Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Genomic alterations in thyroid cancer: biological and clinical insights

Nature Reviews Endocrinology volume 20, pages 93–110 (2024)Cite this article

Subjects

Abstract

Tumours can arise from thyroid follicular cells if they acquire driver mutations that constitutively activate the MAPK signalling pathway. In addition, a limited set of additional mutations in key genes drive tumour progression towards more aggressive and less differentiated disease. Unprecedented insights into thyroid tumour biology have come from the breadth of thyroid tumour sequencing data from patients and the wide range of mutation-specific mechanisms identified in experimental models, in combination with the genomic simplicity of thyroid cancers. This knowledge is gradually being translated into refined strategies to stratify, manage and treat patients with thyroid cancer. This Review summarizes the biological underpinnings of the genetic alterations involved in thyroid cancer initiation and progression. We also provide a rationale for and discuss specific examples of how to implement genomic information to inform both recommended and investigational approaches to improve thyroid cancer prognosis, redifferentiation strategies and targeted therapies.

Key points

  • Most thyroid cancers are initiated by a single genomic alteration, typically BRAFV600E or in RAS genes, which constitutively activate the MAPK signalling pathway.

  • Driver mutations BRAFV600E or in RAS genes determine multiple clinicopathological properties of thyroid tumours, including their histology, level of differentiation and routes for metastatic dissemination.

  • Advanced thyroid cancers usually evolve from BRAF-driven or RAS-driven clones and become more aggressive and less differentiated via the acquisition of additional genomic alterations in specific genes.

  • Preclinical models of thyroid cancers are valuable tools to understand the underlying mechanisms and biological consequences of pathogenic mutations, and to test novel therapeutic strategies.

  • Genomic characterization is a useful tool to refine prognosis of patients with thyroid cancers and can predict their responses to strategies to induce redifferentiation for subsequent radioactive iodine treatment.

  • BRAFV600E mutation and RET or NTRK fusions are actionable alterations with matched drugs that are approved for the treatment of certain patients whose thyroid tumours have these genetic defects.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Genomic and biological characteristics of thyroid cancer initiation.
Fig. 2: Mutational landscape of thyroid cancer progression.
Fig. 3: Genomic–biological hallmarks of thyroid cancer.
Fig. 4: Schematic representation of the main genetic events implicated in thyroid cancer initiation and evolution.
Fig. 5: Role of tumour genotypes in response to radioactive iodine and redifferentiation therapies.
Fig. 6: New mutation-informed treatment strategies for patients with aggressive thyroid cancers.

Similar content being viewed by others

References

  1. Baloch, Z. W. et al. Overview of the 2022 WHO classification of thyroid neoplasms. Endocr. Pathol. 33, 27–63 (2022). This article provides an overview of the new 2022 WHO classification of thyroid tumours, with a focus on pathological aspects.

    Article  PubMed  Google Scholar 

  2. Fagin, J. A. & Wells, S. A. Jr Biologic and clinical perspectives on thyroid cancer. N. Engl. J. Med. 375, 2307 (2016).

    Article  PubMed  Google Scholar 

  3. Haugen, B. R. et al. 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 26, 1–133 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Christofer Juhlin, C., Mete, O. & Baloch, Z. W. The 2022 WHO classification of thyroid tumors: novel concepts in nomenclature and grading. Endocr. Relat. Cancer 30, e220293 (2023).

    Article  CAS  PubMed  Google Scholar 

  5. Bible, K. C. et al. 2021 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 31, 337–386 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Asioli, S. et al. Poorly differentiated carcinoma of the thyroid: validation of the Turin proposal and analysis of IMP3 expression. Mod. Pathol. 23, 1269–1278 (2010).

    Article  PubMed  Google Scholar 

  7. Wong, K. S. et al. Papillary thyroid carcinoma with high-grade features versus poorly differentiated thyroid carcinoma: an analysis of clinicopathologic and molecular features and outcome. Thyroid 31, 933–940 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Martinez-Jimenez, F. et al. A compendium of mutational cancer driver genes. Nat. Rev. Cancer 20, 555–572 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Taylor, A. M. et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 33, 676–689 e673 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 159, 676–690 (2014). This comprehensive genomic and transcriptomic characterization by the TCGA research network defines the main molecular and phenotypic features of PTCs.

    Article  Google Scholar 

  11. Mitsutake, N. et al. Conditional BRAFV600E expression induces DNA synthesis, apoptosis, dedifferentiation, and chromosomal instability in thyroid PCCL3 cells. Cancer Res. 65, 2465–2473 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Lito, P. et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22, 668–682 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Knauf, J. A. et al. Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Res. 65, 4238–4245 (2005). This paper reports that thyroid-specific expression of BRAFV600E in vivo was able to promote PTC development.

    Article  CAS  PubMed  Google Scholar 

  14. Franco, A. T. et al. Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice. Proc. Natl Acad. Sci. USA 108, 1615–1620 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Charles, R. P., Iezza, G., Amendola, E., Dankort, D. & McMahon, M. Mutationally activated BRAF(V600E) elicits papillary thyroid cancer in the adult mouse. Cancer Res. 71, 3863–3871 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vitagliano, D. et al. Thyroid targeting of the N-ras(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas. Oncogene 25, 5467–5474 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Chen, X. et al. Endogenous expression of Hras(G12V) induces developmental defects and neoplasms with copy number imbalances of the oncogene. Proc. Natl Acad. Sci. USA 106, 7979–7984 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Miller, K. A. et al. Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo. Cancer Res. 69, 3689–3694 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jung, S. H. et al. Mutational burdens and evolutionary ages of thyroid follicular adenoma are comparable to those of follicular carcinoma. Oncotarget 7, 69638–69648 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hudson, T. J. et al. Does the likelihood of malignancy in thyroid nodules with RAS mutations increase in direct proportion with the allele frequency percentage? J. Otolaryngol. Head. Neck Surg. 52, 12 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Veschi, V. et al. Recapitulating thyroid cancer histotypes through engineering embryonic stem cells. Nat. Commun. 14, 1351 (2023). This paper shows that CRISPR-mediated editing of BRAF, RAS and TP53 mutations recapitulate specific thyroid histotypes, particularly when generated in thyroid progenitor cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stosic, A. et al. Diverse oncogenic fusions and distinct gene expression patterns define the genomic landscape of pediatric papillary thyroid carcinoma. Cancer Res. 81, 5625–5637 (2021).

    Article  CAS  PubMed  Google Scholar 

  23. Franco, A. T. et al. Fusion oncogenes are associated with increased metastatic capacity and persistent disease in pediatric thyroid cancers. J. Clin. Oncol. 40, 1081–1090 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ricarte-Filho, J. C. et al. Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J. Clin. Invest. 123, 4935–4944 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Morton, L. M. et al. Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident. Science 372, eabg2538 (2021). The most comprehensive genomic characterization of thyroid cancers linked to the Chernobyl nuclear plant accident, showing a radiation dose-dependent increase in DNA double-strand breaks and the generation of fusion drivers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, J. et al. Conditional expression of RET/PTC induces a weak oncogenic drive in thyroid PCCL3 cells and inhibits thyrotropin action at multiple levels. Mol. Endocrinol. 17, 1425–1436 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Jhiang, S. M. et al. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137, 375–378 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Santoro, M. et al. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12, 1821–1826 (1996).

    CAS  PubMed  Google Scholar 

  29. Powell, D. J. Jr. et al. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res. 58, 5523–5528 (1998).

    CAS  PubMed  Google Scholar 

  30. Bongarzone, I. et al. High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma. Oncogene 4, 1457–1462 (1989).

    CAS  PubMed  Google Scholar 

  31. Kelly, L. M. et al. Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer. Proc. Natl Acad. Sci. USA 111, 4233–4238 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nikitski, A. V. et al. Mouse model of poorly differentiated thyroid carcinoma driven by STRN-ALK fusion. Am. J. Pathol. 188, 2653–2661 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Russell, J. P. et al. The TRK-T1 fusion protein induces neoplastic transformation of thyroid epithelium. Oncogene 19, 5729–5735 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Yoo, S. K. et al. Comprehensive analysis of the transcriptional and mutational landscape of follicular and papillary thyroid cancers. PLoS Genet. 12, e1006239 (2016). This paper reports the genomic and transcriptomic characteristics of FTCs, and compares them with other benign and malignant thyroid lesions with follicular growth patterns.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Nicolson, N. G. et al. Comprehensive genetic analysis of follicular thyroid carcinoma predicts prognosis independent of histology. J. Clin. Endocrinol. Metab. 103, 2640–2650 (2018).

    Article  PubMed  Google Scholar 

  36. Kroll, T. G. et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 289, 1357–1360 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Raman, P. & Koenig, R. J. Pax-8–PPAR-γ fusion protein in thyroid carcinoma. Nat. Rev. Endocrinol. 10, 616–623 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mon, S. Y. et al. Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid-stimulating hormone receptor gene mutations. Diagn. Cytopathol. 46, 369–377 (2018).

    Article  PubMed  Google Scholar 

  39. Parma, J. et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365, 649–651 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov. 7, 818–831 (2017).

    Article  Google Scholar 

  41. Dobson, M. E. et al. Pioglitazone induces a proadipogenic antitumor response in mice with PAX8-PPARgamma fusion protein thyroid carcinoma. Endocrinology 152, 4455–4465 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Karunamurthy, A. et al. Prevalence and phenotypic correlations of EIF1AX mutations in thyroid nodules. Endocr. Relat. Cancer 23, 295–301 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Krishnamoorthy, G. P. et al. EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC. Cancer Discov. 9, 264–281 (2019).

    Article  CAS  PubMed  Google Scholar 

  44. Paulsson, J. O. et al. Whole-genome sequencing of follicular thyroid carcinomas reveal recurrent mutations in MicroRNA processing subunit DGCR8. J. Clin. Endocrinol. Metab. 106, 3265–3282 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Landa, I. et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J. Clin. Invest. 126, 1052–1066 (2016). This paper defines the genomic and transcriptomic hallmarks of PDTCs and ATCs, and shows that they probably progress from well-differentiated tumours.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Pozdeyev, N. et al. Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers. Clin. Cancer Res. 24, 3059–3068 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Foulkes, W. D., Priest, J. R. & Duchaine, T. F. DICER1: mutations, microRNAs and mechanisms. Nat. Rev. Cancer 14, 662–672 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Ricarte-Filho, J. C. et al. DICER1 RNase IIIb domain mutations trigger widespread miRNA dysregulation and MAPK activation in pediatric thyroid cancer. Front. Endocrinol. 14, 1083382 (2023).

    Article  Google Scholar 

  49. Juhlin, C. C., Stenman, A. & Zedenius, J. Macrofollicular variant follicular thyroid tumors are DICER1 mutated and exhibit distinct histological features. Histopathology 79, 661–666 (2021).

    Article  PubMed  Google Scholar 

  50. Lee, Y. A. et al. Predominant DICER1 pathogenic variants in pediatric follicular thyroid carcinomas. Thyroid 30, 1120–1131 (2020).

    Article  PubMed  Google Scholar 

  51. Wasserman, J. D. et al. DICER1 mutations are frequent in adolescent-onset papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 103, 2009–2015 (2018).

    Article  PubMed  Google Scholar 

  52. Chernock, R. D. et al. Poorly differentiated thyroid carcinoma of childhood and adolescence: a distinct entity characterized by DICER1 mutations. Mod. Pathol. 33, 1264–1274 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ghossein, C. A., Dogan, S., Farhat, N., Landa, I. & Xu, B. Expanding the spectrum of thyroid carcinoma with somatic DICER1 mutation: a survey of 829 thyroid carcinomas using MSK-IMPACT next-generation sequencing platform. Virchows Arch. 480, 293–302 (2022).

    Article  CAS  PubMed  Google Scholar 

  54. Rivera, B. et al. DGCR8 microprocessor defect characterizes familial multinodular goiter with Schwannomatosis. J. Clin. Invest. 130, 1479–1490 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Juhlin, C. C. On the chopping block: overview of DICER1 mutations in endocrine and neuroendocrine neoplasms. Surg. Pathol. Clin. 16, 107–118 (2023).

    Article  PubMed  Google Scholar 

  56. Chong, A. S. et al. Prevalence and spectrum of DICER1 mutations in adult-onset thyroid nodules with indeterminate cytology. J. Clin. Endocrinol. Metab. 106, 968–977 (2021).

    Article  PubMed  Google Scholar 

  57. Gopal, R. K. et al. Widespread chromosomal losses and mitochondrial DNA alterations as genetic drivers in Hurthle cell carcinoma. Cancer Cell 34, 242–255 e245 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ganly, I. et al. Integrated genomic analysis of Hurthle cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes. Cancer Cell 34, 256–270 e255 (2018). Together with Gopal et al. (2018), this study reports the unique genomic characteristics of OCA (formerly Hürthle cell cancer), including the near-total haploidization of their genomes and the abundance of mutations in mithocondrial respiratory complex I genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ganly, I. et al. Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hurthle cell carcinoma. Sci. Adv. 8, eabn9699 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Frank, A. R. et al. Mitochondrial-encoded complex I impairment induces a targetable dependency on aerobic fermentation in Hurthle cell carcinoma of the thyroid. Cancer Discov. 13, 1884–1903 (2023).

    Article  CAS  PubMed  Google Scholar 

  61. Tsybrovskyy, O. et al. Papillary thyroid carcinoma tall cell variant shares accumulation of mitochondria, mitochondrial DNA mutations, and loss of oxidative phosphorylation complex I integrity with oncocytic tumors. J. Pathol. Clin. Res. 8, 155–168 (2022).

    Article  CAS  PubMed  Google Scholar 

  62. Dong, W. et al. Clonal evolution analysis of paired anaplastic and well-differentiated thyroid carcinomas reveals shared common ancestor. Genes Chromosomes Cancer 57, 645–652 (2018). This paper shows that ATCs probably arise from subclones of their concurrent well-differentiated tumour components.

    Article  CAS  PubMed  Google Scholar 

  63. Nikiforova, M. N. et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J. Clin. Endocrinol. Metab. 88, 5399–5404 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Manenti, G., Pilotti, S., Re, F. C., Della Porta, G. & Pierotti, M. A. Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur. J. Cancer 30A, 987–993 (1994).

    Article  CAS  PubMed  Google Scholar 

  65. Santoro, M. et al. RET activation and clinicopathologic features in poorly differentiated thyroid tumors. J. Clin. Endocrinol. Metab. 87, 370–379 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Yoo, S. K. et al. Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer. Nat. Commun. 10, 2764 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Song, E. et al. Genetic profile of advanced thyroid cancers in relation to distant metastasis. Endocr. Relat. Cancer 27, 285–293 (2020).

    Article  CAS  PubMed  Google Scholar 

  68. Duan, H. et al. Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next-generation sequencing. Histopathology 75, 890–899 (2019).

    Article  PubMed  Google Scholar 

  69. Tiedje, V. et al. NGS based identification of mutational hotspots for targeted therapy in anaplastic thyroid carcinoma. Oncotarget 8, 42613–42620 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Bonhomme, B. et al. Molecular pathology of anaplastic thyroid carcinomas: a retrospective study of 144 cases. Thyroid 27, 682–692 (2017).

    Article  CAS  PubMed  Google Scholar 

  71. Khan, S. A. et al. Unique mutation patterns in anaplastic thyroid cancer identified by comprehensive genomic profiling. Head. Neck 41, 1928–1934 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Zhang, L. et al. Novel recurrent altered genes in Chinese patients with anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 106, 988–998 (2021).

    Article  PubMed  Google Scholar 

  73. Wang, J. R. et al. Impact of somatic mutations on survival outcomes in patients with anaplastic thyroid carcinoma. JCO Precis. Oncol. 6, e2100504 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Nguyen, B. et al. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell 185, 563–575 e511 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chen, H. et al. Molecular profile of advanced thyroid carcinomas by next-generation sequencing: characterizing tumors beyond diagnosis for targeted therapy. Mol. Cancer Ther. 17, 1575–1584 (2018).

    Article  CAS  PubMed  Google Scholar 

  76. Kunstman, J. W. et al. Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing. Hum. Mol. Genet. 24, 2318–2329 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ibrahimpasic, T. et al. Genomic alterations in fatal forms of non-anaplastic thyroid cancer: identification of MED12 and RBM10 as novel thyroid cancer genes associated with tumor virulence. Clin. Cancer Res. 23, 5970–5980 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Xu, B. et al. Primary high-grade non-anaplastic thyroid carcinoma: a retrospective study of 364 cases. Histopathology 80, 322–337 (2022).

    Article  PubMed  Google Scholar 

  79. Capdevila, J. et al. Early evolutionary divergence between papillary and anaplastic thyroid cancers. Ann. Oncol. 29, 1454–1460 (2018).

    Article  CAS  PubMed  Google Scholar 

  80. Gao, R. et al. Delineating copy number and clonal substructure in human tumors from single-cell transcriptomes. Nat. Biotechnol. 39, 599–608 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Luo, H. et al. Characterizing dedifferentiation of thyroid cancer by integrated analysis. Sci. Adv. 7, eabf3657 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Pu, W. et al. Single-cell transcriptomic analysis of the tumor ecosystems underlying initiation and progression of papillary thyroid carcinoma. Nat. Commun. 12, 6058 (2021). Together with Luo et al. (2021), this study delineates the various transcriptional states of PTC and ATC microevolution via single-cell RNA sequencing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lu, L. et al. Anaplastic transformation in thyroid cancer revealed by single-cell transcriptomics. J. Clin. Invest. 133, e169653 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).

    Article  CAS  PubMed  Google Scholar 

  85. Hoxhaj, G. & Manning, B. D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 20, 74–88 (2020).

    Article  CAS  PubMed  Google Scholar 

  86. Castellano, E. & Downward, J. RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2, 261–274 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hou, P. et al. Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin. Cancer Res. 13, 1161–1170 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Garcia-Rostan, G. et al. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res. 65, 10199–10207 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Liu, Z. et al. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J. Clin. Endocrinol. Metab. 93, 3106–3116 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Ricarte-Filho, J. C. et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 69, 4885–4893 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ramirez-Moya, J., Wert-Lamas, L. & Santisteban, P. MicroRNA-146b promotes PI3K/AKT pathway hyperactivation and thyroid cancer progression by targeting PTEN. Oncogene 37, 3369–3383 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Jolly, L. A., Massoll, N. & Franco, A. T. Immune suppression mediated by myeloid and lymphoid derived immune cells in the tumor microenvironment facilitates progression of thyroid cancers driven by Hras(G12V) and Pten loss. J. Clin. Cell Immunol. 7, 451 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Sponziello, M. et al. Molecular differences between human thyroid follicular adenoma and carcinoma revealed by analysis of a murine model of thyroid cancer. Endocrinology 154, 3043–3053 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Charles, R. P., Silva, J., Iezza, G., Phillips, W. A. & McMahon, M. Activating BRAF and PIK3CA mutations cooperate to promote anaplastic thyroid carcinogenesis. Mol. Cancer Res. 12, 979–986 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Jolly, L. A. et al. Fibroblast-mediated collagen remodeling within the tumor microenvironment facilitates progression of thyroid cancers driven by BrafV600E and Pten loss. Cancer Res. 76, 1804–1813 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shimamura, M. et al. Mouse models of sporadic thyroid cancer derived from BRAFV600E alone or in combination with PTEN haploinsufficiency under physiologic TSH levels. PLoS ONE 13, e0201365 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  97. ElMokh, O. et al. Combined MEK and Pi3′-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo. Oncotarget 8, 24604–24620 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Caperton, C. O., Jolly, L. A., Massoll, N., Bauer, A. J. & Franco, A. T. Development of novel follicular thyroid cancer models which progress to poorly differentiated and anaplastic thyroid cancer. Cancers 13, 1094 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Liu, R. et al. The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway. J. Clin. Endocrinol. Metab. 96, E577–E585 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Jin, N., Jiang, T., Rosen, D. M., Nelkin, B. D. & Ball, D. W. Synergistic action of a RAF inhibitor and a dual PI3K/mTOR inhibitor in thyroid cancer. Clin. Cancer Res. 17, 6482–6489 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Burrows, N. et al. GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1alpha (HIF-1alpha) pathways. J. Clin. Endocrinol. Metab. 96, E1934–E1943 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Bedard, P. L. et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin. Cancer Res. 21, 730–738 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Sherr, C. J. & McCormick, F. The RB and p53 pathways in cancer. Cancer Cell 2, 103–112 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Mantovani, F., Collavin, L. & Del Sal, G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 26, 199–212 (2019).

    Article  PubMed  Google Scholar 

  105. Kandoth, C. et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Fagin, J. A. et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J. Clin. Invest. 91, 179–184 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ito, T. et al. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res. 52, 1369–1371 (1992).

    CAS  PubMed  Google Scholar 

  108. Bachmann, K. et al. P53 is an independent prognostic factor for survival in thyroid cancer. Anticancer. Res. 27, 3993–3997 (2007).

    PubMed  Google Scholar 

  109. La Perle, K. M., Jhiang, S. M. & Capen, C. C. Loss of p53 promotes anaplasia and local invasion in ret/PTC1-induced thyroid carcinomas. Am. J. Pathol. 157, 671–677 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Yang, T. et al. p53 induced by ionizing radiation mediates DNA end-jointing activity, but not apoptosis of thyroid cells. Oncogene 14, 1511–1519 (1997).

    Article  CAS  PubMed  Google Scholar 

  111. McFadden, D. G. et al. p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer. Proc. Natl Acad. Sci. USA 111, E1600–E1609 (2014). This study shows that p53 loss of function promotes progression of BRAFV600E-driven PTCs to ATCs in mouse models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zou, M. et al. TSH overcomes Braf(V600E)-induced senescence to promote tumor progression via downregulation of p53 expression in papillary thyroid cancer. Oncogene 35, 1909–1918 (2016).

    Article  CAS  PubMed  Google Scholar 

  113. Knauf, J. A. et al. Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers. J. Clin. Invest. 128, 4086–4097 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Untch, B. R. et al. Tipifarnib inhibits HRAS-driven dedifferentiated thyroid cancers. Cancer Res. 78, 4642–4657 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Champa, D. et al. Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression. Endocr. Relat. Cancer 21, 755–767 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Antico Arciuch, V. G. et al. Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors. Oncotarget 2, 1109–1126 (2011).

    Article  PubMed  Google Scholar 

  117. Nikitski, A. V. et al. Mouse model of thyroid cancer progression and dedifferentiation driven by STRN-ALK expression and loss of p53: evidence for the existence of two types of poorly differentiated carcinoma. Thyroid 29, 1425–1437 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ryder, M., Ghossein, R. A., Ricarte-Filho, J. C., Knauf, J. A. & Fagin, J. A. Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr. Relat. Cancer 15, 1069–1074 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Caillou, B. et al. Tumor-associated macrophages (TAMs) form an interconnected cellular supportive network in anaplastic thyroid carcinoma. PLoS ONE 6, e22567 (2011). Together with Ryder et al. (2008), this paper shows that ATCs are heavily infiltrated by tumour-associated macrophages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Stenman, A. et al. Pan-genomic sequencing reveals actionable CDKN2A/2B deletions and kataegis in anaplastic thyroid carcinoma. Cancers 13, 6340 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Duquette, M. et al. Metastasis-associated MCL1 and P16 copy number alterations dictate resistance to vemurafenib in a BRAFV600E patient-derived papillary thyroid carcinoma preclinical model. Oncotarget 6, 42445–42467 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Antonello, Z. A. et al. Vemurafenib-resistance via de novo RBM genes mutations and chromosome 5 aberrations is overcome by combined therapy with palbociclib in thyroid carcinoma with BRAF(V600E). Oncotarget 8, 84743–84760 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Lopes-Ventura, S. et al. The efficacy of HRAS and CDK4/6 inhibitors in anaplastic thyroid cancer cell lines. J. Endocrinol. Invest. 42, 527–540 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Martinez, P. & Blasco, M. A. Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat. Rev. Cancer 11, 161–176 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Thompson, C. A. H. & Wong, J. M. Y. Non-canonical functions of telomerase reverse transcriptase: emerging roles and biological relevance. Curr. Top. Med. Chem. 20, 498–507 (2020).

    Article  CAS  PubMed  Google Scholar 

  126. Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Huang, F. W. et al. Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957–959 (2013). Together with Horn et al. (2013), this study reports somatic hot-spot mutations in the proximal promoter of TERT in metastatic melanomas.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Killela, P. J. et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl Acad. Sci. USA 110, 6021–6026 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rheinbay, E. et al. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature 578, 102–111 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Landa, I. et al. Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J. Clin. Endocrinol. Metab. 98, E1562–E1566 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Liu, X. et al. Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr. Relat. Cancer 20, 603–610 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Vinagre, J. et al. Frequency of TERT promoter mutations in human cancers. Nat. Commun. 4, 2185 (2013).

    Article  PubMed  Google Scholar 

  133. Fredriksson, N. J., Ny, L., Nilsson, J. A. & Larsson, E. Systematic analysis of noncoding somatic mutations and gene expression alterations across 14 tumor types. Nat. Genet. 46, 1258–1263 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Bullock, M. et al. TERT promoter mutations are a major indicator of recurrence and death due to papillary thyroid carcinomas. Clin. Endocrinol. 85, 283–290 (2016).

    Article  CAS  Google Scholar 

  135. Song, Y. S. et al. Interaction of BRAF-induced ETS factors with mutant TERT promoter in papillary thyroid cancer. Endocr. Relat. Cancer 26, 629–641 (2019).

    Article  CAS  PubMed  Google Scholar 

  136. Liu, R., Zhang, T., Zhu, G. & Xing, M. Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer. Nat. Commun. 9, 579 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Thornton, C. E. M., Hao, J., Tamarapu, P. P. & Landa, I. Multiple ETS factors participate in the transcriptional control of TERT mutant promoter in thyroid cancers. Cancers 14, 357 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).

    Article  CAS  PubMed  Google Scholar 

  139. Montero-Conde, C. et al. Comprehensive molecular analysis of immortalization hallmarks in thyroid cancer reveals new prognostic markers. Clin. Transl. Med. 12, e1001 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Landa, I. et al. Telomerase upregulation induces progression of mouse BrafV600E-driven thyroid cancers and triggers nontelomeric effects. Mol. Cancer Res. 21, 1163–1175 (2023).

    Article  CAS  PubMed  Google Scholar 

  141. Ghosh, A. et al. Telomerase directly regulates NF-κB-dependent transcription. Nat. Cell Biol. 14, 1270–1281 (2012).

    Article  CAS  PubMed  Google Scholar 

  142. Yu, P. et al. TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis. Sci. Adv. 9, eadg7125 (2023).

  143. Hargreaves, D. C. & Crabtree, G. R. ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res. 21, 396–420 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Sun, X. et al. Suppression of the SWI/SNF component arid1a promotes mammalian regeneration. Cell Stem Cell 18, 456–466 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Montero-Conde, C. et al. Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene. Proc. Natl Acad. Sci. USA 114, E4951–E4960 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Saqcena, M. et al. SWI/SNF complex mutations promote thyroid tumor progression and insensitivity to redifferentiation therapies. Cancer Discov. 11, 1158–1175 (2021). This paper shows that loss-of-function mutations in SWI–SNF genes lock BRAFV600E-driven mouse thyroid tumours into a dedifferentiated state and make them unresponsive to redifferentiation therapies.

    Article  CAS  PubMed  Google Scholar 

  147. Helming, K. C., Wang, X. & Roberts, C. W. M. Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell 26, 309–317 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Pestova, T. V., Borukhov, S. I. & Hellen, C. U. Eukaryotic ribosomes require initiation factors 1 and 1A to locate initiation codons. Nature 394, 854–859 (1998).

    Article  CAS  PubMed  Google Scholar 

  149. Martin, M. et al. Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat. Genet. 45, 933–936 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Petrilli, A. M. & Fernandez-Valle, C. Role of Merlin/NF2 inactivation in tumor biology. Oncogene 35, 537–548 (2016).

    Article  CAS  PubMed  Google Scholar 

  151. Liu-Chittenden, Y. et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes. Dev. 26, 1300–1305 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Garcia-Rendueles, M. E. et al. NF2 loss promotes oncogenic RAS-induced thyroid cancers via YAP-dependent transactivation of RAS proteins and sensitizes them to MEK inhibition. Cancer Discov. 5, 1178–1193 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Garcia-Rendueles, M. E. R. et al. Yap governs a lineage-specific neuregulin1 pathway-driven adaptive resistance to RAF kinase inhibitors. Mol. Cancer 21, 213 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Krishnamoorthy, G. P. et al. Abstract 986: RBM10 loss in thyroid cancer leads to aberrant splicing of cytoskeletal and extracellular matrix mRNAs and increased metastatic fitness. Cancer Res. 82, 986 (2022).

    Article  Google Scholar 

  155. Landa, I. et al. Comprehensive genetic characterization of human thyroid cancer cell lines: a validated panel for preclinical studies. Clin. Cancer Res. 25, 3141–3151 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Capdevila, J. et al. PD-1 blockade in anaplastic thyroid carcinoma. J. Clin. Oncol. 38, 2620–2627 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Shonka, D. C. Jr. et al. American Head and Neck Society Endocrine Surgery section and International Thyroid Oncology Group consensus statement on mutational testing in thyroid cancer: defining advanced thyroid cancer and its targeted treatment. Head Neck 44, 1277–1300 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Rivera, M. et al. Encapsulated papillary thyroid carcinoma: a clinico-pathologic study of 106 cases with emphasis on its morphologic subtypes (histologic growth pattern). Thyroid 19, 119–127 (2009).

    Article  PubMed  Google Scholar 

  159. Sabra, M. M. et al. Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases. J. Clin. Endocrinol. Metab. 98, E829–E836 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Tuttle, R. M. et al. Natural history and tumor volume kinetics of papillary thyroid cancers during active surveillance. JAMA Otolaryngol. Head Neck Surg. 143, 1015–1020 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Perera, D. et al. Genomic and transcriptomic characterization of papillary microcarcinomas with lateral neck lymph node metastases. J. Clin. Endocrinol. Metab. 104, 4889–4899 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Leboulleux, S. et al. Thyroidectomy without radioiodine in patients with low-risk thyroid cancer. N. Engl. J. Med. 386, 923–932 (2022).

    Article  CAS  PubMed  Google Scholar 

  163. Liu, T. et al. The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas. Oncogene 33, 4978–4984 (2013).

    Article  PubMed  Google Scholar 

  164. Melo, M. et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J. Clin. Endocrinol. Metab. 99, E754–E765 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Xing, M. et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J. Clin. Oncol. 32, 2718–2726 (2014). This study shows that concomitant BRAFV600E and TERT promoter mutations are biomarkers of worse clinical outcome in PTC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Liu, X. et al. TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J. Clin. Endocrinol. Metab. 99, E1130–E1136 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Song, Y. S. et al. Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients. Cancer 122, 1370–1379 (2016).

    Article  CAS  PubMed  Google Scholar 

  168. Gandolfi, G. et al. TERT promoter mutations are associated with distant metastases in papillary thyroid carcinoma. Eur. J. Endocrinol. 172, 403–413 (2015).

    Article  CAS  PubMed  Google Scholar 

  169. Liu, R. et al. 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. 3, 202–208 (2017).

    Article  PubMed  Google Scholar 

  170. Lee, S. E. et al. Prognostic significance of TERT promoter mutations in papillary thyroid carcinomas in a BRAF(V600E) mutation-prevalent population. Thyroid 26, 901–910 (2016).

    Article  CAS  PubMed  Google Scholar 

  171. Povoa, A. A. et al. Genetic determinants for prediction of outcome of patients with papillary thyroid carcinoma. Cancers 13, 2048 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Alzahrani, A. S., Alsaadi, R., Murugan, A. K. & Sadiq, B. B. TERT promoter mutations in thyroid cancer. Hormones Cancer 7, 165–177 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Moon, S. et al. Effects of coexistent BRAF(V600E) and TERT promoter mutations on poor clinical outcomes in papillary thyroid cancer: a meta-analysis. Thyroid 27, 651–660 (2017).

    Article  CAS  PubMed  Google Scholar 

  174. Chen, B., Shi, Y., Xu, Y. & Zhang, J. The predictive value of coexisting BRAFV600E and TERT promoter mutations on poor outcomes and high tumour aggressiveness in papillary thyroid carcinoma: a systematic review and meta-analysis. Clin. Endocrinol. 94, 731–742 (2021).

    Article  CAS  Google Scholar 

  175. Pappa, T. et al. Oncogenic mutations in PI3K/AKT/mTOR pathway effectors associate with worse prognosis in BRAF(V600E) -driven papillary thyroid cancer patients. Clin. Cancer Res. 27, 4256–4264 (2021).

    Article  CAS  PubMed  Google Scholar 

  176. Song, E. et al. Mutation in genes encoding key functional groups additively increase mortality in patients with BRAF(V600E)-mutant advanced papillary thyroid carcinoma. Cancers 13, 5846 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Bikas, A. et al. Additional oncogenic alterations in RAS-driven differentiated thyroid cancers associate with worse clinicopathologic outcomes. Clin. Cancer Res. 29, 2678–2685 (2023).

    Article  CAS  PubMed  Google Scholar 

  178. Qin, Y. et al. Clinical utility of circulating cell-free DNA mutations in anaplastic thyroid carcinoma. Thyroid 31, 1235–1243 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. De la Vieja, A. & Riesco-Eizaguirre, G. Radio-iodide treatment: from molecular aspects to the clinical view. Cancers 13, 995 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Buffet, C. et al. Redifferentiation of radioiodine-refractory thyroid cancers. Endocr. Relat. Cancer 27, R113–R132 (2020).

    Article  PubMed  Google Scholar 

  181. Ravera, S. et al. Structural insights into the mechanism of the sodium/iodide symporter. Nature 612, 795–801 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Riesco-Eizaguirre, G. et al. The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res. 69, 8317–8325 (2009).

    Article  CAS  PubMed  Google Scholar 

  183. Azouzi, N. et al. NADPH oxidase NOX4 is a critical mediator of BRAF(V600E)-induced downregulation of the sodium/iodide symporter in papillary thyroid carcinomas. Antioxid. Redox Signal. 26, 864–877 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Boelaert, K. et al. PTTG and PBF repress the human sodium iodide symporter. Oncogene 26, 4344–4356 (2007).

    Article  CAS  PubMed  Google Scholar 

  185. Boucai, L. et al. Characterization of subtypes of BRAF-mutant papillary thyroid cancer defined by their thyroid differentiation score. J. Clin. Endocrinol. Metab. 107, 1030–1039 (2022).

    Article  PubMed  Google Scholar 

  186. Chakravarty, D. et al. Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J. Clin. Invest. 121, 4700–4711 (2011). This in vivo study demonstrates an inverse correlation between MAPK pathway activation and RAI avidity in a mouse model of PTC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Nagarajah, J. et al. Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine. J. Clin. Invest. 126, 4119–4124 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Lamartina, L., Anizan, N., Dupuy, C., Leboulleux, S. & Schlumberger, M. Redifferentiation-facilitated radioiodine therapy in thyroid cancer. Endocr. Relat. Cancer 28, T179–T191 (2021).

    Article  CAS  PubMed  Google Scholar 

  189. Van Nostrand, D., Veytsman, I., Kulkarni, K., Heimlich, L. & Burman, K. D. Redifferentiation of differentiated thyroid cancer: clinical insights from a narrative review of literature. Thyroid 33, 674–681 (2023).

    Article  PubMed  Google Scholar 

  190. Ho, A. L. et al. Selumetinib plus adjuvant radioactive iodine in patients with high-risk differentiated thyroid cancer: a phase III, randomized, placebo-controlled trial (ASTRA). J. Clin. Once. 40, 1870–1878 (2022).

    Article  CAS  Google Scholar 

  191. Ho, A. L. et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N. Engl. J. Med. 368, 623–632 (2013). This redifferentiation trial showed that MEK inhibition restored RAI avidity in RAI-refractory thyroid cancers, especially in those driven by RAS mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Leboulleux, S. et al. MERAIODE: a phase II redifferentiation trial with trametinib and 131I in metastatic radioactive iodine refractory RAS mutated differentiated thyroid cancer. Thyroid 33, 1124–1129 (2023).

    CAS  PubMed  Google Scholar 

  193. Leboulleux, S. et al. Redifferentiation of a BRAF(K601E)-mutated poorly differentiated thyroid cancer patient with dabrafenib and trametinib treatment. Thyroid 29, 735–742 (2019).

    Article  CAS  PubMed  Google Scholar 

  194. Dunn, L. A. et al. Vemurafenib redifferentiation of BRAF mutant, RAI-refractory thyroid cancers. J. Clin. Endocrinol. Metab. 104, 1417–1428 (2019).

    Article  PubMed  Google Scholar 

  195. Rothenberg, S. M., McFadden, D. G., Palmer, E. L., Daniels, G. H. & Wirth, L. J. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin. Cancer Res. 21, 1028–1035 (2015).

    Article  CAS  PubMed  Google Scholar 

  196. Jaber, T. et al. Targeted therapy in advanced thyroid cancer to resensitize tumors to radioactive iodine. J. Clin. Endocrinol. Metab. 103, 3698–3705 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Tchekmedyian, V. et al. Enhancing radioiodine incorporation in BRAF-mutant, radioiodine-refractory thyroid cancers with vemurafenib and the anti-ErbB3 monoclonal antibody CDX-3379: results of a pilot clinical trial. Thyroid 32, 273–282 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Weber, M. et al. Enhancing radioiodine incorporation into radioiodine-refractory thyroid cancer with MAPK inhibition (ERRITI): a single-center prospective two-arm study. Clin. Cancer Res. 28, 4194–4202 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Leboulleux, S. et al. A phase II redifferentiation trial with dabrafenib-trametinib and 131I in metastatic radioactive iodine refractory BRAF p.V600E mutated differentiated thyroid cancer. Clin. Cancer Res. 29, 2401–2409 (2023).

    Article  CAS  PubMed  Google Scholar 

  200. Iravani, A. et al. Mitogen-activated protein kinase pathway inhibition for redifferentiation of radioiodine refractory differentiated thyroid cancer: an evolving protocol. Thyroid 29, 1634–1645 (2019).

    Article  CAS  PubMed  Google Scholar 

  201. Groussin, L. et al. Letter to the editor: selpercatinib-enhanced radioiodine uptake in RET-rearranged thyroid cancer. Thyroid 31, 1603–1604 (2021).

    PubMed  Google Scholar 

  202. Groussin, L. et al. Redifferentiating effect of larotrectinib in NTRK-rearranged advanced radioactive-iodine refractory thyroid cancer. Thyroid 32, 594–598 (2022).

    Article  CAS  PubMed  Google Scholar 

  203. Boucai, L. et al. Genomic and transcriptomic characteristics of metastatic thyroid cancers with exceptional responses to radioactive iodine therapy. Clin. Cancer Res. 29, 1620–1630 (2023). This study delineates the genomic features associated with structural responses to RAI therapy in patients with metastatic thyroid cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Yang, X. et al. TERT promoter mutation predicts radioiodine-refractory character in distant metastatic differentiated thyroid cancer. J. Nucl. Med. 58, 258–265 (2017).

    Article  CAS  PubMed  Google Scholar 

  205. Liu, J. et al. The genetic duet of BRAF V600E and TERT promoter mutations robustly predicts loss of radioiodine avidity in recurrent papillary thyroid cancer. J. Nucl. Med. 61, 177–182 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Soe, M. H. et al. Non-iodine-avid disease is highly prevalent in distant metastatic differentiated thyroid cancer with papillary histology. J. Clin. Endocrinol. Metab. 107, e3206–e3216 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Hofmann, M. C. et al. Molecular mechanisms of resistance to kinase inhibitors and redifferentiation in thyroid cancers. Endocr. Relat. Cancer 29, R173–R190 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Schubert, L., Mariko, M. L., Clerc, J., Huillard, O. & Groussin, L. MAPK pathway inhibitors in thyroid cancer: preclinical and clinical data. Cancers 15, 710 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Subbiah, V. et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Ann. Oncol. 33, 406–415 (2022). This study provides the most updated data showing that combined inhibition of RAF and MEK results in relevant responses and improves survival in patients with BRAFV600E-mutant ATC.

    Article  CAS  PubMed  Google Scholar 

  210. Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Danysh, B. P. et al. Long-term vemurafenib treatment drives inhibitor resistance through a spontaneous KRAS G12D mutation in a BRAF V600E papillary thyroid carcinoma model. Oncotarget 7, 30907–30923 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Cabanillas, M. E. et al. Acquired secondary RAS mutation in BRAF(V600E)-mutated thyroid cancer patients treated with BRAF inhibitors. Thyroid 30, 1288–1296 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Lee, M. et al. Genomic and transcriptomic correlates of thyroid carcinoma evolution after BRAF inhibitor therapy. Mol. cancer Res. 20, 45–55 (2022). Together with Cabanillas et al. (2020), this paper reports the acquisition of mutations in RAS and in other genes as a resistance mechanism of BRAFV600E-mutant tumours from patients treated with BRAF inhibitors.

    Article  CAS  PubMed  Google Scholar 

  214. French, J. D. Immunotherapy for advanced thyroid cancers — rationale, current advances and future strategies. Nat. Rev. Endocrinol. 16, 629–641 (2020). This review provides an overview of the current data and future strategies in the use of immunotherapies for patients with advanced thyroid cancers.

    Article  PubMed  Google Scholar 

  215. Gunda, V. et al. Combinations of BRAF inhibitor and anti-PD-1/PD-L1 antibody improve survival and tumour immunity in an immunocompetent model of orthotopic murine anaplastic thyroid cancer. Br. J. Cancer 119, 1223–1232 (2018). This study provides preclinical rationale for combining BRAF inhibitors with PD1–PDL1 inhibitors in ATC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Ryder, M. et al. Genetic and pharmacological targeting of CSF-1/CSF-1R inhibits tumor-associated macrophages and impairs BRAF-induced thyroid cancer progression. PLoS ONE 8, e54302 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Zhang, P. et al. Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors. Nat. Commun. 13, 1588 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Iyer, P. C. et al. Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma. J. Immunother. Cancer 6, 68 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Cabanillas, M. E. et al. BRAF/MEK inhibitor plus immunotherapy for BRAFV600E‐mutated anaplastic thyroid carcinoma [abstract 48]. Thyroid 32, A-136–A-174 (2022).

    Google Scholar 

  220. Dierks, C. et al. Phase II ATLEP trial: final results for lenvatinib/pembrolizumab in metastasized anaplastic and poorly differentiated thyroid carcinoma. Ann. Oncol. 33, S1295 (2022).

    Article  Google Scholar 

  221. Zhao, X. et al. Surgery after BRAF-directed therapy is associated with improved survival in BRAF V600E mutant anaplastic thyroid cancer: a single-center retrospective cohort study. Thyroid 33, 484–491 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Busaidy, N. L. et al. Dabrafenib versus dabrafenib + trametinib in BRAF-mutated radioactive iodine refractory differentiated thyroid cancer: results of a randomized, phase 2, open-label multicenter trial. Thyroid 32, 1184–1192 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Waguespack, S. G. et al. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. Eur. J. Endocrinol. 186, 631–643 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Bowles, D. W. et al. Entrectinib in patients with NTRK fusion-positive (NTRK-FP) thyroid cancer: updated data from STARTRK-2. Endocr. Abstr. 84, OP03-14 (2022).

    Google Scholar 

  225. Subbiah, V. et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol. 9, 491–501 (2021).

    Article  CAS  PubMed  Google Scholar 

  226. Wirth, L. J. et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N. Engl. J. Med. 383, 825–835 (2020). Together with Subbiah et al. (2021), this clinical trial shows the efficacy of specific RET inhibitors to treat thyroid cancers driven by RET alterations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Rosen, E. Y. et al. The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers. Nat. Commun. 13, 1450 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Subbiah, V. et al. Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations. Ann. Oncol. 32, 261–268 (2021).

    Article  CAS  PubMed  Google Scholar 

  229. Lee, Y. A. et al. NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. J. Clin. Invest. 131, e144847 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Yu, Y. et al. Rapid response to monotherapy with MEK inhibitor trametinib for a lung adenocarcinoma patient harboring primary SDN1-BRAF fusion: a case report and literature review. Front. Oncol. 12, 945620 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Godbert, Y. et al. Remarkable response to crizotinib in woman with anaplastic lymphoma kinase-rearranged anaplastic thyroid carcinoma. J. Clin. Oncol. 33, e84–e87 (2015).

    Article  PubMed  Google Scholar 

  232. Battista, S. et al. A mutated p53 gene alters thyroid cell differentiation. Oncogene 11, 2029–2037 (1995).

    CAS  PubMed  Google Scholar 

  233. Santoro, M. et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J. Clin. Invest. 89, 1517–1522 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Cohen, Y. et al. BRAF mutation in papillary thyroid carcinoma. J. Natl Cancer Inst. 95, 625–627 (2003).

    Article  CAS  PubMed  Google Scholar 

  235. Trovisco, V. et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J. Pathol. 202, 247–251 (2004).

    Article  CAS  PubMed  Google Scholar 

  236. Salvatore, G. et al. Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 89, 5175–5180 (2004).

    Article  CAS  PubMed  Google Scholar 

  237. Xing, M. et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J. Clin. Endocrinol. Metab. 90, 6373–6379 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, MA, USA

    Iñigo Landa

  2. Harvard Medical School, Boston, MA, USA

    Iñigo Landa

  3. Department of Endocrine Neoplasia & Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Maria E. Cabanillas

Authors
  1. Iñigo Landa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria E. Cabanillas
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed to all aspects of the article.

Corresponding author

Correspondence to Iñigo Landa.

Ethics declarations

Competing interests

M.E.C. has received grant support from Genetech, Exelixis, Eisai, Merck and Kura, and has received consultation fees from Lilly, Bayer and Exelixis. I.L. declares no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Laura Boucai, Martin Schlumberger and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

The SEER database: https://seer.cancer.gov/

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Landa, I., Cabanillas, M.E. Genomic alterations in thyroid cancer: biological and clinical insights. Nat Rev Endocrinol 20, 93–110 (2024). https://doi.org/10.1038/s41574-023-00920-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-023-00920-6

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer