A new germline mutation, R600Q, within the coding region ofRET proto-oncogene: A rare polymorphism or a MEN 2 causing mutation?

Sáez, María Eugenia; Ruiz, Agustı́n; Cebrián, A; Morales, Fernando; Robledo, Mercedes; Antiñolo, Guillermo; Borrego, Salud

doi:10.1002/(sici)1098-1004(200001)15:1<122::aid-humu41>3.0.co;2-7

Cited by 10 publications

(5 citation statements)

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“…3 ; Table 4 ] [ 7 , 16 , 51 ]. In contrast, a 41-old-year female patient carrying R600Q had MTC, but her father carrying R600Q had no abnormality, similar to a previous report [ 52 ], classifying this variant as UCS. Interestingly, a relatively high frequency of R114H, T278N, and D489N variants was revealed in the current series and in other East Asian populations, mainly associated with HD, but rarely reported to play a role in MTC or in tumorigenesis [ 53 – 56 ].…”

Section: Discussionsupporting

confidence: 84%

Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China

Zhao

Fang

et al. 2021

BMC Cancer

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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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Section: Discussionsupporting

confidence: 84%

Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China

Zhao

Fang

et al. 2021

BMC Cancer

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“…All patients with level 1 mutations were cured, whereas 14% of patients with level 2 mutations were not cured. The results support the relevance of treatment according to the guidelines stratifying management of MTC according to 108 MEN2A, FMTC MTC 532 duplication 109 MEN2A, FMTC MTC C515S 110 MEN2A, FMTC MTC G533C 111,112 MEN2A, FMTC MTC, PHE R600Q 113,114 MEN2A, FMTC MTC K603E 115 MEN2A, FMTC MTC Y606C 107,116 MEN2A, FMTC MTC 635/insertion ELCR;T636P 107 MEN2A, FMTC MTC, PHE S649L 117,118 MEN2A genetic information. In 2010, Schreinemakers et al conducted a case-control study to identify prognostic factors associated with recurrent MTC.…”

Section: Prophylactic Thyroidectomysupporting

confidence: 68%

RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma

Krampitz

Norton

2014

Cancer

113

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The rapid technical advances in molecular biology and accelerating improvements in genomic and proteomic diagnostics have led to increasingly personalized strategies for cancer therapy. Such an approach integrates the genomic, proteomic, and molecular information unique to the individual to provide an accurate genetic diagnosis, molecular risk assessment, informed family counseling, therapeutic profiling, and early preventative management that best fits the particular needs of each patient. The discovery of mutations in the RET proto-oncogene resulting in variable onset and severity of multiple endocrine neoplasia type 2 (MEN2) was the first step in developing direct genetic testing for at-risk individuals. Patients with germline RET mutations may undergo risk assessment and appropriate intervention based on specific mutations. Moreover, family members of affected individuals receive counseling based on understanding of the genetic transmission of the disease. Increasingly, clinicians are able to make therapeutic choices guided by an informative biomarker code. Improvements in detection and management of patients with MEN2 resulting from understanding of the RET proto-oncogene are evidence of the benefits of personalized cancer medicine. This review describes the discovery of the RET proto-oncogene, the association between genotype and phenotype, and the role of mutation analysis on diagnosis and treatment of MEN2. Cancer 2014;120:1920-31.

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“…Thus, S409Y and M918V variants should be classi ed as ATA-MOD mutations associated with familial MTC [Fig.3; Table4][7, 16,50]. In contrast, a 41-old-year female patient carrying R600Q had MTC, but her father carrying R600Q had no abnormality, similar to a previous report[51], classifying this variant as UCS. Interestingly, a relatively high frequency of R114H, T278N, and D489N variants was revealed in the current series and in other East Asian populations, mainly associated with HD, but rarely reported to play a role in MTC or in tumorigenesis[52][53][54][55].…”

supporting

confidence: 57%

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.

show abstract

A new germline mutation, R600Q, within the coding region ofRET proto-oncogene: A rare polymorphism or a MEN 2 causing mutation?

Cited by 10 publications

References 0 publications

Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China

Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China

RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma

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

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