<i>RET</i> S409Y Germline Mutation and Associated Medullary Thyroid Carcinoma

Qi, Xiao-Ping; Jin, Baiye; Li, Pengfei; Wang, Sheng; Zhao, Yihua; Cao, Zhuo; Yu, Xiuhua; Cheng, Jun; Fang, Xu-Dong; Zhao, Jian‐Qiang

doi:10.1089/thy.2018.0385

Cited by 11 publications

(20 citation statements)

References 40 publications

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“…A recent study identified the RET M918V mutation in eight kindreds, none of whom presented clinical features of MEN2B. The RET M918V mutation was also identified in a 69-year-old female patient presenting with left single MTC in our center, similar to previous studies (33,34). Moreover, patients with double tandem mutations present with atypical MEN2B, characterized by MTC with a relatively late age of onset and varying aggressiveness, and none had PHEO.…”

Section: Genotype-phenotype Correlation In Men2supporting

confidence: 86%

“…In addition, 1–7% of patients with presumed sporadic MTC actually have MEN2 or hereditary MTC. Genetic testing is beneficial for correcting an original diagnosis of “sporadic MTC” for these groups of patients and for the treatment and management of their relatives ( 2 , 33 ). For MEN2B, which is most frequently due to de novo RET mutations, performance of large-scale clinical screening via genetic testing is impractical, which makes the timely diagnosis of MEN2B challenging.…”

Section: P Strategies For Management Of Men2mentioning

confidence: 99%

“…Based on these strategies, we identified 23 RET mutations in 73 MEN2 families, most of which are located in hotspot mutation regions ( 52 – 59 ). Recently, our group used T-NGS to identify a novel mutation outside the hotspot mutation regions (S409Y in exon 6 of RET ) in four families ( 33 ). These results demonstrate that T-NGS is an accurate, rapid, and practical sequencing strategy for mutation screening of RET in MEN2 cases.…”

Section: P Strategies For Management Of Men2mentioning

confidence: 99%

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5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine

Ding

et al. 2020

Front. Endocrinol.

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Multiple endocrine neoplasia type 2 (MEN2) is a neuroendocrine cancer syndrome characterized by medullary thyroid carcinoma, in combination or not with pheochromocytoma, hyperparathyroidism, and extra-endocrine features. MEN2 syndrome includes two clinically distinct forms subtyped as MEN2A and MEN2B. Nearly all MEN2 cases are caused by germline mutations of the RET proto-oncogene. In this review, we propose "5P" strategies for management of MEN2: prevention, prediction, personalization, psychological support, and participation, which could effectively improve clinical outcomes of patients. Based on RET mutations, MEN2 could be prevented through prenatal diagnosis or preimplantation genetic testing. Identification of pathogenic mutations in RET can enable early diagnosis of MEN2. Combining RET mutation testing with measurement of serum calcitonin, plasma or urinary metanephrine/normetanephrine, and serum parathyroid hormone levels could allow risk stratification and accurately prediction of MEN2 progression, thus facilitating implementation of personalized precision treatments to increase disease-free survival and overall survival. Furthermore, increased awareness of MEN2 is needed, which requires participation of physicians, patients, family members, and related organizations. Psychological support is also important for patients with MEN2 to promote comprehensive management of MEN2 symptoms. The "5P" strategies for management of MEN2 represent a typical clinical example of precision medicine. These strategies could effectively improve the health of MEN2 patient, and avoid adverse outcomes, including death and major morbidity, from MEN2.

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Section: Genotype-phenotype Correlation In Men2supporting

confidence: 86%

Section: P Strategies For Management Of Men2mentioning

confidence: 99%

Section: P Strategies For Management Of Men2mentioning

confidence: 99%

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5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine

Ding

et al. 2020

Front. Endocrinol.

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“…Rare mutations were identified in ATM (Simbolo, et al, 2014). Targeted sequencing was used to correctly diagnose apparently sporadic MTCs carrying the novel germline RET S409Y mutation that was demonstrated to be pathogenic and associated with a lower penetrance of MTC than that for the C618Y and C634Y mutations (Qi, et al, 2019). The first NGS thyroid cancer specific panel was ThyroSeq, which targeted 284 mutational hot spots in 12 cancer genes.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Role of tissue and circulating microRNAs and DNA as biomarkers in medullary thyroid cancer

Chiacchiarini

Trocchianesi

Besharat

et al. 2021

Pharmacology & Therapeutics

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…The identi cation of RET mutations as the cause of MEN2 has signi cantly changed MEN2 disease management, including disease prevention, risk prediction, early diagnosis, and personalized treatment of MEN2-speci c tumors. Together, these approaches represent a paradigm of precision medicine [1,[4][5][6][7][8][9].The RET proto-oncogene contains 20 exons and encodes a tyrosine kinase transmembrane receptor (https://www.ncbi.nlm.nih.gov/gene/5979). Sequencing of RET has resulted in the identi cation of 199 variants, of which approximately 45% are pathogenic mutants involved in MEN2 [10], and thus far, mutation hotspots are known to mainly occur in exons 8, 10, 11, and 13-16 [1,[9][10][11][12][13][14][15][16][17].…”

mentioning

confidence: 99%

Spectrum of Germline RET Variants Identified by Targeted Sequencing and Associated Multiple Endocrine Neoplasia Type 2 Susceptibility in China

Zhao

Fang

et al. 2021

Preprint

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Background: Germline RET mutations and variants are involved in development of multiple endocrine neoplasia type 2 (MEN2). The present study investigated a spectrum of RET variants, analyzed genotype-phenotype relationships, and evaluated their effect on the MEN2 phenotype in Han Chinese patients. Methods: Targeted sequencing detected germline RET variants in 697 individuals, including 245 MEN2, 120 sporadic medullary thyroid cancer (MTC), and 15 pheochromocytoma (PHEO) patients and their 493 relatives. In silico analyses and classifications following ACMG-2015 were performed. Demographic, clinical variant types, and endocrine neoplasia molecular diagnosis records were also analyzed. Results: Nineteen different RET mutations (18 point and 1 del/ins mutations) in 214 patients with MEN2A (97.7%) or MEN2B (2.3%) were found, of which exon 11/10 mutations accounted for 79% (169/214). Nineteen compound mutations were found in 31 patients with MEN2A. Twenty-three variants (18 single and 5 double base substitution/compound variants) non-classification were also found. Of these, 17 ( 3 of pathogenic, 10 of uncertain significance, 2 of likely benign and 2 as benign) were found in 31 patients with MTC/PHEO. The remaining 6 variants (4 of uncertain significance and 2 of likely benign) found in 8 carriers had no evidence of MEN2. The entire cohort showed MEN2A-related PHEO, all occurring in exons 11/10, particularly at C634. Kaplan-Meier curves showed age-dependent penetration rates of MTC and PHEO, and occurrence rates of PHEO in patients with exon 11 mutations were all higher than those within exon 10; these bilateral PHEO were always associated with exon 11 mutations (all P < 0.05). While patient offspring had PHEO, parents with MEN2A had none, the frequency was approximately 10%. Interestingly, at least 6.8% of families were adoptive. Also, 3 non-hotspot RET variants (R114H, T278N, and D489N) appeared with high frequency. Conversely, polymorphism S836S was absent. Conclusions: These data are largely consistent with current evidence-based recommendations in the clinical practice guidelines. Diversity of RET variants or carriers may involve a different natural disease course. Further large-scale targeted sequencing studies will serve as an accurate and cost-effective approach to investigating MEN2 genotype-phenotype correlations for discovery of rare or unknown variants of RET.

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RET S409Y Germline Mutation and Associated Medullary Thyroid Carcinoma

Cited by 11 publications

References 40 publications

5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine

5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine

Role of tissue and circulating microRNAs and DNA as biomarkers in medullary thyroid cancer

Spectrum of Germline RET Variants Identified by Targeted Sequencing and Associated Multiple Endocrine Neoplasia Type 2 Susceptibility in China

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