Novel p.C620L RET Mutation Detected in a Patient with Medullary Thyroid Carcinoma

Abstract

A patient with an apparent sporadic medullary thyroid carcinoma was tested for RET germline mutations by Sanger sequencing of RET exons 10, 11, and 13-16. The patient was heterozygous for two known mutations causative of Multiple Endocrine Neoplasia type 2 disorder, and both mutations were within codon 620 of RET exon 10, c.1859G > T (p.C620F) and c.1860C > G (p.C620W). In order to determine if these adjacent mutations were in cis or in trans, an unlabeled probe method and high-resolution melting analysis were utilized. The mutations were confirmed to occur in cis, representing a novel mutation, c.1859_1860delinsTG (p.C620L). Sanger sequencing of parental samples did not identify any changes at codon 620, so the p.C620L mutation is also de novo. The early age of onset for medullary thyroid carcinoma and the presence of lymph node metastasis in this patient suggests individuals with the p.C620L mutation should be treated and screened (for pheochromocytomas and parathyroid hyperplasia) as Multiple Endocrine Neoplasia type 2 patients with other RET codon 620 mutations (American Thyroid Association risk level B).

Share and Cite:

R. Margraf, P. Krautscheid, D. Pattison, K. Voelkerding and R. Mao, "Novel p.C620L RET Mutation Detected in a Patient with Medullary Thyroid Carcinoma," International Journal of Clinical Medicine, Vol. 3 No. 6, 2012, pp. 498-501. doi: 10.4236/ijcm.2012.36089.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] J. W. de Groot, T. P. Links, J. T. Plukker, et al., “Ret as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors,” Endocrine Reviews, Vol. 27, No. 5, 2006, pp. 535-560. doi:10.1210/er.2006-0017
[2] P. J. Morrison and N. C. Nevin, “Multiple Endocrine Neoplasia Type 2B (Mucosal Neuroma Syndrome, Wagenmann-Froboese Syndrome),” Journal of Medical Genetics, Vol. 33, No. 9, 1996, pp. 779-782. doi:10.1136/jmg.33.9.779
[3] C. Eng, D. Clayton, I. Schuffenecker, et al., “The Relationship between Specific Ret Proto-Oncogene Mutations and Disease Phenotype in Multiple Endocrine Neoplasia Type 2. International Ret Mutation Consortium Analysis,” Journal of the American Medical Association, Vol. 276, No. 19, 1996, pp. 1575-1579. doi:10.1001/jama.276.19.1575
[4] R. L. Margraf, D. K. Crockett, P. M. Krautscheid, et al., “Multiple Endocrine Neoplasia Type 2 Ret Protooncogene Database: Repository of Men2-Associated Ret Sequence Variation and Reference for Genotype/Phenotype Correlations,” Human Mutation, Vol. 30, No. 4, 2009, pp. 548-556. doi:10.1002/humu.20928
[5] M. Santoro, F. Carlomagno, A. Romano, et al., “Activation of Ret as a Dominant Transforming Gene by Germline Mutations of Men2a and Men2b,” Science, Vol. 267, No. 5196, 1995, pp. 381-383. doi:10.1126/science.7824936
[6] S. Chappuis-Flament, A. Pasini, G. De Vita, et al., “Dual Effect on the Ret Receptor of Men 2 Mutations Affecting Specific Extracytoplasmic Cysteines,” Oncogene, Vol. 17, No. 22, 1998, pp. 2851-2861. doi:10.1038/sj.onc.1202202
[7] A. Z. Lai, T. S. Gujral and L. M. Mulligan, “Ret Signaling in Endocrine Tumors: Delving Deeper into Molecular Mechanisms,” Endocrine Pathology, Vol. 18, No. 2, 2007, pp. 57-67. doi:10.1007/s12022-007-0009-5
[8] R. L. Margraf, R. Mao, W. E. Highsmith, et al., “Ret Proto-Oncogene Genotyping Using Unlabeled Probes, the Masking Technique, and Amplicon High-Resolution Melting Analysis,” Journal of Molecular Diagnostics, Vol. 9, No. 2, 2007, pp. 184-196. doi:10.2353/jmoldx.2007.060091
[9] L. Zhou, A. N. Myers, J. G. Vandersteen, et al., “Closed-Tube Genotyping with Unlabeled Oligonucleotide Probes and a Saturating DNA Dye,” Clinical Chemistry, Vol. 50, No. 8, 2004, pp. 1328-1335. doi:10.1373/clinchem.2004.034322
[10] M. Wiench, Z. Wygoda, E. Gubala, et al., “Estimation of Risk of Inherited Medullary Thyroid Carcinoma in Apparent Sporadic Patients,” Journal of Clinical Oncology, Vol. 19, No. 5, 2001, pp. 1374-1380.
[11] D. P. Smith, C. Houghton and B. A. Ponder, “Germline Mutation of Ret Codon 883 in Two Cases of de Novo Men 2b,” Oncogene, Vol. 15, No. 10, 1997, pp. 1213-1217. doi:10.1038/sj.onc.1201481
[12] K. Frank-Raue, S. Rondot, E. Schulze, et al., “Change in the Spectrum of Ret Mutations Diagnosed between 1994 and 2006,” Clinical Laboratory, Vol. 53, No. 5-6, 2007, pp. 273-282.
[13] I. Berndt, M. Reuter, B. Saller, et al., “A New Hot Spot for Mutations in the Ret Protooncogene Causing Familial Medullary Thyroid Carcinoma and Multiple Endocrine Neoplasia Type 2a,” Journal of Clinical Endocrinology & Metabolism, Vol. 83, No. 3, 1998, pp. 770-774. doi:10.1210/jc.83.3.770
[14] R. L. Margraf, J. D. Durtschi, J. E. Stephens, et al., “Determination of Ret Sequence Variation in an Men2 Unaffected Cohort Using Multiple-Sample Pooling and Next-Generation Sequencing,” Journal of Thyroid Research, Vol. 2012, 2012, Article ID: 318232. doi:10.1155/2012/318232
[15] K. Frank-Raue, L. A. Rybicki, Z. Erlic, et al., “Risk Profiles and Penetrance Estimations in Multiple Endocrine neoplasia Type 2a Caused by Germline Ret Mutations Located in Exon 10,” Human Mutation, Vol. 32, No. 1, 2010, pp. 51-58. doi:10.1002/humu.21385
[16] R. T. Kloos, C. Eng, D. B. Evans, et al., “Medullary Thyroid Cancer: Management Guidelines of the American Thyroid Association,” Thyroid, Vol. 19, No. 6, 2009, pp. 565-612. doi:10.1089/thy.2008.0403

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.