van den Broek Medard F M, van Nesselrooij Bernadette P M, Pieterman Carolina R C, Verrijn Stuart Annemarie A, van de Ven Annenienke C, de Herder Wouter W, Dekkers Olaf M, Drent Madeleine L, Havekes Bas, Kerstens Michiel N, Bisschop Peter H, Valk Gerlof D
Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Medical Genetics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
J Clin Endocrinol Metab. 2020 Jul 1;105(7). doi: 10.1210/clinem/dgaa257.
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs.
To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands.
All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared.
A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results.
These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.
多发性内分泌腺瘤1型（MEN1）是一种罕见的常染色体显性遗传病，由MEN1基因功能丧失引起，MEN1基因是一种肿瘤抑制基因，编码蛋白menin。其特征是发生原发性甲状旁腺功能亢进（pHPT）、十二指肠胰腺神经内分泌肿瘤（dpNET）、垂体肿瘤（PIT）、肾上腺腺瘤以及支气管肺（bp-NET）、胸腺和胃神经内分泌肿瘤。深入了解影响MEN1临床表现年龄相关外显率的因素可为更个性化的筛查方案提供线索。
研究基因早现是否在荷兰已知最大的MEN1家系中起作用。
确定荷兰所有连续两代中≥10名受累成员的MEN1家系。使用针对竞争风险进行调整的回归分析比较各代中不同MEN1相关表现的发现年龄。为校正监测的有益效果，还分别比较了监测期间出现的表现。
纳入了来自10个家系的152例MEN1患者。发现连续几代中pHPT、dpNET、PIT和bp-NET的发现年龄显著降低（P<0.0001）。校正分析得出相同结果。
这些结果提示存在基因早现。然而，由于存在残留偏倚的风险，结果必须谨慎解释。在其他队列中进行独立验证并开展进一步的转化研究以探究解释MEN1中这一现象的分子机制后，这些结果可能会为未来更个性化的筛查方案以及MEN1患者后代的早期筛查提供参考。
