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Published on: April 11, 2016
Prevalence of Germline Pathogenic RET Variants in a Pan-Cancer Patient Population
Matilde Borio1, Margaret Sheehan1, Nora Katabi2
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
JCO Precision Oncology
|May 22, 2026
Summary
Germline RET variants (LP/PV) are linked to medullary thyroid cancer (MTC). Many patients with RET LP/PVs lack MTC history, highlighting the need for surveillance and potential thyroidectomy.
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- Germline likely pathogenic or pathogenic variants (LP/PV) in the RET proto-oncogene are implicated in approximately 25% of medullary thyroid cancers (MTCs).
- Individuals with RET LP/PVs face a significant lifetime risk of MTC or C-cell hyperplasia, a precursor lesion.
Purpose of the Study:
- To assess the prevalence and genotype-phenotype correlations of RET LP/PVs in a diverse, pan-cancer population undergoing agnostic multigene germline cancer genetic testing.
- To identify incidental findings of RET LP/PVs in patients without a personal or family history of MTC.
Main Methods:
- Utilized data from Memorial Sloan Kettering Cancer Center patients undergoing paired tumor-normal genomic sequencing (ClinicalTrials.gov identifier: NCT01775072) from 2015 to 2023.
- Included multigene germline testing for RET variants and categorized LP/PVs according to standardized MTC risk levels.
- Extracted clinical data, including family history, surveillance results, and pathology, from electronic medical records.
Main Results:
- Identified 21 patients with RET LP/PVs out of 31,866 patients; the most common variant was p.Val804Met (n=10).
- 71% of patients (15/21) with RET LP/PVs had no personal or family history of MTC.
- Among those without a history, nine underwent high-risk surveillance, leading to thyroidectomy in five due to precursor lesions or MTC.
Conclusions:
- A significant proportion of germline RET LP/PV findings in a pan-cancer cohort are incidental, lacking a prior MTC history.
- High-risk surveillance and consideration for thyroidectomy are crucial for patients with incidental germline RET LP/PV findings due to the risk of MTC and precursor lesions.
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