Sudan Journal of Medical Sciences Volume 17, Issue no. 3, DOI 10.18502/sjms.v17i3.12083 Production and Hosting by Knowledge E Research Article Familial Medullary Thyroid Cancer: Five-year Review of the Most Frequent Mutations in the RET Gene: An Update Blanca Estela Díaz Castañeda1, Mariela Eulogio Vences1, Brian Emmanuel Díaz Gordillo1, Miriam Deyanira Rodríguez Piña1, and Hugo Mendieta Zerón1,2* 1Faculty of Medicine, Autonomous University of the State of Mexico, Mexico 2Ciprés Grupo Médico CGM SC ORCID: Blanca Estela Díaz Castañeda: https://orcid.org/0000-0001-7330-1427 Mariela Eulogio Vences: https://orcid.org/0000-0003-2788-6174 Brian Emmanuel Díaz Gordillo: https://orcid.org/0000-0002-0367-6343 Miriam Deyanira Rodríguez Piña: https://orcid.org/0000-0003-1882-2814 Hugo Mendieta Zerón: https://orcid.org/0000-0003-3492-8950 Abstract 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. Keywords: familial medullary thyroid cancer, RET proto-oncogene, thyroidectomy Two points why this article is of interest: 1. It is an update on the most frequent RET mutations, associated with medullary thyroid cancer. 2. From a clinical point of view, knowing the RET two main mutations are in codons 620 and 804 of exons 10 and 14, respectively, would allow to request a specific molecular biology study to confirm the mutations when there is a case with criteria for familial medullary thyroid cancer. How to cite this article: Blanca Estela Díaz Castañeda, Mariela Eulogio Vences, Brian Emmanuel Díaz Gordillo, Miriam Deyanira Rodríguez Piña, and Hugo Mendieta Zerón* (2022) “Familial Medullary Thyroid Cancer: Five-year Review of the Most Frequent Mutations in the RET Gene: An Update,” Sudan Journal of Medical Sciences, vol. 17, Issue no. 3, pages 303–312. DOI 10.18502/sjms.v17i3.12083 Page 303 Corresponding Author: Hugo Mendieta Zerón; email: drmendietaz@yahoo.com Received 21 January 2022 Accepted 16 May 2022 Published 30 September 2022 Production and Hosting by Knowledge E Castañeda et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Editor-in-Chief: Prof. Nazik Elmalaika Obaid Seid Ahmed Husain, MD, M.Sc, MHPE, PhD http://www.knowledgee.com https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ Sudan Journal of Medical Sciences Castañeda et al 1. Introduction Medullary thyroid cancer (MTC) is a neuroendocrine tumor of parafollicular or C cells of the thyroid gland, responsible for calcitonin production [1]. It accounts for 5% of all thyroid cancers and frequently occurs sporadically (75% of MTCs are sporadic and unilateral) or hereditarily (bilateral multifocal). Since the latter is associated with genetic conditions that depend on clinical data or other extra-thyroid manifestations, they have been classified into multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid cancer (FMTC), with 25% of understudied patients corresponding to the familial type or MEN2 [2, 3]. Approximately 25% of MTC cases associated with pathogenic variants at the germline level are based on RET proto-oncogenes (10q11.2 locus), representing etiologic factors for FMTC or MEN2 development, including genetic conditions associated with autoso- mal dominant inheritance patterns [3]. Usually, ligand binding activates the RET receptor, promoting the signal transduction pathway that results in cell proliferation. However, the RET protein could become a nonphosphorylated tyrosine kinase receptor when no ligand is bound. Contrastively, mutations in the RET proto-oncogene of cancer cells could lead to autophosphorylation of tyrosine residues, causing the RET receptor to be activated. Hence, there is a relationship between the site of RET mutations and the phenotype. In addition, these mutations present diverse transformations, which could depend on their location in the RET molecule [4]. The RET protein comprises two regions: (i) an extracellular region with a ligand- binding domain that consists of a cadherin-like domain and a highly conserved cysteine- rich domain and (ii) an intracellular region comprising two tyrosine kinase domains. Ligand binding causes the cysteine-rich domain to facilitate receptor dimerization and autophosphorylation, activating the tyrosine kinase and signaling pathways, including JAK/STAT, PI3K/AKT, and RAS/RAF/MAPK. Subsequently, RET produces neoplasms in two main ways: RET mutations or RET fusions [5]. Furthermore, typical FMTC mutations occur in exons 10 (codons 618 and 620) and 11 (codons 630, 631, and 634) of the RET gene, they mainly affect cysteine-rich extracellular domains and are less associated with the tyrosine kinase domain. Finally, MTC accounts for 13% of all thyroid cancer- related deaths, with an overall survival rate and prognosis that is intermediate to those of patients with differentiated thyroid and anaplastic thyroid cancers [3]. DOI 10.18502/sjms.v17i3.12083 Page 304 Sudan Journal of Medical Sciences Castañeda et al 2. Materials and Methods A narrative review of articles that focused on FMTC pathology was conducted using the following databases: PubMed, ScienceDirect, BMC, Springer, Frontiers, PMC, Wiley Online Library, Cold Spring Harbor, and ELSEVIER. This search was performed between August 2, 2021 and September 10, 2021. Three independent authors conducted the search and selection of articles. The final choices of the included articles were based first on the title and abstract and then on the specified inclusion and exclusion criteria. Finally, once all necessary information had been collected, full texts were read and the main ideas extracted. The inclusion criteria were studies that focused on FMTC, which was related to genetic mutations and in association with the RET proto-oncogene, its presenting pathology, and/or related family lines. Furthermore, studies considered included case reports, case series, retrospective studies, letters to the editor, cohort studies, and peer reviews. However, the exclusion criteria were as follows: studies with publication dates older than five years, those related to sporadic MTC and familial non-MTCs, clinical trials, systematic reviews, narrative reviews, meta-analyses, and multicenter/cross-sectional studies. 3. Results Following the systematic search, 118 related articles were obtained, 19 of which were of interest and importance to this study. Of the 19 included studies, 5 reported mutations in exon 10 (26.31%); 3 studies each reported mutations in exons 11 (15.78%), 13 (one of them associated with a rare mutation in exon 7) (10.52% plus 5.26%), and 14 (15.78%); 2 studies each reported mutations in exons 15 (10.52%) and 16 (10.52%); and then 1 rare FMTC NO RET (5.26%) was reported. The two most frequent mutations were in codons 620 and 804 of exons 10 and 14, respectively. Interestingly, of the 17 clinical cases reported, 12 (70.58%) were female and 5 (29.42%) were male. The mean age within the clinical cases was 38 years and the median was 44 years (age range, 2–70 years). Table 1 shows the most critical findings of the MTC investigation identified in this review. DOI 10.18502/sjms.v17i3.12083 Page 305 Sudan Journal of Medical Sciences Castañeda et al Table 1: MTC clinical cases. Country Patient’s age (yr) Sex Family history Exon(s) Codon(s)/ Variant(s) Peru [3] 24 Female Fourth generation with FMTC 11 Cys630ser Spain [6] 2 Female The patient is the index case 10 Cys620ser China [7] 57 Male Deceased sister 10 C620Y China [7] 61 Male Deceased sister 10 C620Y Israel [8] 45 Male Consanguinity history 7 y 13 A432A & L769L India [9] 44 Female Four sisters and two members of the next generation 15 Ser891Ala Turquía [10] 44 Female Big brother 11 634 Lebanon [11] 14 Female Mother 13 L790F (c.2370G> T) Denmark [11] 70 Female Mother and aunt 13 L790F (c.2370G> T) USA [12] 62 Female Sister, maternal aunt, and son 14 p.V804M Italy [13] 66 Male Older sister 16 p.Met918Thr Italy [13] 68 Female Younger brother 16 p.Met918Thr USA [14] 3 Female Father and three siblings 14 V804M Japan [15] 5 Female Mother 11 634/Cys634Gly China [16] 48 Female Patient is the index case 10 p.C611Y Germany [17] 17 Male Eight family members 15 p.S891A United King- dom [18] 22 Female Patient is index case Familial non- RET MTC Familial non-RET MTC Hungary [19] NA Six members of the second generation Several generations 14 V804M and the variant S836S China [20] NA Six RET mutation- positive members Three-generation family 10 Y606C 4. Discussion Functions of RET proto-oncogene germline mutations in the pathogenesis of FMTC cause presenting clinical manifestations to depend on the organs, specific mutation, and age of follow-up. Therefore, diagnosis in patients with FMTC requires a procedure involving a biopsy of the thyroid nodule or thyroidectomy to detect the final pathology. DOI 10.18502/sjms.v17i3.12083 Page 306 Sudan Journal of Medical Sciences Castañeda et al Likewise, its evaluation requires imaging methods, such as ultrasound with lymph-node mapping, calcitonin and carcinoembryonic antigen-level measurements, and genetic testing (to rule out RET proto-oncogene germline mutations). These assessments also evaluate the presence of hyperparathyroidism and rule out the possibility of pheochro- mocytoma (PHEO) [5]. Although symptomatic thyroid nodule is a frequent reason for consultation, it is estimated that 35% of the population will have a nodule during their lifetime. However, only 10% of these will be associated with some thyroid cancer types. Based on the above hypothesis, there are different ways to determine whether the nodule is neoplastic. For this purpose, ultrasonographic characteristics of the nodule can be estimated with a biopsy, obtained using a fine needle guided by ultrasound. This procedure reduces false negatives and the fact that, more frequently, a nodule of fixed and complex characteristics is mostly associated with a neoplastic etiology, including the existence of ipsilateral cervical lymphadenopathies, which should also be considered a warning sign. In clinical history, it is also prevalent to find data of altered thyroid functions, such as hypothyroidism or hyperthyroidism, leading to hormone measurements, such as triiodothyronine (T3/T3L), thyroxine (T4L), and thyroid-stimulating hormone (TSH). How- ever, it has been estimated that more than half of the thyroid cancer cases are clinically asymptomatic. Therefore, it is important to inquire about voice alterations (dysphonia), cervical, digestive, and airway compression, dysphagia, and/or foreign body sensations during interrogations. Furthermore, since thyroid hyperfunction is closely related to cancer, serum TSH levels are useful to rule out nodule hyperfunction. Nevertheless, elevated thyroglobulin levels are often considered a warning sign (particularly useful in following up patients undergoing total thyroidectomy and radioactive iodine ablation), including hormone estimation. Ultrasound is considered important for evaluating nodule characteristics. Therefore, this procedure should be performed in the thyroid gland and lateral necks. If the findings of this last study are a hypogenic nodule, microcalcifications, intranodular vascular flow, disproportionate measures, infiltrating margins, or the presence of cervical nodes with loss of the fatty hilum, then, a fine needle biopsy guided by ultrasound should be conducted. Although a thyroid scan should not be a routine, it is essential when there is evidence of hyperthyroidism or a functioning nodule (decrease in TSH, with or without elevation of thyroid hormones in the blood). In addition, supposing there is a need to assess metastasis or neoplastic extensions in the mediastinum, deep cervical fascia, DOI 10.18502/sjms.v17i3.12083 Page 307 Sudan Journal of Medical Sciences Castañeda et al or upper airway, computerized tomography or magnetic resonance imaging studies are recommended [21]. During diagnosis, parathyroid hyperplasia (PPH) and/or PHEO should be ruled out during the preoperative stage in any patient with suspected MTC. If the study confirms RET mutations, PHEO should be ruled out by measuring 24-hr urinary metanephrines and evaluating the presence of PPH through the parathyroid hormone, calcium, and phosphorus in the blood, ruling out an association with MEN2. However, if performing an RET proto-oncogene study before surgery is impossible, the presence of PHEO and PPH should always be ruled out [21]. Diagnosis in patients with MTC can be preoperative during the study of a thyroid nodule that is active in RET proto-oncogene mutation carrier relatives. It can even be postoperative. Nevertheless, the high penetrance of RET mutation pathogenesis implies the need for early diagnosis. Since MTC is aggressive and produces calcitonin, therapeutic surgery is essential, with an objective prognosis according to the tumor stage and adequate initial surgical treatment being crucial. Furthermore, based on the dominant condition of inheritance and the close relationship between genotype and phenotype that is associated with the disease aggressiveness, it is important to perform a genetic study on these patient groups. According to the American Thyroid Association guidelines, three risk groups have been established when identifying an RET mutation: 1. ATA-HST→ very high risk 2. ATA-H → high risk 3. ATA-M → moderate risk The first group, ATA-HST, presents a very high risk of mutations in codon M918T of exon 16 and an invasive MTC phenotype in children under one year. As a result, prophylactic thyroidectomy is recommended before that corresponding age. However, the second group, ATA-H, is characterized by a high risk of mutations in codons C634F/G/R/S/W/Y and A883F of exons 11 and 13. Its phenotype corresponds to MEN2A with a high incidence of OEF at 20 years and MEN2B. Therefore, its management comprises prophylactic thyroidectomy at five years of age. Finally, the third group, cor- responding to ATA-M or ATA-MOD, is a moderate risk. Mutations here were distributed in exons 5, 8, 10, 11, 13–15, and 16, and its phenotype was that of later onset of MTC. Hence, less aggressive evolution (NEM2A and MTC) studies for which a prophylactic DOI 10.18502/sjms.v17i3.12083 Page 308 Sudan Journal of Medical Sciences Castañeda et al thyroidectomy, including PHEO and PPH, is advisable. The above classification guides the time and extent of thyroid surgery. Emphasis has also been placed on exons 10, 11, 13–15, and 16 (90% of the mutations), including exons 5 and 8. Subsequently, RET gene studies were conducted through Sanger sequencing of the exons previously amplified by PCR [22]. Surgical treatment is not only the therapeutic alternative for cases of sporadic or hereditary MTC but also the best prophylactic measure to reduce thyroid cancer, includ- ing neoplasms associated with MEN2A and 2B. Therefore, for postsurgical manage- ment, levothyroxine supplementation (initial dose 1.6–1.8 mcg/kg/day) is recommended. In addition, while TSH should be maintained in the normal range based on age, it should not be suppressed. Besides, radioiodine (radioactive iodine) should not be used in MTC since it has no use [21]. 5. Conclusion Based on the data collected and the understudied literature, FMTC was identified as an essential dominant genetic entity in patients with a presumptive diagnosis. From the genetic studies (identification of germline mutations in the RET proto-oncogene, located on chromosome 10q11.2), the characteristic mutations of FMTC notably occurred in exons 10 (codons 618 and 620) and 11 (codons 630, 631, and 634) of the RET proto- oncogene, consistent with the findings of this review. However, exon 10 and codon 620 were the sites where mutations occurred most frequently. As for treatments, evidence in favor of radical thyroidectomy was postulated not only as the surgical procedure of choice but also as a prophylactic measure. 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