Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 19, 2026.

Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer

Seong-Keun Yoo, Young Shin Song, Eun Kyung Lee and 13 more

Nature Communications · 2019 · CC BY

doi:10.1038/s41467-019-10680-5

Abstract

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT , AKT1 , PIK3CA , and EIF1AX were frequently co-mutated with driver genes ( BRAF V600E and RAS ) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A ) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS -positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.

References 72

  1. 1.

    Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676-690.

    Not in our library10.1016/j.cell.2014.09.050

  2. 2.
    Comprehensive Analysis of the Transcriptional and Mutational Landscape of Follicular and Papillary Thyroid Cancers · 2016
    No notice
  3. 3.

    Keutgen XM, Sadowski SM, Kebebew E. Management of anaplastic thyroid cancer. Gland Surg. 2015;4:44-51.

    Not in our library10.3978/j.issn.2227-684x.2014.12.02

  4. 4.

    Molinaro E, et al. Anaplastic thyroid carcinoma: from clinicopathology to genetics and advanced therapies. Nat. Rev. Endocrinol. 2017;13:644-660.

    Not in our library10.1038/nrendo.2017.76

  5. 5.

    D’Avanzo A, et al. Follicular thyroid carcinoma: histology and prognosis. Cancer. 2004;100:1123-1129.

    Not in our library10.1002/cncr.20081

  6. 6.

    Durante C, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J. Clin. Endocrinol. Metab. 2006;91:2892-2899.

    Not in our library10.1210/jc.2005-2838

  7. 7.

    Ibrahimpasic T, et al. Outcomes in patients with poorly differentiated thyroid carcinoma. J. Clin. Endocrinol. Metab. 2014;99:1245-1252.

    Not in our library10.1210/jc.2013-3842

  8. 8.

    Landa I, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J. Clin. Invest. 2016;126:1052-1066.

    Not in our library10.1172/jci85271

  9. 9.

    Pozdeyev Nikita, Gay Laurie M., Sokol Ethan S., Hartmaier Ryan, Deaver Kelsi E., Davis Stephanie, French Jena D., Borre Pierre Vanden, LaBarbera Daniel V., Tan Aik-Choon, Schweppe Rebecca E., Fishbein Lauren, Ross Jeffrey S., Haugen Bryan R., Bowles Daniel W. Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers. Clinical Cancer Research. 2018;24(13):3059-3068.

    Not in our library10.1158/1078-0432.ccr-18-0373

  10. 10.

    Cancer Genome Atlas Research N.. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519-525.

    Not in our library10.1038/nature11404

  11. 11.

    Alaei-Mahabadi B, Bhadury J, Karlsson JW, Nilsson JA, Larsson E. Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human cancers. Proc. Natl Acad. Sci. USA. 2016;113:13768-13773.

    Not in our library10.1073/pnas.1606220113

  12. 12.

    Jung SH, et al. Mutational burdens and evolutionary ages of thyroid follicular adenoma are comparable to those of follicular carcinoma. Oncotarget. 2016;7:69638-69648.

    Not in our library10.18632/oncotarget.11922

  13. 13.

    Ye L, et al. The genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing. Nat. Commun. 2017;8:15533.

    Not in our library10.1038/ncomms15533

  14. 14.

    Graubert TA, et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat. Genet. 2011;44:53-57.

    Not in our library10.1038/ng.1031

  15. 15.

    Ju YS, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 2012;22:436-445.

    Not in our library10.1101/gr.133645.111

  16. 16.

    Taylor PN, et al. Whole-genome sequence-based analysis of thyroid function. Nat. Commun. 2015;6:5681.

    Not in our library10.1038/ncomms6681

  17. 17.

    Hayashi M, et al. Molecular cloning and characterization of human PDE8B, a novel thyroid-specific isozyme of 3’,5’-cyclic nucleotide phosphodiesterase. Biochem. Biophys. Res. Commun. 1998;250:751-756.

    Not in our library10.1006/bbrc.1998.9379

  18. 18.

    Valentijn LJ, et al. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat. Genet. 2015;47:1411-1414.

    Not in our library10.1038/ng.3438

  19. 19.

    Peifer M, et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature. 2015;526:700-704.

    Not in our library10.1038/nature14980

  20. 20.

    Alexandrov LB, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-421.

    Not in our library10.1038/nature12477

  21. 21.

    Rubinstein JC, et al. Shifting patterns of genomic variation in the somatic evolution of papillary thyroid carcinoma. BMC Cancer. 2016;16:646.

    Not in our library10.1186/s12885-016-2665-7

  22. 22.

    Ogata H, et al. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 1999;27:29-34.

    Not in our library10.1093/nar/27.1.29

  23. 23.

    Kofler NM, et al. Notch signaling in developmental and tumor angiogenesis. Genes Cancer. 2011;2:1106-1116.

    Not in our library10.1177/1947601911423030

  24. 24.

    Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb. Perspect. Med. 2012;2:a006502.

    Not in our library10.1101/cshperspect.a006502

  25. 25.

    Song YS, 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. 2016;122:1370-1379.

    Not in our library10.1002/cncr.29934

  26. 26.

    Liu R, Xing M. TERT promoter mutations in thyroid cancer. Endocr. Relat. Cancer. 2016;23:R143-R155.

    Not in our library10.1530/erc-15-0533

  27. 27.

    Yin DT, et al. Clinicopathological significance of TERT promoter mutation in papillary thyroid carcinomas: a systematic review and meta-analysis. Clin. Endocrinol. 2016;85:299-305.

    Not in our library10.1111/cen.13017

  28. 28.

    Bell RJ, et al. Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 2015;348:1036-1039.

    Not in our library10.1126/science.aab0015

  29. 29.

    Davis CF, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell. 2014;26:319-330.

    Not in our library10.1016/j.ccr.2014.07.014

  30. 30.

    Endo M, et al. Prognostic significance of p14ARF, p15INK4b, and p16INK4a inactivation in malignant peripheral nerve sheath tumors. Clin. Cancer Res. 2011;17:3771-3782.

    Not in our library10.1158/1078-0432.ccr-10-2393

  31. 31.

    Aesif SW, et al. Loss of p16(INK4A) expression and homozygous CDKN2A deletion are associated with worse outcome and younger age in thymic carcinomas. J. Thorac. Oncol. 2017;12:860-871.

    Not in our library10.1016/j.jtho.2017.01.028

  32. 32.

    Song YS, et al. Aberrant thyroid-stimulating hormone receptor signaling increases VEGF-A and CXCL8 secretion of thyroid cancer cells, contributing to angiogenesis and tumor growth. Clin. Cancer Res. 2019;25:414-425.

    Not in our library10.1158/1078-0432.ccr-18-0663

  33. 33.

    Elvin JA, et al. Clinical benefit in response to palbociclib treatment in refractory uterine leiomyosarcomas with a common CDKN2A alteration. Oncologist. 2017;22:416-421.

    Not in our library10.1634/theoncologist.2016-0310

  34. 34.

    Konecny GE, et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin. Cancer Res. 2011;17:1591-1602.

    Not in our library10.1158/1078-0432.ccr-10-2307

  35. 35.

    Wiedemeyer WR, et al. Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc. Natl Acad. Sci. USA. 2010;107:11501-11506.

    Not in our library10.1073/pnas.1001613107

  36. 36.

    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. 2015;6:42445-42467.

    Not in our library10.18632/oncotarget.6442

  37. 37.
    Cancer immunotherapy: the beginning of the end of cancer? · 2016
    No notice
  38. 38.

    Rizvi NA, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-128.

    Not in our library10.1126/science.aaa1348

  39. 39.

    Rizvi H, et al. Molecular determinants of response to anti-Programmed Cell Death (PD)-1 and anti-Programmed Death-Ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J. Clin. Oncol. 2018;36:633-641.

    Not in our library10.1200/jco.2017.75.3384

  40. 40.

    Chintakuntlawar AV, et al. Expression of PD-1 and PD-L1 in anaplastic thyroid cancer patients treated with multimodal therapy: results from a retrospective study. J. Clin. Endocrinol. Metab. 2017;102:1943-1950.

    Not in our library10.1210/jc.2016-3756

All 72 references

Cited by papers we hold 5

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.