Mutational profile of papillary thyroid microcarcinoma with extensive lymph node metastasis
- 50 Downloads
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.
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.
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.
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.
KeywordsPapillary thyroid microcarcinoma DNA mutational analysis High-throughput nucleotide sequencing Translational research
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.
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 was obtained from all participants included in the study, except 2two patients who died before the initiation of this study.
- 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.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.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
- 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.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
- 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.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
- 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.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.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
- 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.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
- 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.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
- 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
- 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.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