RET Y791F Variant Does Not Increase the Risk for Medullary Thyroid Carcinoma

Dear Editor:

We read with interest the revised 2015 American Thyroid Association (ATA) Guidelines for the Management of Medullary Thyroid Carcinoma (MTC) recently published in Thyroid by Wells et al. (1), in which the authors updated the 2009 ATA guidelines for MTC.

As with the previous guidelines, the revised 2015 ATA guidelines gave great attention to the heritability of MTC, which was intensely discussed in recommendations 1–12, as well as throughout the text. Of note, the ATA mutation risk categories were changed from D, C, B–A to “highest risk” (HST, M918T mutation), “high risk” (H, C634 mutations), and “moderate risk” (MOD, non-C634 or M918 mutations), respectively. As established previously, the suggested timing for thyroidectomy depends on the strength of the RET mutation. The revised 2015 ATA consensus recommends that thyroidectomy should be performed in the first year/months of age in patients harboring a M918T RET mutation and before five years of age in patients with a C634 RET mutation. Thyroidectomy in patients carrying RET mutations classified as MOD was recommended to be performed during childhood or young adulthood, depending primarily on serum calcitonin levels (1).

In this letter, we would like to point out relatively new data about the RET Y791F variant, which has not been commented on in the 2015 ATA guidelines, and our understanding of its implications in the management of MTC patients.

The Y791F variant was first identified in MTC patients in an extended genetic analysis that included exon 13 of the RET gene and was reported as a new potential pathogenic mutation. A number of subsequent studies confirmed the occurrence of this variant in cases with MTC, especially in sporadic patients from central Europe presenting with a less aggressive phenotype. These findings led to acceptance, at that time, of Y791F as a new MTC susceptibility allele associated with variable and a mostly mild form of the disease.

However, several large, well-controlled recent studies have clearly demonstrated that RET Y791F (alone) does not increase the risk for MTC. Erlic et al. first reported a family in which the index patient who presented with a head and neck paraganglioma harbored the SDHC R72C missense mutation, while the Y791F variant was observed in three tumor-free adult relatives (2). In addition, very similar frequencies of Y791F were found comparing 1475 endocrine tumor patients (0.9%) and 1000 population-based controls (0.8%) (2). The same group later reported a coincidental RET Y791F variant in a patient with bilateral metachronous pheochromocytomas (and no MTC) who also carried a truncating germline MAX mutation associated with a biallelic knockdown in the tumor samples (3).

Recently, a comprehensive study analyzed the prevalence of RET Y791F in 11,544 healthy individuals from multiple genetic backgrounds and 18,163 cancer samples, and the results support the conclusion that Y791F is indeed a rare genetic polymorphism instead of a disease-causing mutation (4). In addition, this study also performed an extended review of the literature and was able to identify adult cases harboring Y791F that inadvertently underwent thyroidectomy and had no histopathological signs of MTC (4).

In conclusion, there is robust evidence showing that the RET Y791F alone must be considered a nonpathogenic polymorphism of RET not associated with increased heritability of MTC (2 –4).

On the other hand, cases with co-occurrence of RET Y791F and a bona fide mutation in any other endocrine tumor susceptibility gene should be clinically managed according to the recommendations of the bona fide disease-causing mutation.