A 6-Base Pair in Frame Germline Deletion in Exon 7 Of <i>RET</i> Leads to Increased RET Phosphorylation, ERK Activation, and MEN2A

Latteyer, Soeren; Klein-Hitpass, L.; Khandanpour, Cyrus; Zwanziger, Denise; Poeppel, Thorsten D.; Schmid, Kurt Werner; Führer, Dagmar; Moeller, Lars C.

doi:10.1210/jc.2015-2948

Cited by 13 publications

(10 citation statements)

References 21 publications

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“…Segregation analysis undertaken in the family demonstrated that it occurred "de novo", supporting its pathogenicity. Generally, RET defects associated with MEN2 and FMTC are typically gain of function, while deletions of part of the gene are mostly expected to cause loss of function; however, cases of RET deletions associated with MEN2 have been reported [40]. Moreover, Borganzone et al studied a similar somatic alteration of RET, p.Glu632_Leu633del (c.1894_1899delGAGCTG), and demonstrated that this in-frame deletion reduces the spacing between two Cysteine residues, causing ligand-independent constitutive dimerization and activation of RET.…”

Section: Families With Unclassified Variantsmentioning

confidence: 99%

Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance

Innella

Rossi

Romagnoli

et al. 2020

Cancers

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Germline RET variants are responsible for approximately 25% of medullary thyroid carcinoma (MTC) cases. Identification of RET variant carriers allows for the adoption of preventative measures which are dependent on the risk associated with the specific alteration. From 2002 to 2020, at our cancer genetics clinic, RET genetic testing was performed in 163 subjects (102 complete gene analyses and 61 targeted analyses), 72 of whom presented with MTC. A germline RET variant was identified in 31.9% of patients affected by MTC (93.8% of those having positive family history and 14.3% of clinically sporadic cases). Subsequent target testing in relatives allowed us to identify 22 asymptomatic carriers, who could undertake appropriate screening. Overall, patients with germline RET variants differed significantly from those who tested negative by family history (p < 0.001) and mean age at MTC diagnosis (44.45 vs. 56.42 years; p = 0.010), but the difference was not significant when only carriers of moderate risk variants were considered (51.78 vs. 56.42 years; p = 0.281). Out of 12 different variants detected in 49 patients, five (41.7%) were of uncertain significance (VUS). For two of these, p.Ser904Phe and p.Asp631_Leu633delinsGlu, co-segregation and genotype/phenotype analysis, matched with data from the literature, provided evidence supporting their classification in the moderate and the highest/high risk class (with a MEN2B phenotype), respectively.

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Section: Families With Unclassified Variantsmentioning

confidence: 99%

Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance

Innella

Rossi

Romagnoli

et al. 2020

Cancers

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“…Furthermore, the inclusion of just the hotspot exons of two PPGLs oncogenes, EPAS1 (exons 9 and 12) and RET (exons 8, 10, 11 and 13-16), instead of the entire coding region, was favoured for gene panels given the highly selective mutation distribution of these oncogenes 2,15,43,52 . However, these settings might need to be re-evaluated as the field evolves 53 .…”

Section: The Target Areamentioning

confidence: 99%

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

et al. 2016

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Phaeochromocytomas and paragangliomas (PPGLs) are neural-crest-derived tumours of the sympathetic or parasympathetic nervous system that are often inherited and are genetically heterogeneous. Genetic testing is recommended for patients with these tumours and for family members of patients with hereditary forms of PPGLs. Due to the large number of susceptibility genes implicated in the diagnosis of inherited PPGLs, next-generation sequencing (NGS) technology is ideally suited for carrying out genetic screening of these individuals. This Consensus Statement, formulated by a study group comprised of experts in the field, proposes specific recommendations for the use of diagnostic NGS in hereditary PPGLs. In brief, the study group recommends target gene panels for screening of germ line DNA, technical adaptations to address different modes of disease transmission, orthogonal validation of NGS findings, standardized classification of variant pathogenicity and uniform reporting of the findings. The use of supplementary assays, to aid in the interpretation of the results, and sequencing of tumour DNA, for identification of somatic mutations, is encouraged. In addition, the study group launches an initiative to develop a gene-centric curated database of PPGL variants, with annual re-evaluation of variants of unknown significance by an expert group for purposes of reclassification and clinical guidance.

Funding Agencies|Cancer Prevention and Research Institute of Texas (CPRIT) [RP101202, RP57154]; Department of Defense [CDMRP W81XWH-12-1-0508]; Voelcker Fund; National Institutes of Health (NIH)s National Center for Research Resources; National Center for Advancing Translational Sciences [8UL1TR000149]; INSERM; French National Cancer Institute (INCA); Direction Generale de lOffre de Soins (DGOS); INCA [INCA-DGOS_8663]; European Union [633983]; Brazilian National Council for Scientific and Technological Development (CNPq); Cancer Research for PErsonalized Medicine (CARPEM); ERC Advanced Researcher Award

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“…As the involvement of exon 7 in RET was not known when TGPs were designed, it was analyzed by SS. 36 DNA libraries were prepared according to the manufacturer's protocol, and samples were sequenced using the MiSeq platform (Illumina) with a paired-end mode using Composite tumor with ganglioneuroma, n Z 7: ID65, ID100, ID209, ID232, ID294, ID306, and ID435 Composite tumor with lymphoma, n Z 1: ID248 Presence of ACTH in the immunohistochemical study, n Z 3: ID108, ID304, and ID451…”

Section: Targeted Gene Panelsmentioning

confidence: 99%

PheoSeq

Currás-Freixes

Piñeiro-Yáñez

Montero‐Conde

et al. 2017

The Journal of Molecular Diagnostics

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Genetic diagnosis is recommended for all pheochromocytoma and paraganglioma (PPGL) cases, as driver mutations are identified in approximately 80% of the cases. As the list of related genes expands, genetic diagnosis becomes more time-consuming, and targeted next-generation sequencing (NGS) has emerged as a cost-effective tool. This study aimed to optimize targeted NGS in PPGL genetic diagnostics. A workflow based on two customized targeted NGS assays was validated to study the 18 main PPGL genes in germline and frozen tumor DNA, with one of them specifically directed toward formalin-fixed paraffin-embedded tissue. The series involved 453 unrelated PPGL patients, of whom 30 had known mutations and were used as controls. Partial screening using Sanger had been performed in 275 patients. NGS results were complemented with the study of gross deletions. NGS assay showed a sensitivity ≥99.4%, regardless of DNA source. We identified 45 variants of unknown significance and 89 pathogenic mutations, the latter being germline in 29 (7.2%) and somatic in 58 (31.7%) of the 183 tumors studied. In 37 patients previously studied by Sanger sequencing, the causal mutation could be identified. We demonstrated that both assays are an efficient and accurate alternative to conventional sequencing. Their application facilitates the study of minor PPGL genes, and enables genetic diagnoses in patients with incongruent or missing clinical data, who would otherwise be missed.

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A 6-Base Pair in Frame Germline Deletion in Exon 7 Of RET Leads to Increased RET Phosphorylation, ERK Activation, and MEN2A

Cited by 13 publications

References 21 publications

Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance

Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

PheoSeq

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