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Abstract
ContextTo 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.ObjectiveTo 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.DesignFor 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.SettingPopulation-based.ResultsTen 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%].ConclusionsBased 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.
Highlights
Ten of 61 American Thyroid Association (ATA) disease-causing rearranged during transfection (RET) mutations were present in the non-The Cancer Genome Atlas (TCGA) Exome Aggregation Consortium (ExAC) population with observed frequency consistent with penetrance for medullary thyroid cancer (MTC) of .90%
Given our unbiased estimate of penetrance for RET p.Val804Met of 4%, the current recommendation by the ATA of prophylactic thyroidectomy as standard for all RET mutation carriers is likely inappropriate. (J Clin Endocrinol Metab 103: 4275–4282, 2018)
Calculation of “expected” allele counts With the use of the methods of Whiffin et al [14], we calculated the maximum number of mutant alleles that we would expect to observe in the non-TCGA ExAC data for a pathogenic RET mutation
Summary
Identification of pathogenic RET mutations RET protein alterations, designated as disease causing (pathogenic) by the ATA, were identified within the published guidelines, and matching variants were retrieved from ClinVar, along with their corresponding changes at the nucleotide level [6, 7, 12, 13]. Consortium (ExAC) database that had excluded individuals from The Cancer Genome Atlas (TGCA; non-TCGA ExAC; release 0.3.1) to obtain estimates of the frequency of pathogenic RET mutations in common complex disease cohorts not related to cancer [8] This subset of ExAC comprises ;51,000 individuals, the vast majority of which are aged between 40 and 70 years at the time of ascertainment [10], with a male-to-female ratio of 1.3:1. Calculation of “expected” allele counts With the use of the methods of Whiffin et al [14], we calculated the maximum number of mutant alleles that we would expect to observe in the non-TCGA ExAC data for a pathogenic RET mutation This method leverages the logic that a fully penetrant allele cannot be more common than the disease it causes.
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