: https://doi.org/10.3389/fendo.2021.748238
18- Limaiem F, Rehman A, Mazzoni T. Papillary Thyroid Carcinoma. (Updated 2024). In: StatPearls (Internet). Treasure Island (FL): StatPearls Publishing; 2025.
19- LeClair K, Bell KJ, Furuya-Kanamori L, et al. 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;181:1351-8. DOI: https://doi.org/10.1001/jamainternmed.2021.4804
20- Moleti M, Sturniolo G, Di Mauro M, et al. Female reproductive factors and differentiated thyroid cancer. Front Endocrinol 2017;8:111. DOI: https://doi.org/10.3389/fendo.2017.00111
21- Lu Z, Zhang Y, Feng D, et al. Targeted next generation sequencing identifies somatic mutations and gene fusions in papillary thyroid carcinoma. Oncotarget 2017;8:45784. DOI: https://doi.org/10.18632/oncotarget.17412
22- Chauhan A, Sen S, Amin K, Burmeister LA. Papillary Thyroid Carcinoma with 5 unique point mutations and typical behavior. JCEM Case Rep 2025;3:luaf062. DOI: https://doi.org/10.1210/jcemcr/luaf062
23- Cong R, Ouyang H, Zhou D et al. BRAF V600E mutation in thyroid carcinoma: a large-scale study in Han Chinese population. World J Surg Oncol 2024;22:259. DOI: https://doi.org/10.1186/s12957-024-03539-7
24- Nhung NT, Mussazhanova Z, Kurohama H, et al. BRAF V600E and TERT promoter mutations and their impact on recurrent papillary thyroid carcinoma progression. Endocr Connect 2025;14:e250116. DOI: https://doi.org/10.1530/EC-25-0116
25- Kim SY, Kim T, Kim K, et al. Highly prevalent BRAF V600E and low-frequency TERT promoter mutations underlie papillary thyroid carcinoma in Koreans. J Pathol Transl Med 2020;54:310-7. DOI: https://doi.org/10.4132/jptm.2020.05.12
26- Perou C. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014;159:676-90.
27- Huang J, Wang J, Xv J, et al. Genetic alterations and allele frequency of BRAF V600E and TERT mutation in papillary thyroid carcinoma with intermediate-to-high recurrence risk: a retrospective study. Clin Exp Med 2024;24:76. DOI: https://doi.org/10.1007/s10238-024-01320-4
28- Brumfield A, Azar SA, Nordgren R, et al. Prevalence and clinical impact of BRAF p. V600E mutation in papillary thyroid carcinoma. Endocr Pathol 2025;36:1-4. DOI: https://doi.org/10.1007/s12022-025-09859-y
29- Bandoh N, Goto T, Kato Y, et al. BRAF V600E mutation co-existing with oncogenic mutations is associated with aggressive clinicopathologic features and poor prognosis in papillary thyroid carcinoma. Asian J Surg 2024;47:413-9. DOI: https://doi.org/10.1016/j.asjsur.2023.09.049
30- Yang H, Park H, Ryu HJ, et al. Frequency of TERT promoter mutations in real-world analysis of 2,092 thyroid carcinoma patients. Endocrinol Metab 2022;37:652-63. DOI: https://doi.org/10.3803/EnM.2022.1477
31- Melo M, da Rocha AG, Vinagre J, et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab 2014;99:E754-65. DOI: https://doi.org/10.1210/jc.2013-3734
32- Amen AM, Fellmann C, Soczek KM, et al. Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage. Proc Natl Acad Sci 2021;118:e2008772118. DOI: https://doi.org/10.1073/pnas.2008772118
33- Muzza M, Pogliaghi G, Colombo C, et al. Extra-nuclear TERT counteracts oxidative stress and promotes progression in papillary thyroid carcinoma. Transl Res 2024;271:1-2. DOI: https://doi.org/10.1016/j.trsl.2024.04.004
34- Kyriacou A, Tziaferi V, Toumba M. Stress, thyroid dysregulation, and thyroid cancer in children and adolescents: proposed impending mechanisms. Horm Res Paediatr 2023;96:44-53. DOI: https://doi.org/10.1159/000524477
35- Lin J, Epel E. Stress and telomere shortening: Insights from cellular mechanisms. Ageing Res Rev 2022;73:101507. DOI: https://doi.org/10.1016/j.arr.2021.101507
36- Rusinek D, Pfeifer A, Cieslicka M, et al. TERT promoter mutations and their impact on gene expression profile in papillary thyroid carcinoma. Cancers 2020;12:1597. DOI: https://doi.org/10.3390/cancers12061597
37- Rahman ST, Pandeya N, Neale RE, et al. Obesity is associated with BRAFV600E-mutated thyroid cancer. Thyroid 2020;30:1518-27. DOI: https://doi.org/10.1089/thy.2019.0654
38- Censi S, Cavedon E, Bertazza L, et al. Frequency and significance of Ras, Tert promoter, and Braf mutations in cytologically indeterminate thyroid nodules: a monocentric case series at a tertiary-level endocrinology unit. Front Endocrinol 2017;8:273. DOI: https://doi.org/10.3389/fendo.2017.00273
39- Semsar-Kazerooni K, Morand GB, Payne AE, et al. Mutational status may supersede tumor size in predicting the presence of aggressive pathologic features in well differentiated thyroid cancer. J Otolaryngol Head Neck Surg 2022;51:9. DOI: https://doi.org/10.1186/s40463-022-00559-9
40- Vianello F, Censi S, Watutantrige-Fernando S, et al. The role of the size in thyroid cancer risk stratification. Sci Rep 2021;11:7303. DOI: https://doi.org/10.1038/s41598-021-86611-6
41- Wikanta ER, Prajoko YW, Issakh B, Istiadi H, Puspasari D. Relationship between the BRAF V600E and tumor size, lymph node, and distant metastasis in papillary thyroid carcinoma. Russ Open Med J 2022;11:216. DOI: https://doi.org/10.15275/rusomj.2022.0216
42- Junainah EM. Genetic alterations in papillary thyroid cancer: clinicopathological correlations and diagnostic implications. Folia Histochem Cytobiol 2025;63:113-20. DOI: https://doi.org/10.5603/fhc.106400
43- Mustafa DH, Ahmed BS, Haweizy RM, Dewana AM. Evaluation of anaplastic thyroid carcinoma in the Kurdistan region of Iraq. BMC Surg 2022;22:364. DOI: https://doi.org/10.1186/s12893-022-01810-w
44- Shakor FN, Abdalqader MH, Saeed AH. Histopathology analysis of thyroid cancer tumor size in Sulaymaniyah-Kurdistan Region-Iraq. Iraq Med J 2020;4.52-7. DOI: https://doi.org/10.22317/imj.v4i2.771
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CRediT authorship contribution
Rawezh Qadir M. Salih was involved in the conception and design of the study, in the literature review and in the writing of the manuscript. Dlnya A. Mohammed was major contribution to the conception of the study, as well as to the literature search for related studies. Nizar M.T. Hamawandi was involved in the literature review, in the study design, in the critical revision of the manuscript and in the processing of the tables. All authors have read and approved the final manuscript.
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available because they form part of an ongoing master’s degree project and may be used in future publications. Data may be available from the corresponding author upon reasonable request and with permission of the Institution.
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