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Endocrine

, Volume 64, Issue 1, pp 130–138 | Cite as

Mutational profile of papillary thyroid microcarcinoma with extensive lymph node metastasis

  • Min Ji Jeon
  • Sung Min Chun
  • Ji-Young Lee
  • Kyeong Woon Choi
  • Deokhoon Kim
  • Tae Yong Kim
  • Se Jin Jang
  • Won Bae Kim
  • Young Kee Shong
  • Dong Eun SongEmail author
  • Won Gu KimEmail author
Original Article
  • 134 Downloads

Abstract

Purpose

Papillary thyroid microcarcinoma (PTMC) has excellent outcomes, but extensive lymph node (LN) metastasis can be associated with fatal outcomes. We evaluated the mutational profiles of primary tumors and their metastatic LNs of PTMCs with extensive lateral cervical LN metastases.

Methods

Formalin-fixed, paraffin-embedded archival samples from 16 sets of normal thyroid tissue, the primary PTMC, and the largest metastatic LN were used for targeted sequencing.

Results

A total of seven somatic variants were confirmed in the PTMCs compared to the normal tissue. The BRAFV600E mutation was the most common and seen in 12 primary tumors (75%) and 11 metastatic LNs (69%). A nonsense mutation in AR and an in-frame deletion in ACVR2A were detected in one primary tumor and its metastatic LN (6%). Missense mutations in KMT2A, RAF1, and ROS1 were detected in one primary tumor (3%). A frameshift deletion mutation in JAK2 was detected in a metastatic LN (3%). In PTMCs without the BRAF mutation, an ALK and RET rearrangement (one PTMC and its metastatic LN, 6%) was detected. In one patient, the BRAF mutation was detected in the primary tumor, but only a RET rearrangement was detected in its metastatic LN. No mutations were detected in two patients.

Conclusion

The mutational frequency of PTMCs was really low, even in those with extensive LN metastasis. The mutational status of the primary tumor and its metastatic LNs were not significantly different, and this suggests a minor role for genetic alterations in the process of LN metastasis in PTMC.

Keywords

Papillary thyroid microcarcinoma DNA mutational analysis High-throughput nucleotide sequencing Translational research 

Notes

Funding

This study was supported by the National Research Foundation (NRF) of Korea Research Grant (NRF-2017R1D1A1B03028231).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all participants included in the study, except 2two patients who died before the initiation of this study.

Supplementary material

12020_2019_1842_MOESM1_ESM.docx (21 kb)
Supplementary Tables

References

  1. 1.
    B.R. Haugen, E.K. Alexander, K.C. Bible, G.M. Doherty, S.J. Mandel, Y.E. Nikiforov, F. Pacini, G.W. Randolph, A.M. Sawka, M. Schlumberger, K.G. Schuff, S.I. Sherman, J.A. Sosa, D.L. Steward, R.M. Tuttle, L. Wartofsky, 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), 1–133 (2016).  https://doi.org/10.1089/thy.2015.0020 CrossRefGoogle Scholar
  2. 2.
    H. Kwon, H.S. Oh, M. Kim, S. Park, M.J. Jeon, W.G. Kim, W.B. Kim, Y.K. Shong, D.E. Song, J.H. Baek, K.W. Chung, T.Y. Kim, Active surveillance for patients with papillary thyroid microcarcinoma: a single center’s experience in Korea. J. Clin. Endocrinol. Metab. 102(6), 1917–1925 (2017).  https://doi.org/10.1210/jc.2016-4026 CrossRefGoogle Scholar
  3. 3.
    M.J. Jeon, W.G. Kim, Y.M. Choi, H. Kwon, Y.M. Lee, T.Y. Sung, J.H. Yoon, K.W. Chung, S.J. Hong, T.Y. Kim, Y.K. Shong, D.E. Song, W.B. Kim, Features predictive of distant metastasis in papillary thyroid microcarcinomas. Thyroid 26(1), 161–168 (2016).  https://doi.org/10.1089/thy.2015.0375 CrossRefGoogle Scholar
  4. 4.
    D. Li, M. Gao, X. Li, M. Xing, Molecular aberrance in papillary thyroid microcarcinoma bearing high aggressiveness: identifying a “Tibetan Mastiff dog” from puppies. J. Cell. Biochem. 117(7), 1491–1496 (2016).  https://doi.org/10.1002/jcb.25506 CrossRefGoogle Scholar
  5. 5.
    F. Li, G. Chen, C. Sheng, A.M. Gusdon, Y. Huang, Z. Lv, H. Xu, M. Xing, S. Qu, BRAFV600E mutation in papillary thyroid microcarcinoma: a meta-analysis. Endocr. Relat. Cancer 22(2), 159–168 (2015).  https://doi.org/10.1530/erc-14-0531 CrossRefGoogle Scholar
  6. 6.
    D. de Biase, G. Gandolfi, M. Ragazzi, M. Eszlinger, V. Sancisi, M. Gugnoni, M. Visani, A. Pession, G. Casadei, C. Durante, G. Costante, R. Bruno, M. Torlontano, R. Paschke, S. Filetti, S. Piana, A. Frasoldati, G. Tallini, A. Ciarrocchi, TERT promoter mutations in papillary thyroid microcarcinomas. Thyroid 25(9), 1013–1019 (2015).  https://doi.org/10.1089/thy.2015.0101 CrossRefGoogle Scholar
  7. 7.
    M.J. Jeon, S.M. Chun, D. Kim, H. Kwon, E.K. Jang, T.Y. Kim, W.B. Kim, Y.K. Shong, S.J. Jang, D.E. Song, W.G. Kim, Genomic alterations of anaplastic thyroid carcinoma detected by targeted massive parallel sequencing in a BRAF(V600E) mutation-prevalent area. Thyroid 26(5), 683–690 (2016).  https://doi.org/10.1089/thy.2015.0506 CrossRefGoogle Scholar
  8. 8.
    H. Li, R. Durbin, Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25(14), 1754–1760 (2009).  https://doi.org/10.1093/bioinformatics/btp324 CrossRefGoogle Scholar
  9. 9.
    A. McKenna, M. Hanna, E. Banks, A. Sivachenko, K. Cibulskis, A. Kernytsky, K. Garimella, D. Altshuler, S. Gabriel, M. Daly, M.A. DePristo, The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20(9), 1297–1303 (2010).  https://doi.org/10.1101/gr.107524.110 CrossRefGoogle Scholar
  10. 10.
    K. Cibulskis, M.S. Lawrence, S.L. Carter, A. Sivachenko, D. Jaffe, C. Sougnez, S. Gabriel, M. Meyerson, E.S. Lander, G. Getz, Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31(3), 213–219 (2013).  https://doi.org/10.1038/nbt.2514 CrossRefGoogle Scholar
  11. 11.
    E. Talevich, A.H. Shain, T. Botton, B.C. Bastian, CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing. PLoS Comput. Biol. 12(4), e1004873 2016).  https://doi.org/10.1371/journal.pcbi.1004873 CrossRefGoogle Scholar
  12. 12.
    R.P. Abo, M. Ducar, E.P. Garcia, A.R. Thorner, V. Rojas-Rudilla, L. Lin, L.M. Sholl, W.C. Hahn, M. Meyerson, N.I. Lindeman, P. Van Hummelen, L.E. MacConaill, BreaKmer: detection of structural variation in targeted massively parallel sequencing data using kmers. Nucleic Acids Res. 43(3), e19 2015).  https://doi.org/10.1093/nar/gku1211 CrossRefGoogle Scholar
  13. 13.
    C.H. Mermel, S.E. Schumacher, B. Hill, M.L. Meyerson, R. Beroukhim, G. Getz, GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12(4), R41 (2011).  https://doi.org/10.1186/gb-2011-12-4-r41 CrossRefGoogle Scholar
  14. 14.
    M.B. Amin, S. Edge, F. Greene, D.R. Byrd, R.K. Brookland, M.K. Washington, J.E. Gershenwald, C.C. Compton, K.R. Hess, D.C. Sullivan, J.M. Jessup, J.D. Brierley, L.E. Gaspar, R.L. Schilsky, C.M. Balch, D.P. Winchester, E.A. Asare, M. Madera, D.M. Gress, L.R. Meyer, AJCC Cancer Staging Manual, 8th edn (Springer, New York, 2017)Google Scholar
  15. 15.
    T.C.G.A.R. Network, Integrated genomic characterization of papillary thyroid carcinoma. Cell 159(3), 676–690 (2014).  https://doi.org/10.1016/j.cell.2014.09.050 CrossRefGoogle Scholar
  16. 16.
    L.B. Alexandrov, S. Nik-Zainal, D.C. Wedge, S.A. Aparicio, S. Behjati, A.V. Biankin, G.R. Bignell, N. Bolli, A. Borg, A.L. Borresen-Dale, S. Boyault, B. Burkhardt, A.P. Butler, C. Caldas, H.R. Davies, C. Desmedt, R. Eils, J.E. Eyfjord, J.A. Foekens, M. Greaves, F. Hosoda, B. Hutter, T. Ilicic, S. Imbeaud, M. Imielinski, N. Jager, D.T. Jones, D. Jones, S. Knappskog, M. Kool, S.R. Lakhani, C. Lopez-Otin, S. Martin, N.C. Munshi, H. Nakamura, P.A. Northcott, M. Pajic, E. Papaemmanuil, A. Paradiso, J.V. Pearson, X.S. Puente, K. Raine, M. Ramakrishna, A.L. Richardson, J. Richter, P. Rosenstiel, M. Schlesner, T.N. Schumacher, P.N. Span, J.W. Teague, Y. Totoki, A.N. Tutt, R. Valdes-Mas, M.M. van Buuren, L. van ‘t Veer, A. Vincent-Salomon, N. Waddell, L.R. Yates, J. Zucman-Rossi, P.A. Futreal, U. McDermott, P. Lichter, M. Meyerson, S.M. Grimmond, R. Siebert, E. Campo, T. Shibata, S.M. Pfister, P.J. Campbell, M.R. Stratton, Signatures of mutational processes in human cancer. Nature 500(7463), 415–421 (2013).  https://doi.org/10.1038/nature12477 CrossRefGoogle Scholar
  17. 17.
    M. Melo, A. Gaspar da Rocha, R. Batista, J. Vinagre, M.J. Martins, G. Costa, C. Ribeiro, F. Carrilho, V. Leite, C. Lobo, J.M. Cameselle-Teijeiro, B. Cavadas, L. Pereira, M. Sobrinho-Simoes, P. Soares, TERT, BRAF, and NRAS in primary thyroid cancer and metastatic disease. J. Clin. Endocrinol. Metab. 102(6), 1898–1907 (2017).  https://doi.org/10.1210/jc.2016-2785 CrossRefGoogle Scholar
  18. 18.
    K.T. Huynh, D.S. Hoon, Epigenetics of regional lymph node metastasis in solid tumors. Clin. Exp. Metastasis 29(7), 747–756 (2012).  https://doi.org/10.1007/s10585-012-9491-3 CrossRefGoogle Scholar
  19. 19.
    C. Eloy, J. Santos, P. Soares, M. Sobrinho-Simoes, The preeminence of growth pattern and invasiveness and the limited influence of BRAF and RAS mutations in the occurrence of papillary thyroid carcinoma lymph node metastases. Virchows Arch. 459(3), 265–276 (2011).  https://doi.org/10.1007/s00428-011-1133-7 CrossRefGoogle Scholar
  20. 20.
    W. Qing, W.Y. Fang, L. Ye, L.Y. Shen, X.F. Zhang, X.C. Fei, X. Chen, W.Q. Wang, X.Y. Li, J.C. Xiao, G. Ning, Density of tumor-associated macrophages correlates with lymph node metastasis in papillary thyroid carcinoma. Thyroid 22(9), 905–910 (2012).  https://doi.org/10.1089/thy.2011.0452 CrossRefGoogle Scholar
  21. 21.
    G. Gandolfi, V. Sancisi, S. Piana, A. Ciarrocchi, Time to re-consider the meaning of BRAF V600E mutation in papillary thyroid carcinoma. Int. J. Cancer 137(5), 1001–1011 (2015).  https://doi.org/10.1002/ijc.28976 CrossRefGoogle Scholar
  22. 22.
    A. Chou, S. Fraser, C.W. Toon, A. Clarkson, L. Sioson, M. Farzin, C. Cussigh, A. Aniss, C. O’Neill, N. Watson, R.J. Clifton-Bligh, D.L. Learoyd, B.G. Robinson, C.I. Selinger, L.W. Delbridge, S.B. Sidhu, S.A. O’Toole, M. Sywak, A.J. Gill, A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma. Am. J. Surg. Pathol. 39(5), 652–659 (2015).  https://doi.org/10.1097/pas.0000000000000368 CrossRefGoogle Scholar
  23. 23.
    G. Perot, I. Soubeyran, A. Ribeiro, B. Bonhomme, F. Savagner, N. Boutet-Bouzamondo, I. Hostein, F. Bonichon, Y. Godbert, F. Chibon, Identification of a recurrent STRN/ALK fusion in thyroid carcinomas. PLoS ONE 9(1), e87170 (2014).  https://doi.org/10.1371/journal.pone.0087170 CrossRefGoogle Scholar
  24. 24.
    J. Bauer, O. Ozden, N. Akagi, T. Carroll, D.R. Principe, J.J. Staudacher, M.E. Spehlmann, L. Eckmann, P.J. Grippo, B. Jung, Activin and TGFbeta use diverging mitogenic signaling in advanced colon cancer. Mol. Cancer 14, 182 (2015).  https://doi.org/10.1186/s12943-015-0456-4 CrossRefGoogle Scholar
  25. 25.
    R.J. Hause, C.C. Pritchard, J. Shendure, S.J. Salipante, Classification and characterization of microsatellite instability across 18 cancer types. Nat. Med. 22(11), 1342–1350 (2016).  https://doi.org/10.1038/nm.4191 CrossRefGoogle Scholar
  26. 26.
    Z. Culig, F.R. Santer, Androgen receptor signaling in prostate cancer. Cancer Metastasis Rev. 33(2–3), 413–427 (2014).  https://doi.org/10.1007/s10555-013-9474-0 CrossRefGoogle Scholar
  27. 27.
    F. Magri, V. Capelli, M. Rotondi, P. Leporati, L. La Manna, R. Ruggiero, A. Malovini, R. Bellazzi, L. Villani, L. Chiovato, Expression of estrogen and androgen receptors in differentiated thyroid cancer: an additional criterion to assess the patient’s risk. Endocr. Relat. Cancer 19(4), 463–471 (2012).  https://doi.org/10.1530/erc-11-0389 CrossRefGoogle Scholar
  28. 28.
    G. Gandolfi, M. Ragazzi, D. de Biase, M. Visani, E. Zanetti, F. Torricelli, V. Sancisi, M. Gugnoni, G. Manzotti, L. Braglia, S. Cavuto, D.F. Merlo, G. Tallini, A. Frasoldati, S. Piana, A. Ciarrocchi, Genome-wide profiling identifies the THYT1 signature as a distinctive feature of widely metastatic papillary thyroid carcinomas. Oncotarget 9(2), 1813–1825 (2018).  https://doi.org/10.18632/oncotarget.22805 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Internal Medicine, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  2. 2.Department of Pathology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  3. 3.Center for Cancer Genome Discovery, Asan Institute for Life Science, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  4. 4.Asan Medical Institute of Convergence Science and Technology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea

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