Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations
Abstract
:1. Introduction
2. Patients and Methods
2.1. Subjects
2.2. RET Genetic Analysis
3. Results
4. Discussion
5. Conclusions
Author Contributions
Acknowledgments
Conflicts of Interest
References
- Romei, C.; Pardi, E.; Cetani, F.; Elisei, R. Genetic and clinical features of multiple endocrine neoplasia types 1 and 2. J. Oncol. 2012, 2012, 15. [Google Scholar] [CrossRef]
- Wohllk, N.; Schweizer, H.; Erlic, Z.; Schmid, K.W.; Walz, M.K.; Raue, F.; Neumann, H.P.H. Multiple endocrine neoplasia type 2. Best Pract. Res. Clin. Endocrinol. Metab. 2010, 24, 371–387. [Google Scholar] [CrossRef] [PubMed]
- Mulligan, L.M. GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential. Front. Physiol. 2018, 9, 1873. [Google Scholar] [CrossRef] [PubMed]
- Mulligan, L.M.; Kwok, J.B.J.; Healey, C.S.; Elsdon, M.J.; Eng, C.; Gardner, E.; Love, D.R.; Mole, S.E.; Moore, J.K.; Papi, L.; et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993, 363, 458–460. [Google Scholar] [CrossRef] [PubMed]
- Mulligan, L.M. RET revisited: Expanding the oncogenic portfolio. Nat. Rev. Cancer 2014, 14, 173–186. [Google Scholar] [CrossRef] [PubMed]
- Wells, S.A.J. Advances in the management of MEN2: From improved surgical and medical treatment to novel kinase inhibitors. Endocr. Relat. Cancer 2018, 25, T1–T13. [Google Scholar] [CrossRef]
- Romei, C.; Ciampi, R.; Elisei, R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat. Rev. Endocrinol. 2016, 12, 192–202. [Google Scholar] [CrossRef]
- Hofstra, R.M.W.; Landsvater, R.M.; Ceccherini, I.; Stulp, R.P.; Stelwagen, T.; Luo, Y.; Pasini, B.; Höppener, J.W.M.; Van Amstel, H.K.P.; Romeo, G.; et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994, 367, 375–376. [Google Scholar] [CrossRef]
- Antinolo, G.; Marcos, I.; Fernandez, R.M.; Romero, M.; Borrego, S. A novel germline point mutation, c.2304 G-->T, in codon 768 of the RET proto-oncogene in a patient with medullary thyroid carcinoma. Am. J. Med. Genet. 2002, 110, 85–87. [Google Scholar] [CrossRef]
- Berndt, I.; Reuter, M.; Saller, B.; Frank-Raue, K.; Groth, P.; Grussendorf, M.; Raue, F.; Ritter, M.M.; Hoppner, W. A New Hot Spot for Mutations in the ret Protooncogene Causing Familial Medullary Thyroid Carcinoma and Multiple Endocrine Neoplasia Type 2A. J. Clin. Endocrinol. Metab. 1998, 83, 770–774. [Google Scholar] [CrossRef]
- Fink, M.; Weinhäusel, A.; Niederle, B.; Haas, O.A. Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. Int. J. Cancer 1996, 69, 312–316. [Google Scholar] [CrossRef]
- Marsh, D.J.; Learoyd, D.L.; Andrew, S.D.; Krishnan, L.; Pojer, R.; Richardson, A.L.; Delbridge, L.; Eng, C.; Robinson, B.G. Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma. Clin. Endocrinol. 1996, 44, 249–257. [Google Scholar] [CrossRef] [PubMed]
- Dang, G.T.; Cote, G.J.; Schultz, P.N.; Khorana, S.; Decker, R.A.; Gagel, R.F. A codon 891 exon 15 RET proto-oncogene mutation in familial medullary thyroid carcinoma: A detection strategy. Mol. Cell. Probes 1999, 13, 77–79. [Google Scholar] [CrossRef] [PubMed]
- Crockett, D.K.; Piccolo, S.R.; Ridge, P.G.; Margraf, R.L.; Lyon, E.; Williams, M.S.; Mitchell, J.A. Predicting Phenotypic Severity of Uncertain Gene Variants in the RET Proto-Oncogene. PLoS ONE 2011, 6, e18380. [Google Scholar] [CrossRef] [PubMed]
- Cosci, B.; Vivaldi, A.; Romei, C.; Gemignani, F.; Landi, S.; Ciampi, R.; Tacito, A.; Molinaro, E.; Agate, L.; Bottici, V.; et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr. Relat. Cancer 2011, 18, 603–612. [Google Scholar] [CrossRef] [PubMed]
- Margraf, R.L.; Crockett, D.K.; Krautscheid, P.M.F.; Seamons, R.; Calderon, F.R.O.; Wittwer, C.T.; Mao, R. Multiple endocrine neoplasia type 2 RET protooncogene database: Repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum. Mutat. 2009, 30, 548–556. [Google Scholar] [CrossRef] [PubMed]
- Raue, F.; Frank-Raue, K. Update on Multiple Endocrine Neoplasia Type 2: Focus on Medullary Thyroid Carcinoma. J. Endocr. Soc. 2018, 2, 933–943. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Romei, C.; Cosci, B.; Renzini, G.; Bottici, V.; Agate, L.; Passannanti, P.; Viola, D.; Biagini, A.; Materazzi, G.; Pinchera, A.; et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin. Endocrinol. 2011, 74, 241–247. [Google Scholar] [CrossRef] [PubMed]
- Wiench, M.; Wygoda, Z.; Gubala, E.; Wloch, J.; Lisowska, K.; Krassowski, J.; Scieglinska, D.; Fiszer-Kierzkowska, A.; Lange, D.; Kula, D.; et al. Estimation of Risk of Inherited Medullary Thyroid Carcinoma in Apparent Sporadic Patients. J. Clin. Oncol. 2001, 19, 1374–1380. [Google Scholar] [CrossRef]
- Niccoli-Sire, P.; Murat, A.; Rohmer, V.; Franc, S.; Chabrier, G.; Baldet, L.; Maes, B.; Savagner, F.; Giraud, S.; Bezieau, S.; et al. Familial Medullary Thyroid Carcinoma with Noncysteine RET Mutations: Phenotype-Genotype Relationship in a Large Series of Patients. J. Clin. Endocrinol. Metab. 2001, 86, 3746–3753. [Google Scholar] [CrossRef]
- Catalogue of Somatic Mutations in Cancer. Available online: https://cancer.sanger.ac.uk (accessed on 13 June 2019).
- Romei, C.; Ugolini, C.; Cosci, B.; Torregrossa, L.; Vivaldi, A.; Ciampi, R.; Tacito, A.; Basolo, F.; Materazzi, G.; Miccoli, P.; et al. Low Prevalence of the Somatic M918T RET Mutation in Micro-Medullary Thyroid Cancer. Thyroid 2012, 22, 476–481. [Google Scholar] [CrossRef] [PubMed]
- Romei, C.; Casella, F.; Tacito, A.; Bottici, V.; Valerio, L.; Viola, D.; Cappagli, V.; Matrone, A.; Ciampi, R.; Piaggi, P.; et al. New insights in the molecular signature of advanced medullary thyroid cancer: Evidence of a bad outcome of cases with double RET mutations. J. Med. Genet. 2016, 53, 729–734. [Google Scholar] [CrossRef] [PubMed]
- Maciel, R.M.B.; Camacho, C.P.; Assumpção, L.V.M.; Bufalo, N.E.; Carvalho, A.L.; De Carvalho, G.A.; Castroneves, L.A.; De Castro, F.M.; Ceolin, L.; Cerutti, J.M.; et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: The BrasMEN study. Endocr. Connect. 2019, 8, 289–298. [Google Scholar] [CrossRef] [PubMed]
- Machens, A.; Hoegel, J.; Van Vroonhoven, T.J.; Roeher, H.-D.; Wahl, R.A.; Raue, F.; Niccoli-Sire, P.; Frank-Raue, K.; Lamesch, P.; Conte-Devolx, B.; et al. Early Malignant Progression of Hereditary Medullary Thyroid Cancer. N. Engl. J. Med. 2003, 349, 1517–1525. [Google Scholar] [CrossRef] [PubMed]
- Sarika, H.L.; Papathoma, A.; Garofalaki, M.; Vasileiou, V.; Vlassopoulou, B.; Anastasiou, E.; Alevizaki, M. High prevalence of exon 8 G533C mutation in apparently sporadic medullary thyroid carcinoma in Greece. Clin. Endocrinol. 2012, 77, 857–862. [Google Scholar] [CrossRef]
- Fanis, P.; Skordis, N.; Frangos, S.; Christopoulos, G.; Spanou-Aristidou, E.; Andreou, E.; Manoli, P.; Mavrommatis, M.; Nicolaou, S.; Kleanthous, M.; et al. Multiple endocrine neoplasia 2 in Cyprus: Evidence for a founder effect. J. Endocrinol. Investig. 2018, 41, 1149–1157. [Google Scholar] [CrossRef]
- Romei, C.; Mariotti, S.; Fugazzola, L.; Taccaliti, A.; Pacini, F.; Opocher, G.; Mian, C.; Castellano, M.; Degli Uberti, E.; Ceccherini, I.; et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): Results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur. J. Endocrinol. 2010, 163, 301–308. [Google Scholar] [CrossRef]
- Wells, S.A.J.; Asa, S.L.; Dralle, H.; Elisei, R.; Evans, D.B.; Gagel, R.F.; Lee, N.; Machens, A.; Moley, J.F.; Pacini, F.; et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015, 25, 567–610. [Google Scholar] [CrossRef]
- Elisei, R.; Alevizaki, M.; Conte-Devolx, B.; Frank-Raue, K.; Leite, V.; Williams, G. 2012 European Thyroid Association Guidelines for Genetic Testing and Its Clinical Consequences in Medullary Thyroid Cancer. Eur. Thyroid J. 2012, 1, 216–231. [Google Scholar] [CrossRef] [Green Version]
- Elisei, R.; Romei, C.; Renzini, G.; Bottici, V.; Cosci, B.; Molinaro, E.; Agate, L.; Cappagli, V.; Miccoli, P.; Berti, P.; et al. The Timing of Total Thyroidectomy in RET Gene Mutation Carriers Could Be Personalized and Safely Planned on the Basis of Serum Calcitonin: 18 Years Experience at One Single Center. J. Clin. Endocrinol. Metab. 2012, 97, 426–435. [Google Scholar] [CrossRef]
- Elisei, R.; Cosci, B.; Romei, C.; Bottici, V.; Sculli, M.; Lari, R.; Barale, R.; Pacini, F.; Pinchera, A. RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. J. Clin. Endocrinol. Metab. 2004, 89, 3579–3584. [Google Scholar] [CrossRef] [PubMed]
- Pecce, V.; Sponziello, M.; Damante, G.; Rosignolo, F.; Durante, C.; Lamartina, L.; Grani, G.; Russo, D.; di Gioia, C.R.; Filetti, S.; et al. A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency. PLoS Genet. 2018, 14, e1007678. [Google Scholar] [CrossRef] [PubMed]
- Eng, C.; Mulligan, L.M.; Smith, D.P.; Healey, C.S.; Frilling, A.; Raue, F.; Neumann, H.P.; Ponder, M.A.; Ponder, B.A. Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin. Endocrinol. 1995, 43, 123–127. [Google Scholar] [CrossRef] [PubMed]
- Eng, C. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996, 276, 1575–1579. [Google Scholar] [CrossRef] [PubMed]
- Pinna, G.; Orgiana, G.; Riola, A.; Ghiani, M.; Lai, M.L.; Carcassi, C.; Mariotti, S. RET Proto-Oncogene in Sardinia: V804M Is the Most Frequent Mutation and May Be Associated with FMTC/MEN-2A Phenotype. Thyroid 2007, 17, 101–104. [Google Scholar] [CrossRef]
- Machens, A.; Dralle, H. Familial prevalence and age of RET germline mutations: Implications for screening. Clin. Endocrinol. 2008, 69, 81–87. [Google Scholar] [CrossRef] [PubMed]
- Frank-Raue, K.; Raue, F. Hereditary Medullary Thyroid Cancer Genotype–Phenotype Correlation. Methods Mol. Biol. 2015, 204, 139–156. [Google Scholar]
- Toledo, R.A.; Maciel, R.M.B.; Erlic, Z.; Lourenco, D.M.J.; Cerutti, J.M.; Eng, C.; Neumann, H.P.; Toledo, S.P. RET Y791F Variant Does Not Increase the Risk for Medullary Thyroid Carcinoma. Thyroid 2015, 25, 973–974. [Google Scholar] [CrossRef]
- Nagal, M.A.; Healey, C.S.; Ponder, M.A.; Gardner, E.; Scheumann, G.F.; Jackson, C.E.; Tunnacllffe, A.; Eng, C.; Smith, D.P.; Mulligan, L.M. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum. Mol. Genet. 1994, 3, 237–241. [Google Scholar]
- Brauckhoff, M.; Machens, A.; Lorenz, K.; Bjoro, T.; Varhaug, J.E.; Dralle, H. Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: A changing perspective. Ann. Surg. 2014, 259, 800–806. [Google Scholar] [CrossRef]
- Carlson, K.M.; Bracamontes, J.; Jackson, C.E.; Clark, R.; Lacroix, A.; Wells, S.A.; Goodfellow, P.J. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am. J. Hum. Genet. 1994, 55, 1076–1082. [Google Scholar] [PubMed]
- Raue, F.; Frank-Raue, K. Genotype-phenotype correlation in multiple endocrine neoplasia type 2. Clinics (Sao Paulo) 2012, 67, 69–75. [Google Scholar] [CrossRef]
- Santoro, M.; Carlomagno, F.; Romano, A.; Bottaro, D.; Dathan, N.; Grieco, M.; Fusco, A.; Vecchio, G.; Matoskova, B.; Kraus, M.; et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 1995, 267, 381–383. [Google Scholar] [CrossRef] [PubMed]
- Martucciello, G.; Ceccherini, I.; Lerone, M.; Jasonni, V. Pathogenesis of Hirschsprung’s disease. J. Pediatr. Surg. 2000, 35, 1017–1025. [Google Scholar] [CrossRef] [PubMed]
- Amiel, J.; Sproat-Emison, E.; Garcia-Barcelo, M.; Lantieri, F.; Burzynski, G.; Borrego, S.; Pelet, A.; Arnold, S.; Miao, X.; Griseri, P.; et al. Hirschsprung disease, associated syndromes and genetics: A review. J. Med. Genet. 2008, 45, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Arighi, E.; Popsueva, A.; Degl’Innocenti, D.; Borrello, M.G.; Carniti, C.; Perälä, N.M.; Pierotti, M.A.; Sariola, H. Biological Effects of the Dual Phenotypic Janus Mutation of ret Cosegregating with Both Multiple Endocrine Neoplasia Type 2 and Hirschsprung’s Disease. Mol. Endocrinol. 2004, 18, 1004–1017. [Google Scholar] [CrossRef] [PubMed]
RET Mutation | Families | PATIENTS (n.) | In Silico Prediction | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Studied | RET Positive | RET Negative | Affected | Gene Carriers | SIFT | POLYPHEN | CADD | REVEL | META LR | MUTATION ASSESSOR | ||
R215L a | 1 | 1 | 1 | 0 | 1 | 0 | tolerated | likely benign | likely benign | benign | tolerated | 0.medium |
K666Q | 1 | 1 | 1 | 0 | 1 | 0 | deleterious | possibly damaging | likely benign | Likely disease causing | damaging | low |
K821E | 1 | 3 | 3 | 0 | 1 | 2 | deleterious | probably damaging | likely benign | Likely disease causing | damaging | low |
V871I | 1 | 4 | 3 | 1 | 1 | 2 | deleterious | probably damaging | likely benign | Likely disease causing | damaging | neutral |
T338I | 1 | 3 | 2 | 1 | 1 | 1 | tolerated | benign | likely benign | likely benign | tolerated | medium |
E632K | 1 | 1 | 1 | 0 | 1 | 0 | tolerated | possibly damaging | likely benign | Likely disease causing | damaging | medium |
V648I | 2 | 6 | 2 | 4 | 1 | 1 | tolerated | benign | likely benign | Likely disease causing | damaging | neutral |
R833C | 1 | 2 | 2 | 0 | 1 | 1 | deleterious | probably damaging | likely benign | Likely disease causing | damaging | medium |
M848T | 1 | 2 | 2 | 0 | 1 | 1 | tolerated | probably damaging | likely benign | Likely disease causing | damaging | neutral |
A883T | 2 | 14 | 9 | 5 | 3 | 7 | deleterious | probably damaging | likely deleterious | Likely disease causing | tolerated | neutral |
RET Mutation | Number of Families | Number of Families with PHEO/Number of Total Families | Number of Families with hyperPTH/Number of Total Families | Number of Families with Other Diseases/NUMBER of Total Families |
---|---|---|---|---|
V648I | 3 | 0/3 | 0/3 | 1/3 a |
E768D | 7 | 0/7 | 0/7 | 1/7 b |
V804M | 50 | 2/50 | 1/50 | 12/50 a |
S891A | 12 | 0/12 | 0/12 | 2/12 b,1/12 d |
C609R | 1 | 0/1 | 0/1 | 1/1 b |
C6111F | 1 | 0/1 | 1/1 | 0/1 |
C618R | 5 | 2/5 | 0/5 | 1/5 b |
C618S | 5 | 1/5 | 0/5 | 0/5 |
C620R | 4 | 1/4 | 0/4 | 1/4 a |
C620S | 4 | 0/4 | 0/4 | 1/4 a |
C620Y | 2 | 0/2 | 0/2 | 1/2 b, 1/2 a |
C630Y | 3 | 0/3 | 1/3 | 1/3 c, a |
C634F | 3 | 3/3 | 0/3 | 1/3 c |
C634G | 4 | 2/4 | 0/4 | 1/4 c |
C634R | 20 | 13/20 | 3/20 | 2/20 c |
C634S | 1 | 1/1 | 0/1 | 0/1 |
C634Y | 15 | 11/15 | 3/15 | 1/15 c |
C634W | 2 | 2/2 | 0/2 | 0/2 |
M918T | 15 | 4/15 | 0/15 | 15/15 |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Elisei, R.; Tacito, A.; Ramone, T.; Ciampi, R.; Bottici, V.; Cappagli, V.; Viola, D.; Matrone, A.; Lorusso, L.; Valerio, L.; et al. Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations. Genes 2019, 10, 698. https://doi.org/10.3390/genes10090698
Elisei R, Tacito A, Ramone T, Ciampi R, Bottici V, Cappagli V, Viola D, Matrone A, Lorusso L, Valerio L, et al. Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations. Genes. 2019; 10(9):698. https://doi.org/10.3390/genes10090698
Chicago/Turabian StyleElisei, Rossella, Alessia Tacito, Teresa Ramone, Raffaele Ciampi, Valeria Bottici, Virginia Cappagli, David Viola, Antonio Matrone, Loredana Lorusso, Laura Valerio, and et al. 2019. "Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations" Genes 10, no. 9: 698. https://doi.org/10.3390/genes10090698