RET Y791F in MEN2: a variant presumed non-pathogenic, yet lacking conclusive evidence of insignificance

Introduction

Background

Patients with a pathogenic variant in the rearranged-during-transfection (RET) proto-oncogene may develop aggressive medullary thyroid carcinoma (MTC) within the multiple endocrine neoplasia 2 (MEN2) syndrome. Neoplastic C-cell hyperplasia (nCCH) is considered to be a precursor of MTC, indicating its significant role in the early stages of the disease’s development (1). Aside from that, pheochromocytoma (PCC) and—in some cases—primary hyperparathyroidism (PHPT) develop characteristically (2). It is known that the clinical phenotype of MEN2 syndrome and the aggressiveness of MTC depend on the respective genotype (3-8). This determines the indication for prophylactic thyroidectomy (pTT) and required intervals of clinical follow-up. To classify various mutations based on their risk of early-onset disease manifestations (especially of MTC and its precursor lesions), numerous risk classifications have been consistently published over the past decades. In 2001, a pathogenic variant in Y791F was assigned to the “late-onset” category within “Level 1” of three risk categories (thus, the one with the lowest MTC risk) (9). There has been little consensus over recommendations on pTT (surgery before the manifestation of MTC), ranging from a latest timing by the age of 5 or 10 to avoid surgery and merely regular monitoring through stimulated calcitonin (Ct) testing. In the American Thyroid Association (ATA) guidelines of 2009, the pathogenic variant in Y791F was classified as the lowest risk level among four established categories (10), recommending pTT by the age of five years. Most recently, in 2015, the MEN2 classification was revised by the ATA and reduced to only three persisting categories: ATA highest risk (HST RISK), ATA high risk (HIGH RISK) and ATA moderate risk (MOD RISK). The Y791F variant is not mentioned in this classification (nor is it in the current guidelines).

Rationale and knowledge gap

A mutation in Y791F is considered rare and has been analysed in different studies, yet recommendations are based on a small number of cases. Recent recommendations apart from the American Guidelines regarding pTT and the optimal timing vary between the age of five and twenty years, with some advocating for mere clinical observation (5,11-14).

Objective

The intention of this study is to contribute to the assessment of the role of a Y791F variant for respective carriers. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-130/rc).

Methods

This is a retrospective single-centre study of 36 carriers of the pathogenic RET variant c.2372A>T p.(Tyr791Phe) (reference sequence NM_020975.6), who were tested and/or surgically treated at a tertiary care centre between 1994 and 2022. In accordance with the standard operative procedures, basal Ct (bCt) levels were determined in all patients at the time of biochemical or imaging-based diagnosis of thyroid nodules (15), PCC and PHPT. The study was conducted in compliance with the ethical principles outlined in the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the Medical University of Vienna (approval number: 1069/2023). For retrospective data analysis, the Ethics Committee approved a waiver of informed consent. The primary endpoint of this study was the clinical manifestation of common MEN2-associated diseases (MTC, PCC, PHPT).

Statistical analysis

We conducted descriptive analyses using IBM SPSS Statistics Version 28.0.0.0. Quantitative variables were analysed as continuous data. Descriptive statistics such as minimum and maximum were used to describe their distribution.

Biochemical analysis

The Ct concentrations were determined with an immunochemiluminescent assay (ICMA) from Diagnostic Products Corporation (DPC; Los Angeles, CA, USA), running as a fully automated test on a Siemens 2000 Immunoassay System, as previously described in detail (16). Some Ct concentrations were also determined with the Roche Cobas Assay (Roche; Mannheim, Germany). Values resulting from the Cobas assay were converted to values of the Siemens assay using the appropriate conversion factor to enable a direct comparison in this study (17). The Siemens 2000 Immunoassay has been used world-wide in many publications. Therefore, the results of this study are comparable to findings in other studies applying the same assay. The presence of renal failure concurrent with the Ct measurement was considered to ensure a correct interpretation of the results. For pentagastrin- or calcium (Ca)-stimulated Ct, blood samples were drawn with an indwelling catheter before (0) and 2, 3, 5 and 10 minutes after an i.v. bolus of 0.5 µg/kg pentagastrin (Cambridge Laboratories Limited; Newcastle upon Tyne, UK) or after a 30-second infusion of 2.5 mg Ca per kilogram body weight [Ca gluconate 10% (10 mL containing Ca 2.25 mmol =90 mg Ca²⁺; Calcium Braun 10%^®, B. Braun Melsungen AG; Melsungen, Germany)], as recently described in detail (18).

Molecular genetic analysis

In all patients with reproducible elevated bCt and PCC, the presence of germline mutations was tested by screening exons 5, 8, 10, 11, 13, 14, 15 and 16 of the RET proto-oncogene (19-21). Corresponding to the study protocol, the first member of a family diagnosed with a germline mutation was termed “index patient”. For patients who underwent a positive testing for codon Y791F of exon 13 between 1994 and 2022, the clinical files including biochemical data and—in the case of surgery—details of the surgical procedure, as well as histological findings were retrospectively reviewed. Every patient included in this analysis underwent clinical visits during which bCt, albumin-adjusted total serum calcium, parathyroid hormone (PTH), as well as plasma metanephrine and normetanephrine concentrations and/or urine metanephrine concentrations were measured at least once.

Follow-up

The follow-up period ended at the time of the last consultation.

Surgery

In the case of surgical intervention, total thyroidectomy (TT) and bilateral central neck dissection (Robbins level 6) were performed, regardless of preoperative bCt and stimulated Ct levels (22). The patient with PCC underwent unilateral transperitoneal endoscopic adrenalectomy. Targeted resection of a single enlarged parathyroid gland was performed in the patient with PHPT, guided by preoperative morphological and functional imaging.

Pathologic examinations

All surgical specimens were submitted to pathologic examinations. The surgeon provided the pathologist with the Ct levels before starting histological examinations, allowing for a detailed microscopic evaluation of C-cell abnormalities (23). C-cell hyperplasia (CCH) was considered when at least one area with >50 C-cells per one low power field (×100) was found in both thyroid lobes. CCH was morphologically classified as focal, diffuse, nodular (summarised as “physiological”) or nCCH (1). MTC was diagnosed if a focal loss or reduplication of the thyroid follicular basement membrane, which surrounds the thyroid follicular cells, was observed upon immunohistochemistry. This finding distinguishes MTC from CCH, as MTC is characterized by the presence of c-cells outside the thyroid follicular basement membranes (24). The tumours were classified in accordance with the Union for International Cancer Control 2017 (25).

Results

Baseline characteristics

Between 1994 and 2022, 222 patients fulfilled the criteria of a positive genetic testing on Exons 5, 8, 10, 11, 13, 14, 15, 16 with a pathogenic variant in the RET proto-oncogene. Thirty-six patients (14 females and 22 males) were tested positive for a mutation in codon Y791F of exon 13. Patients were longitudinally monitored for a median [min–max] of 101.5 [0–263] months from the time of mutation diagnosis to the final follow-up, thereby encompassing observation until reaching the median age [min–max] of 56.5 [18–82] years, assuming a lifelong condition. Seventeen patients (5 females and 12 males) were index patients, identified by testing the presence of germline mutations because of elevated bCt levels or PCC. The index patients follow-up ends at a median [min–max] age of 68 [19–82] years. Of the index patients, twelve underwent TT because of elevated bCt. One of the index patients was treated with adrenalectomy due to unilateral PCC and another with PHPT underwent targeted neck exploration with an extirpation of a single inferior parathyroid adenoma. The remaining 19 patients (9 females and 10 males) were screening patients, aged between 18 and 82 years, with a median of 45 years, at the time of their last follow-up. Of the screening patients, nine underwent (total) thyroidectomy. The indication for surgery in screening patients was an explicit wish for pTT in six cases, nodular goiter in two cases and Graves’ disease in one case. Thus, a total of 21 surgical specimens of the thyroid, one from an adrenal gland, and one from a parathyroid gland were submitted to the pathologist. An overview of the baseline characteristics is provided in Table 1.

Manifestation of MEN2—index patients

Among twelve histological findings of thyroid tissue in index patients, there were three cases of MTC pT1a pN0. The patients with MTC were 56, 68, and 69 years old at the time of surgery. The preoperative bCt levels were 15 pg/mL in the female patient and 21 and 23 pg/mL in the male patients, respectively. Besides MTC, there were five cases of nCCH among all histological findings of thyroid tissue. At the time of surgery, the patients with nCCH were 48, 51, 55, 61 and 69 years old. The preoperative bCt levels in patients with nCCH were 19 pg/mL in the female patient and 18, 20, 21 and 33 pg/mL in the male patients, respectively. The patient with 33 pg/mL suffered from renal insufficiency [Kidney Disease: Improving Global Outcomes (KDIGO) G3b]. In the remaining four patients, histological findings revealed nodular CCH twice, diffuse CCH once and nodular hyperplasia of the thyroid without CCH once (with concurrent renal insufficiency upon Ct measurement). The preoperative bCt levels in these (all male) patients were 20, 20, 25 and 46 pg/mL. The patient with a bCt level of 46 pg/mL suffered from renal insufficiency (KDIGO G3b). One 68-year-old man was diagnosed with unilateral PCC, while one 54-year-old woman was diagnosed with PHPT. The seven index patients who did not exhibit any MEN2-associated manifestations were aged between 19 and 74 years, with a median age of 51 years, at the time of their last follow-up. An overview of the clinical manifestation of index patients is provided in Table 2.

Manifestation of MEN2—screening patients

Neither MTC nor nCCH were documented among the nine thyroid specimens collected from screening patients after thyroidectomy. Additionally, none of the screening patients experienced PCC or PHPT. An overview of the clinical manifestation of screening patients is provided in Table 3.

Discussion

Several studies investigating the rare codon Y791F variant in exon 13 over the last decades suggested various approaches ranging from clinical observance to prophylactic surgery. In 2009, the ATA recommended pTT for this variant by the age of five years. The recommendation was primarily based on the following three studies: Berndt et al. [1998] who defined Y791F as a definite pathogenic variant due to the occurrence of MTC (no minimum age at diagnosis described) and PCC in a cohort of 12 patients (26). Frank-Raue et al. [2008] examined a Y791F cohort of 56 cases (22 index and 34 screening patients), among whom a total of eight patients presented with MTC, two of whom had lymph node metastasis, with the youngest patient at the time of diagnosis being 37 years old (5). Vestergaard et al. [2007] investigated a family of twelve members, in which no member presented with MTC, thus possibly suggesting a low level of penetrance (14).

Expanding the discussion to the biological mechanism of the potential pathogenicity of RET codon 791 variants, it is known that the RET-proto-oncogene encodes a receptor tyrosine kinase playing a major role in the development of neural-crest derived cells, of the urogenital system, of the central, peripheral, and particularly of the enteric nervous system. Pathogenic RET-variants detected in MEN2-patients are primarily single nucleotide substitutions leading to amino acid alterations either in the cysteine rich region in the extracellular domain or in the intracellular tyrosine kinase domains. A high number of reports have evaluated the impact of different pathogenic RET-variants on outcome and aggressiveness of familial MTC and MEN2. The majority of MEN2B cases are caused by codon 918 or codon 883 mutations, which are located near the C-terminal lobe of the RET-kinase. These variants cause a very strong activation of the RET-receptor in the absence of ligand stimulation and destabilization of the inactive RET-form, resulting in a very aggressive phenotype of the disease (12,27,28). As they are located in proximity of the N-terminal lobe and ATP-binding pocket, it is speculated that pathogenic variants of codons 791 affect ATP-binding and inter-lobe flexibility destabilizing the inactive and favouring the active form of the RET-kinase (28,29). In vitro experiments indicated Y791F to promote signal transduction by STAT3- activation (30).

Nevertheless, in the revised 2015 ATA guidelines, the mutation of codon Y791F was no longer considered in the risk stratification of aggressive hereditary MTC. This remains in contrast to several high-risk mutations that mandate pTT during childhood, illustrating the range of aggressiveness in MTC (31). Their current position for mutations with moderate risk is pTT in childhood to be preferred when serum bCt levels become elevated or when parents do not want to take up an observation period lasting for decades. Adults with normal bCt should undergo annual testing and thyroidectomy with central neck dissection when levels rise. However, Y791F as a pathogenic variant is no longer considered in the current ATA guidelines. The studies mentioned for Y791F are those by Gimm et al. [2002], Vierhapper et al. [2005] and Frank-Raue et al. [2008] (5,12,32). Gimm et al. [2002] described 6 index and 11 screening patients with a Y791F mutation of whom four index cases presented with MTC including one case with lymph node metastasis, recommending pTT by no later than 10 years of age (12). The study by Vierhapper et al. [2005] describes the manifestation of PHPT in a case report about a Y791F patient, discussing that Y791F shows a low penetrance for MEN2 associated manifestations and may therefore be more frequently found in seemingly sporadic cases (32). Frank-Raue et al. [2008] have analysed the probably largest cohort of 22 index and 34 screening patients (5). In their cohort, eight index patients presented with MTC, two of them with lymph node metastasis. They state, that the mutation may come along with only a low probability of developing MTC. The reported MTC cases showed only low preoperative bCt levels, early tumor stages and high biochemical cure rates. It is discussed that surgery may be an overtreatment and could be postponed or even avoided, performing regular bCt testings insteadKlicken oder tippen Sie hier, um Text einzugeben. Gimm et al. [2004] changed their recommendation suggesting pTT until the end of the second decade of life by the latest (12,13). Machens et al. [2007] addressed genotype-phenotype-based surgery for MTC and agreed with the 1999 Consensus Statements, recommending thyroidectomy by ten years of age at the latest (9,11). They referred to the lowest known age at diagnosis: 21 years for MTC N0, 40 years for MTC N1 and 37 years for MTC M1. In the same year, Vestergaard et al. suggested the option of watchful waiting (14).

In a study by Toledo et al. [2015], a single mutation in codon Y791F was labelled as non-pathogenic. This assertion was based on sequencing blood DNA samples from a large control cohort, in which the prevalence of Y791F in control databases was extremely high compared to the 40 known pathogenic RET mutations. The simultaneous occurrence of Y791F and the strong C634Y mutation was demonstrated to explain the aggressive MTC phenotypes observed in a large, affected family initially reported as Y791F-only. The investigation of Y791F as a potentially pathogenic variant for MTC or the MEN2 syndrome failed to yield robust evidence. It is emphasised that the presence of Y791F alone does not imply an increased risk for MTC (33,34).

In our study, 10 of 36 patients presented with either early stage MTC, nCCH, PCC or PHPT, all of them index cases. Of the three patients with node-negative MTC and five patients with nCCH, the lowest age at diagnosis was 56 years in MTC and 48 years in nCCH, respectively, all presenting with low preoperative bCt levels. Within this very small patient group, this observation indicates a rather late onset of a mild malignant disease of the thyroid. The occurrence of three MTC cases among 36 patients is higher than the known prevalence of MTC. However, the isolated occurrence without any further MEN2-associated manifestations raises the question of whether these cases might be sporadic. Normal ranges of bCt levels may vary between laboratories and different assays. It is up to each institution to establish its own cut-off values to distinguish between CCH, low grade MTC and larger tumours. In the British Thyroid Association guidelines, published in 2014, concentrations ranging from 60 to 100 pg/mL were identified as highly indicative or characteristic of MTC, without specific details regarding the characteristics of the CT assay and without gender differentiation (35). Niederle et al. published gender-specific Ct cut-off values (for the Siemens DPC assay) in diagnosing C-cell disease (36). According to their study, it is not possible to differentiate between CCH and MTC below a bCT level of 23 pg/mL in women and 43 pg/ml in men, respectively. Using predefined cut-off levels, patients could effectively be subdivided into a group above the cut-off level with a definitive diagnosis of MTC (100%) and a “grey zone” below the cut-off level (6–23 pg/mL in women and 8–43 pg/mL in men) with a significant overlap of CCH and MTC pT1a (18). This applies to all MTC (pT1a) and nCCH diagnosed in Y791F patients in this study, confirming the cut-off hypotheses. Both, (unilateral) PCC and PHPT occurred in only two single patients, who never presented with an indication for thyroid surgery. None of the patients in this study experienced more than one MEN2 specific manifestation, which, raises the question of whether unilateral PCC or PHPT (without MTC) occurred is sporadically. On the other hand, assuming the occurrence of PCC in one 68-year-old man and of PHPT in one 54-year-old woman is sporadic appears rather unlikely when compared to studies on the prevalence of both diseases (37-39). For instance, a Swedish study on the occurrence of PHPT in post-menopausal women shows a prevalence of 2%; in this study PHPT occurred in one of 14 women (7.4%) (40). To make an evidence-based statement about the cause of the disease development of patients with a RET Y791F variant, molecular analyses for RET somatic mutations in tumoral tissue would be a useful approach and should be subject to further investigations.

Limitations

Aside from its retrospective character, it is important to consider that perhaps only a small number of individuals with a mutation in Y791F were duly identified. This may be evidenced by the fact that none of the screening patients showed typical morphological and clinical manifestations of MEN2. Additionally, due to their young age at the time of this analysis, some patients may potentially develop a manifestation of the mutation in the future. Future multicentre prospective validation studies are necessary to strengthen the significance of the results.

Conclusions

Objectively, one might conclude that this genetic variant is insignificant. However, due to the ongoing uncertainty regarding whether a RET proto-oncogene mutation in codon Y791F of exon 13 is a pathogenic variant associated with a late onset of mild MTC or further MEN2-associated manifestations, further investigations like RET somatic mutation screening in tumoral tissue of Y791F patients should be performed. The role of regular monitoring should remain open for consideration, until the significance of this mutation is definitively disproven.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-130/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-130/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-130/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-130/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in compliance with the ethical principles outlined in the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the Medical University of Vienna (approval number: 1069/2023). For retrospective data analysis, the Ethics Committee approved a waiver of informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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