Affiliation:
1. 1Department of Visceral, Vascular and Endocrine Surgery, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
2. 2Section of Endocrine Surgery, Department of General, Visceral and Transplantation Surgery, University of Duisburg-Essen, Essen, Germany
Abstract
Objective
This study aimed to delineate the age-dependent clinical penetrance and expression of heterozygous rearranged during transfection (RET) missense mutations associated with multiple endocrine neoplasia 2A (MEN2A) according to parental inheritance.
Design
This was an observational study of RET carriers operated for MEN2A-associated tumors between 1985 and 2021.
Methods
Kaplan−Meier time-to-event and multivariable Cox proportional hazards regression analyses were performed on node metastases from medullary thyroid cancer, pheochromocytoma, bilateral pheochromocytoma, and primary hyperparathyroidism.
Results
Some 405 (70.1%) of 578 patients carrying heterozygous MEN2A RET missense mutations had information about the parental inheritance of the trait. On Kaplan−Meier analysis, offspring who inherited the trait from the father developed node metastases (Plog-rank= 0.007), pheochromocytoma (Plog-rank= 0.029), bilateral pheochromocytoma (Plog-rank= 0.002), and primary hyperparathyroidism (Plog-rank= 0.018) at a significantly younger age than offspring who inherited the trait from the mother. On multivariable Cox regression, controlling for index status, offspring sex, and (where feasible) mutational risk, parental inheritance was consistently associated with each MEN2A-associated tumor (hazard ratios (HR) = 1.7–1.8 for the earlier manifestations node metastases and pheochromocytoma vs HR of 2.9–3.4 for the late manifestations bilateral pheochromocytoma and primary hyperparathyroidism). Herein, node metastases were 3.1- and 1.7-fold more closely associated with mutational risk (HR of 5.3 for high and 2.9 for moderate-high risk mutations vs low-moderate risk mutations) than parental inheritance (HR = 1.7).
Conclusion
These findings illustrate the importance of considering not just mutational risk but also parental inheritance when it comes to personalization of screening for and early detection of the various components of MEN2A-associated tumors.
Publisher
Oxford University Press (OUP)
Subject
Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism
Cited by
7 articles.
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