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p.Val804Met, the Most Frequent Pathogenic Mutation in RET, Confers a Very Low Lifetime Risk of Medullary Thyroid Cancer

Loveday, C; Josephs, K; Chubb, D; Gunning, A; Izatt, L; Tischkowitz, M; Ellard, S; Turnbull, C (2018) p.Val804Met, the Most Frequent Pathogenic Mutation in RET, Confers a Very Low Lifetime Risk of Medullary Thyroid Cancer. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 103 (11). pp. 4275-4282. ISSN 0021-972X https://doi.org/10.1210/jc.2017-02529
SGUL Authors: Josephs, Katherine Sarah

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Abstract

Context To date, penetrance figures for medullary thyroid cancer (MTC) for variants in rearranged during transfection (RET) have been estimated from families ascertained because of the presence of MTC. Objective To gain estimates of penetrance, unbiased by ascertainment, we analyzed 61 RET mutations assigned as disease causing by the American Thyroid Association (ATA) in population whole-exome sequencing data. Design For the 61 RET mutations, we used analyses of the observed allele frequencies in ∼51,000 individuals from the Exome Aggregation Consortium (ExAC) database that were not contributed via The Cancer Genome Atlas (TCGA; non-TCGA ExAC), assuming lifetime penetrance for MTC of 90%, 50%, and unbounded. Setting Population-based. Results Ten of 61 ATA disease-causing RET mutations were present in the non-TCGA ExAC population with observed frequency consistent with penetrance for MTC of >90%. For p.Val804Met, the lifetime penetrance for MTC, estimated from the allele frequency observed, was 4% [95% confidence interval (CI), 0.9% to 8%]. Conclusions Based on penetrance analysis in carrier relatives of p.Val804Met-positive cases of MTC, p.Val804Met is currently understood to have high-lifetime penetrance for MTC (87% by age 70), albeit of later onset of MTC than other RET mutations. Given our unbiased estimate of penetrance for RET p.Val804Met of 4% (95% CI, 0.9% to 8%), the current recommendation by the ATA of prophylactic thyroidectomy as standard for all RET mutation carriers is likely inappropriate.

Item Type: Article
Additional Information: This article has been published under the terms of the Creative Commons Attribution License (CC BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s).
Keywords: 1103 Clinical Sciences, 1114 Paediatrics And Reproductive Medicine, Endocrinology & Metabolism
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
ISSN: 0021-972X
Dates:
DateEvent
November 2018Published
23 March 2018Published Online
20 March 2018Published Online
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDInstitute of Cancer Researchhttp://dx.doi.org/10.13039/501100000027
Web of Science ID: WOS:000456136900038
URI: https://openaccess.sgul.ac.uk/id/eprint/110697
Publisher's version: https://doi.org/10.1210/jc.2017-02529

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