Lairmore Terry C, Piersall Linda D, DeBenedetti Mary K, Dilley William G, Mutch Matthew G, Whelan Alison J, Zehnbauer Barbara
Department of Surgery, Section of Endocrine and Oncologic Surgery, Washington University School of Medicine, Box 8109, 660 S. Euclid Avenue, St. Louis, Missouri, USA.
Ann Surg. 2004 May;239(5):637-45; discussion 645-7. doi: 10.1097/01.sla.0000124383.98416.8d.
We sought to develop a comprehensive program for clinical genetic testing in a large group of extended families with multiple endocrine neoplasia type 1 (MEN 1), with the ultimate aim of early tumor detection and surgical intervention.
Germline mutations in the MEN1 tumor suppressor gene are responsible for the MEN 1 syndrome. Direct genetic testing for a disease-associated MEN1 mutation is now possible in selected families. The neuroendocrine tumors of the pancreas/duodenum and the intrathoracic neuroendocrine tumors that occur in MEN 1 carry a malignant potential. Importantly, these tumors arise in otherwise young healthy patients and are complicated by the potential for multifocality and involvement of multiple target tissues. The optimal screening methods and indications for early surgical intervention in genetically positive patients have yet to be defined.
Nine MEN 1 kindreds were included in the study. The mutations for each kindred were initially identified in the research laboratory. Subsequently, mutation detection was independently validated in the clinical Molecular Diagnostic Laboratory. Each patient in the study underwent formal genetic counseling before testing.
Genetic testing was performed in 56 at-risk patients. Patients were stratified according to risk: Group I (n = 25), 50% risk, younger than 30 years old; Group II (n = 20), 50% risk, 30 years old or older; Group III (n = 11) 25% risk. Seven patients (age, 12 to 42 years; mean, 20.6 +/- 3.8 years) had a positive genetic test. Patients with a novel positive genetic test were in either Group I (n = 6) or Group II (n = 1) and have been followed for 35.8 +/- 2.0 months. Of the 7 genetically positive patients, hypercalcemia was either present at the time of diagnosis or developed during the period of follow-up in 6 patients. Four patients have undergone parathyroidectomy as early as age 16 years. One genetically positive patient has not yet developed hyperparathyroidism. Intensive biochemical screening in this select group of patients identified an elevated pancreatic polypeptide level and pancreatic tail mass lesion in a 15-year-old male who is asymptomatic and currently normocalcemic.
Genetic testing identifies patients harboring an MEN1 mutation before the development of clinical signs or symptoms of endocrine disease. When genetically positive patients are carefully studied prospectively, biochemical evidence of neoplasia can be detected an average of 10 years before clinically evident disease, allowing for early surgical intervention. Genetically positive individuals should undergo focused cancer surveillance for early detection of the potentially malignant neuroendocrine tumors that account for most of the disease-related morbidity and mortality.
我们试图为一大群患有1型多发性内分泌腺瘤（MEN 1）的大家庭制定一个全面的临床基因检测方案，最终目标是早期肿瘤检测和手术干预。
MEN1肿瘤抑制基因中的种系突变是MEN 1综合征的病因。现在可以在特定家庭中对与疾病相关的MEN1突变进行直接基因检测。MEN 1中发生的胰腺/十二指肠神经内分泌肿瘤和胸内神经内分泌肿瘤具有恶性潜能。重要的是，这些肿瘤发生在其他方面健康的年轻患者中，并且因多灶性和多个靶组织受累的可能性而变得复杂。基因检测呈阳性的患者早期手术干预的最佳筛查方法和指征尚未确定。
9个MEN 1家族被纳入研究。每个家族的突变最初在研究实验室中被鉴定出来。随后，在临床分子诊断实验室中对突变检测进行了独立验证。研究中的每位患者在检测前都接受了正式的遗传咨询。
对56名高危患者进行了基因检测。患者根据风险分层：I组（n = 25），风险50%，年龄小于30岁；II组（n = 20），风险50%，年龄30岁或以上；III组（n = 11），风险25%。7名患者（年龄12至42岁；平均20.6 +/- 3.8岁）基因检测呈阳性。基因检测新呈阳性的患者在I组（n = 6）或II组（n = 1）中，并已随访35.8 +/- 2.0个月。在7名基因检测呈阳性的患者中，6名患者在诊断时或随访期间出现高钙血症。4名患者早在16岁时就接受了甲状旁腺切除术。1名基因检测呈阳性的患者尚未发生甲状旁腺功能亢进。对这一特定患者群体进行的强化生化筛查在一名15岁无症状且目前血钙正常的男性中发现胰腺多肽水平升高和胰尾肿块病变。
基因检测可在内分泌疾病的临床体征或症状出现之前识别出携带MEN1突变的患者。当对基因检测呈阳性的患者进行前瞻性仔细研究时，肿瘤的生化证据平均可在临床明显疾病出现前10年被检测到，从而实现早期手术干预。基因检测呈阳性的个体应接受针对性的癌症监测，以早期发现导致大多数疾病相关发病率和死亡率的潜在恶性神经内分泌肿瘤。
