Most Frequent Pathogenic Mutation in RET Carries Very Low Lifetime Risk of Medullary Thyroid Cancer

The most frequent pathogenic mutation in the rearranged during transfection (RET) mutation — p.Val804Met – carries with it a very low lifetime risk of medullary thyroid cancer (MTC), which could mean the American Thyroid Association’s (ATA) recommendation of prophylactic thyroidectomy as standard for all RET mutation carriers is inappropriate, according to a study recently published in The Journal of Clinical Endocrinology & Metabolism.

Researchers led by Clare Turnbull, MD, PhD, of The Institute of Cancer Research in Sutton, U.K., write that in 1993 the RET protooncogene was definitively identified as the gene underlying multiple endocrine neoplasia type 2 (MEN2) and that germline mutations have subsequently been detected in nearly all families with MEN2A, MEN2B, and familial medullary thyroid cancer (FMTC), with emergence of a distinct pattern of genotype-phenotype correlation. “More recently, the American Thyroid Association (ATA) categorized RET mutations based on age-related penetrance of MTC,” the authors write. “The 2009 ATA guidance adopted classes A through D (with D as the most severe); in the 2015 revisions, they were updated to ‘moderate,’ ‘high,’ and ‘highest’ risk of MTC, with accordant guidance on timing of prophylactic thyroidectomy for unaffected RET mutation carriers.”

The researchers wanted to estimate penetrance figures, unbiased by ascertainment, for MTC, so they analyzed 61 RET mutations that the ATA has deemed disease-causing in population whole-exome sequencing data. They used the analyses of the observed allele frequencies in about 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. The group calculated the maximum number of mutant alleles that they would expect to observe in non-TCGA ExAC data for a pathogenic RET mutation. “In brief,” the authors write, “this method leverages the logic that a fully penetrant allele cannot be more common than the disease it causes.”

Fifty of the 61 disease-causing mutations were not detected in this cohort, and of the 11 mutations present, nine were in the moderate risk category and two were in the high-risk category. p.Val804Met shows a frequency greater than fivefold higher than that of any other pathogenic RET mutation, the researchers found. “For all other pathogenic RET mutations, the observed frequency is consistent with a lifetime penetrance of MTC of >90%, whereas for RET p.Val804Met, the observed frequency is not even consistent with a lifetime penetrance of 50%,” the authors write. “We go on to demonstrate that the observed frequency of p.Val804Met in non-TCGA ExAC supports a lifetime penetrance of MTC for p.Val804Met of 4%.”

The authors go on to point out that even with an unrealistically high estimate of lifetime risk of MTC in combination with implausible estimates of allelic heterogeneity (45%) and genetic heterogeneity (40%) the observed frequency of p.Val804Met still only equates to a penetrance for MTC of 46%.

The ATA currently recommends prophylactic thyroidectomy for all RET mutation carriers, but based on the results of this study, that recommendation should be clarified, Turnbull and her group write. “Inevitable prophylactic surgery may be a reasonable presumptive model for the carriers of most RET mutations who have close relatives affected by disease,” they write. “However, for individuals with RET p.Val804Met, ascertained through population-based testing [i.e., with no (or an only distant) family history of disease], truly prophylactic thyroidectomy is likely inappropriate.”

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