JCO precision oncology · 2026
Prevalence of Germline Pathogenic RET Variants in a Pan-Cancer Patient Population.
СтатьяМногоцентровое исследованиеНаблюдательное исследованиеНазвание и аннотация: Перевод в очереди
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Borio Matilde, Sheehan Margaret, Katabi Nora, Sacca Rosalba E, Maio Anna, Kemel Yelena, Khurram Aliya, Mandelker Diana, Birsoy Ozge, Solit David, Carlo Maria I, Liu Ying, Abbass Mohammad, Banaszak Lauren, Kesserwan Chimene, Murciano-Goroff Yonina R, Latham Alicia, Offit Kenneth, Wong Richard J, Ghossein Ronald, Boucai Laura, Tuttle Michael, Stadler Zsofia K
Аннотация
PURPOSE: Germline likely pathogenic or pathogenic variants (LP/PV) in the RET proto-oncogene account for approximately 25% of medullary thyroid cancers (MTCs). Depending on the variant, individuals with RET LP/PV can have > 70% lifetime risk for MTC or C-cell hyperplasia, an MTC precursor. We assessed prevalence and genotype-phenotype correlations of RET LP/PV in a pan-cancer population undergoing agnostic multigene germline cancer genetic testing.
METHODS: Patients with cancer at Memorial Sloan Kettering Cancer Center provided informed consent to Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, a paired tumor-normal genomic sequencing protocol (ClinicalTrials.gov identifier: NCT01775072) from 2015 to 2023. Consent included multigene germline testing inclusive of RET. LP/PVs in RET were categorized per standardized MTC risk levels. Clinical data, including family history, surveillance results, and pathology, were extracted from medical records.
RESULTS: Twenty-one of 31,866 patients harbored an LP/PV in the RET gene, with the most common variant being p.Val804Met (n = 10) of moderate risk. Although six patients had a personal history of MTC, 15 of 21 patients (71%) had neither a personal nor a family history of MTC. Of the 15, nine underwent endocrinology high-risk surveillance, with five patients deciding to proceed with thyroidectomy due to abnormal surveillance findings. Pathologic findings consisted of isolated C-cell hyperplasia only (n = 1), microMTC and C-cell hyperplasia (n = 2), stage I MTC and C-cell hyperplasia (n = 1), and stage IVA MTC (n = 1).
CONCLUSION: In this pan-cancer cohort, 71% of RET LP/PV findings were incidental, with no prior personal or family history of MTC. High-risk surveillance and potential thyroidectomy are warranted in patients with an incidental germline RET LP/PV finding due to high rates of precursor lesions and MTC even among these patients.
METHODS: Patients with cancer at Memorial Sloan Kettering Cancer Center provided informed consent to Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, a paired tumor-normal genomic sequencing protocol (ClinicalTrials.gov identifier: NCT01775072) from 2015 to 2023. Consent included multigene germline testing inclusive of RET. LP/PVs in RET were categorized per standardized MTC risk levels. Clinical data, including family history, surveillance results, and pathology, were extracted from medical records.
RESULTS: Twenty-one of 31,866 patients harbored an LP/PV in the RET gene, with the most common variant being p.Val804Met (n = 10) of moderate risk. Although six patients had a personal history of MTC, 15 of 21 patients (71%) had neither a personal nor a family history of MTC. Of the 15, nine underwent endocrinology high-risk surveillance, with five patients deciding to proceed with thyroidectomy due to abnormal surveillance findings. Pathologic findings consisted of isolated C-cell hyperplasia only (n = 1), microMTC and C-cell hyperplasia (n = 2), stage I MTC and C-cell hyperplasia (n = 1), and stage IVA MTC (n = 1).
CONCLUSION: In this pan-cancer cohort, 71% of RET LP/PV findings were incidental, with no prior personal or family history of MTC. High-risk surveillance and potential thyroidectomy are warranted in patients with an incidental germline RET LP/PV finding due to high rates of precursor lesions and MTC even among these patients.