Familial Medullary Thyroid Cancer: Five-year Review of the Most Frequent Mutations in the RET Gene: An Update


Background: Familial Medullary Thyroid Cancer (FMTC) is hereditary in 25% of cases. Patients with an inherited form of FMTC usually have a germline mutation in the RET proto-oncogene (10q11.2); these mutations generally occur in exons 10 (codons 618 and 620) and 11 (codons 630, 631, and 634).

Methods: A narrative review of articles focused on the pathology of familial medullary thyroid cancer was carried out using the next databases PubMed, ScienceDirect, BMC, Springer, Frontiers, PMC, Wiley Online Library, Cold Spring Harbor and ELSEVIER. This search was carried out between August and September 2021.

Results: 19 studies were selected in which the following mutations were found: five studies (26.31%) reported mutation in exon 10; three studies (15.78%) in exon 11; three studies in exon 13 (one of them associated with a rare mutation in exon 7) (10.52% plus 5.26%); three studies (15.78%) in exon 14; two studies (10.52%) in exon 15; two (10.52%) in exon 16; and one (5.26%) rare FMTC NO RET. The two most frequent mutations were in codons 620 of exon 10 and 804 of exon 14.

Conclusion: The findings of this review are consistent with the medical literature, finding the most common RET mutations in exon 10 and codon 620. It is essential that in patients with a presumptive diagnosis, genetic studies (identification of germline mutations in the RET proto-oncogene, located on chromosome 10q11.2) be performed.


familial medullary thyroid cancer, RET proto-oncogene, thyroidectomy

[1] Kroiss, M., Koehler, V. F., & Spitzweg, C. (2021). Medulläres Schilddrüsenkarzinom. [Medullary thyroid carcinoma: Current clinical progress]. Deutsche Medizinische Wochenschrift, 146(23), 1527–1532. https://doi.org/10.1055/a-1495-2991

[2] Cipri, C., Vescini, F., Torresan, F., Pennelli, G., Pelizzo, M. R., Triggiani, V., Guastamacchia, E., & Grimaldi, F. (2019). An unusual case of medullary thyroid carcinoma and a revision of current literature. Endocrine, Metabolic & Immune Disorders Drug Targets, 19(2), 226–229. https://doi.org/10.2174/1871530319666181220165350

[3] Carrillo, C. F. B., Rojas, J. A. P., Cornejo, C. B., Zambrano, S. C., Cárdenas, A. P., Santibañez, I. Q., et al. (2018). Cáncer Medular de Tiroides familiar: Reporte de un caso y revisión de la literatura. Revista de la Facultad de Ciencias Medicas de Cordoba, 75(4), 303–309. https://doi.org/10.31053/1853.0605.v75.n4.20947

[4] Oczko-Wojciechowska, M., Swierniak, M., Krajewska, J., Kowalska, M., Kowal, M., Stokowy, T., Wojtas, B., Rusinek, D., Pawlaczek, A., Czarniecka, A., Szpak-Ulczok, S., Gawlik, T., Chmielik, E., Tyszkiewicz, T., Nikiel, B., Lange, D., Jarzab, M., Wiench, M., Jarzab, B. (2017). Differences in the transcriptome of medullary thyroid cancer regarding the status and type of RET gene mutations. Scientific Reports, 7, 42074.

[5] Román-González, A., Mejía, S., & Zapata, M. (2019). Nuevos tratamientos médicos para el cáncer medular de tiroides. Revista Colomb. Endocrinology, Diabetes & Metabolism, 6(4), 306–310.

[6] Morlán Herrador, L., de Arriba, A., Miguel, G., Ferrera, M., & Labarta, J. I. (2016). Estudio de carcinoma medular de tiroides a partir de un caso índice. Archivos Argentinos de Pediatria, 114(6), e421–e424.

[7] Huang, Q., Hu, A., & Zhang, M. (2020). Chinese siblings with hereditary medullary thyroid carcinoma caused by RET mutation: Implications for RET oncogene detection. BMC Endocrine Disorders, 20(1), 64. https://doi.org/10.1186/s12902-020-0544-3

[8] Azzam, N., Bar-Shalom, R., Saab, A., & Fares, F. (2017). Germline polymorphisms on RET proto-oncogene involved in medullary thyroid carcinoma in a Druze family. European Journal of Cancer, 82, 149–152. https://doi.org/10.1016/j.ejca.2017.06.007

[9] Vijayan, R., Nair, V., Menon, U., & Kumar, H. (2021). A rare RET mutation in an Indian pedigree with familial medullary thyroid carcinoma. Indian Journal of Cancer, 58(1), 98–100.

[10] Sezer, A., & Çelik, M. (2019). Prophylactic and therapeutic surgery in familial medullary thyroid cancer. In T. Özülker, M. Adaş, S. Günay (Eds.) Thyroid and parathyroid diseases. (pp. 371–375). Springer, Cham. https://doi.org/10.1007/978-3-319-78476- 2_59

[11] Mathiesen, J. S., Nielsen, S. G., Rasmussen, Å. K., Kiss, K., Wadt, K., Hermann, A. P., Nielsen, M. F., Larsen, S. R., Brusgaard, K., Frederiksen, A. L., Godballe, C., & Rossing, M. (2020). Variability in medullary thyroid carcinoma in RET L790F carriers: A case comparison study of index patients. Frontiers in Endocrinology, 11, 251. https://doi.org/10.3389/fendo.2020.00251

[12] Ghazani, A. A., Breen, K. M., Dwan, M., Barletta, J. A., Vatnick, D. R., Stokes, S. M., Block, C., Doherty, G. M., Cohn, A. Y., Marqusee, E., Garber, J. E., & Rana, H. Q. (2020). Unexpected pathogenic RET p.V804M variant leads to the clinical diagnosis and management of medullary thyroid carcinoma. The American Journal of Case Reports, 21, e927415–e1. https://doi.org/10.12659/AJCR.927415

[13] Sponziello, M., Benvenuti, S., Gentile, A., Pecce, V., Rosignolo, F., Virzì, A. R., Milan, M., Comoglio, P. M., Londin, E., Fortina, P., Barnabei, A., Appetecchia, M., Marandino, F., Russo, D., Filetti, S., Durante, C., & Verrienti, A. (2018). Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer. Human Mutation, 39(3), 371– 377. https://doi.org/10.1002/humu.23378

[14] Pendrick, D. M., Oberg, J. A., Hsiao, S. J., Chung, W. K., Koval, C., Sireci, A., Kuo, J. H., Satwani, P., Glasser, C. L., Sulis, M. L., Mansukhani, M. M., & Glade Bender, J. L. (2019). Identification of a secondary RET mutation in a pediatric patient with relapsed acute myeloid leukemia leads to the diagnosis and treatment of asymptomatic metastatic medullary thyroid cancer in a parent: A case for sequencing the germline. Cold Spring Harbor Molecular Case Studies, 5(2), a003889. https://doi.org/10.1101/mcs.a003889

[15] Abe, Y., & Tsukano, S. (2017). Detection of early stage medullary thyroid carcinoma by measuring serum calcitonin using an electro chemiluminescence immuno-assay: A case report of a young Japanese woman with a high-risk RET mutation. Clinical Pediatric Endocrinology, 26(4), 243–249. https://doi.org/10.1297/cpe.26.243

[16] Zhang, G., Jiang, Y., Zhang, S., Zhao, L., Fan, J., Zhang, Z., Ma, J., Chen, R., & Xu, Y. (2019). Genetic analysis of a hereditary medullary thyroid carcinoma case with normal preoperative serum calcitonin levels. Pathology, Research and Practice, 215(10), 152529. https://doi.org/10.1016/j.prp.2019.152529

[17] Dralle, H., & Machens, A. (2016). Timing and extent of surgery for a pediatric patient with hereditary MTC and positive screening for the S891A RET mutation. In D. Cooper & C. Durante (Eds.) Thyroid cancer. Springer. https://doi.org/10.1007/978-3- 319-22401-5_45

[18] Smith, J., Read, M. L., Hoffman, J., Brown, R., Bradshaw, B., Campbell, C., Cole, T., Navas, J. D., Eatock, F., Gundara, J. S., Lian, E., Mcmullan, D., Morgan, N. V., Mulligan, L., Morrison, P. J., Robledo, M., Simpson, M. A., Smith, V. E., Stewart, S., … Woodward, E. R. (2016). Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression. Human Molecular Genetics, 25(9), 1836–1845. https://doi.org/10.1093/hmg/ddw057

[19] Valkusz, Z., Sepp, K., Gardi, J., & Patocs, A. (2016). Screening and follow up of an extended Hungarian family with familial medullary thyroid cancer. Endocrine Abstracts, 41, EP1109. Advance online publication. https://doi.org/10.1530/endoabs.41.EP1109

[20] Wang, J., Yu, Y., Li, D., Wei, S., Yun, X., Jia, Y (2016). The rare RET mutation Y606C in a Chinese family with familial medullary thyroid carcinoma. Chinese Journal of Clinical Oncology, 43(21), 947–951.

[21] Letelier, C. (2017). Cáncer hereditario de tiroides, síndromes asociados y estudio genético. Revista Médica Clínica Las Condes, 28(4), 610–616. https://doi.org/10.1016/j.rmclc.2017.06.008

[22] Fuenzalida, R. R., Vial, L. I., Rojas, O. V., Pizarro, C. F., Puebla, R. V., & Vial, L. G. (2017). Cirugía profiláctica en cáncer medular de tiroides hereditario. Revista Chilena de Cirugía, 69(3), 268–272. https://doi.org/10.1016/j.rchic.2016.11.002