根据父母遗传，MEN 2A 外显率和表现的性别差异。

Sex differences in MEN 2A penetrance and expression according to parental inheritance.

机构信息

Department of Visceral, Vascular and Endocrine Surgery, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

Section of Endocrine Surgery, Department of General, Visceral and Transplantation Surgery, University of Duisburg-Essen, Essen, Germany.

出版信息

Eur J Endocrinol. 2022 Feb 25;186(4):469-476. doi: 10.1530/EJE-21-1086.

DOI:10.1530/EJE-21-1086

PMID:35130180

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.

摘要

目的

本研究旨在根据亲代遗传，描绘与多发性内分泌肿瘤 2A（MEN2A）相关的杂合性转染后重排（RET）错义突变的年龄依赖性临床外显率和表达。

设计

这是一项针对 1985 年至 2021 年间因 MEN2A 相关肿瘤接受手术的 RET 携带者的观察性研究。

方法

对来自甲状腺髓样癌、嗜铬细胞瘤、双侧嗜铬细胞瘤和原发性甲状旁腺功能亢进症的淋巴结转移进行 Kaplan-Meier 时间事件和多变量 Cox 比例风险回归分析。

结果

在 578 名携带杂合性 MEN2A RET 错义突变的患者中，有 405 名（70.1%）提供了关于该特征亲代遗传的信息。在 Kaplan-Meier 分析中，从父亲那里遗传该特征的后代比从母亲那里遗传该特征的后代更早出现淋巴结转移（Plog-rank=0.007）、嗜铬细胞瘤（Plog-rank=0.029）、双侧嗜铬细胞瘤（Plog-rank=0.002）和原发性甲状旁腺功能亢进症（Plog-rank=0.018）。在多变量 Cox 回归中，在控制指数状态、后代性别以及（在可行的情况下）突变风险的情况下，亲代遗传始终与每种 MEN2A 相关肿瘤相关（较早表现为淋巴结转移和嗜铬细胞瘤的风险比（HR）为 1.7-1.8，而较晚表现为双侧嗜铬细胞瘤和原发性甲状旁腺功能亢进症的 HR 为 2.9-3.4）。在此，淋巴结转移与突变风险的相关性更为密切（高风险和中高风险突变的 HR 为 5.3，低中风险突变的 HR 为 2.9），而与亲代遗传的相关性较低（HR=1.7）。