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MEDULLARY THYROID CANCER
Does my RET mutation put me at higher risk for medullary thyroid cancer?
BACKGROUND
Medullary thyroid cancer is a relatively rare type of thyroid cancer that often runs in families. Multiple endocrine neoplasia, type 2A (MEN 2A) is a hereditary syndrome that runs in families in which MTC is often seen in association with other endocrine tumors such as pheochromocytoma (a tumor of the adrenal glands) and hyperparathyroidism (elevated parathyroid hormone levels usually caused by tumors of the parathyroid glands). MEN 2A is associated with mutations in the RET cancerassociated gene, which is classically known to increase risk of MTC. MTC that does not run in families (know as sporadic MTC) is not associated with RET mutations.
With the increased availability of genetic testing, more patients without clinical indications are obtaining genetic analyses to determine their risk of developing cancer. Some of these individuals are found to have RET mutations. By contrast, there are patients who have clinical indications for genetic testing for other disorders such as type 1 diabetes or breast cancer which can help with diagnosis and/or prognosis. When data from symptomatic patients having a clinical indication to get genetic testing is applied to patients who do not have this indication, the risk of getting cancer might be overestimated.
The aim of the study is to compare the risk of developing and dying from MTC in patients who had clinical indications for the RET positive testing to the risk in patients when the RET mutation was found without a clinical indication on general screening.
THE FULL ARTICLE TITLE
West CE, et al. Medullary thyroid cancer risk and mortality in carriers of incidentally identified MEN2A RET variants. JAMA Netw Open 2025;8(6):e251793.
SUMMARY OF THE STUDY
The following three databases were used to study patients: UK Biobank, Geisinger My Code, and Exeter. The patients in these databases were analyzed to see if they have a RET mutation and MTC for 13.8 years until October 2022 for the UK Biobank and for 5 years until June 2023 for the Geisinger patients. The study was limited due to its reliance on the hospitals’ electronic medical record system to detect MTC cases and to the inclusion of only adult patients, excluding pediatric patients.
In the UK Biobank database, 1 out of 2,500 patients had a RET mutation, yet 1.88% of the patients had MTC. The UK Biobank patients were estimated to have a risk of developing thyroid cancer of 2.2% by the age 75. Even though 166 out of the 169 RET mutation patient from the UK Biobank did not undergo a total thyroidectomy, the death risk by age 75 was only 6.1%, similar to 5.7% of non-RET mutated patients.
In the Geisinger group, 77 out of 122,640 patients had a RET mutation and 13% had MTC. The Geisinger patients’ estimated risk of having thyroid cancer by age 75 was 19%. The higher incidence of thyroid cancer of the Geisinger group might be attributed to hospitalized patients being sicker than clinic patients and presenting with MEN2 syndrome. Even though none of the Geisinger patients underwent a total thyroidectomy, by age 75, the patients with the RET mutation had a risk of death of 11.6% compared to 13.6% of the patients without the mutation. By age 75, 95.7% of the Exeter patients with RET mutations found with clinical indications had developed MTC compared to 1.3% and 15.9% of the patients in the UK Biobank and Geisinger groups, respectively.
WHAT ARE THE IMPLICATIONS OF THIS STUDY?
Among the approximate total of 500,000 patients studied, 1 out of the 2,000 patients were found to have a moderate risk RET mutations without an initial indication for the testing. The risk of these patients with the mutation having MTC is lower than that of patients with suspected MEN2 syndrome. Of the patients who had the mutation found without clinical indication, only 1.9-2.2% of them develop MTC by the age of 75.
Patients with the RET mutations found without a clinical indication should receive genetic counseling indicating that they do not have a higher risk of death, even without treatment compared to patients without the mutations. When providing genetic counseling, providers might choose to do surveillance of the thyroid gland instead of recommending a thyroid surgery to remove the gland completely in patients who were found to have a RET mutation without symptoms.
— Pinar Smith, MD
ATA RESOURCES
Thyroid Cancer (Medullary): https://www.thyroid.org/medullary-thyroid-cancer/
ABBREVIATIONS & DEFINITIONS
Medullary thyroid cancer: a relatively rare type of thyroid cancer that often runs in families. Medullary cancer arises from the C-cells in the thyroid.
Cancer-associated genes: these are genes that are normally expressed in cells. Cancer cells frequently have mutations in these genes. It is unclear whether mutations in these genes cause the cancer or are just associated with the cancer cells. The cancer-associated genes important in thyroid cancer are BRAF, RET/PTC, TERT and RAS.
RET mutations: the RET gene is a cancer-associated gene. Mutations in the RET gene are associated with genetic syndromes, including MEN 2A and familial medullary thyroid cancer
Multiple endocrine neoplasia, type 2A (MEN 2A): A hereditary syndrome in which medullary thyroid cancer is often seen in association with other endocrine tumors such as pheochromocytoma (a tumor of the adrenal glands) and hyperparathyroidism (elevated parathyroid hormone levels usually caused by tumors of the parathyroid glands).
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