多发性内分泌肿瘤2型的基因型与表现型相关性分析

Genotype-phenotype correlations in multiple endocrine neoplasia type 2

目的 探讨多发性内分泌肿瘤2型（multiple endocrine neoplasia type 2,MEN2）中RET基因的不同突变型,与遗传性甲状腺髓样癌恶性程度相关性,及与携带的其他内分泌疾病的相关性.方法 对2010年1月至2015年12月中国医学科学院肿瘤医院头颈外科诊治的甲状腺髓样癌患者筛选,共纳入MEN2家系22个,对患者及家系亲属行RET基因外显子筛查,纳入致病基因携带者73例.结果 根据临床资料及2015年版美国甲状腺协会（American Thyroid Association,ATA）髓样癌指南,73例患者中,ATA-中危24例,高危48例,极高危1例.多因素Logistics回归分析显示,遗传性甲状腺髓样癌随着年龄及危险度增高,初治时出现Ⅲ/Ⅳ期的可能性越大.初治年龄每增加1年,Ⅲ/Ⅳ期可能性增加11.6％ （P =0.002）,ATA-高危患者罹患Ⅲ/Ⅳ期风险是ATA-中危者的7.89倍（P=0.003）.本组中MEN2A共72例,MEN2B仅1例.MEN2A分4种亚型：经典型共7个家系28例（38.9％）,突变位点为634及618密码子.伴皮肤苔藓淀粉样变型3个家系14例（19.4％）,均为634密码子突变.伴先天性巨结肠型1个家系4例（5.6％）,家族性甲状腺髓样癌型10个家系26例（36.1％）.结论 特异的RET突变基因与MEN2患者的遗传性甲状腺髓样癌的恶性度及其他内分泌疾病的表现相关.应依据RET突变基因型,对携带者进行MTC及其他内分泌疾病进行早期诊治.

Objective To evaluate the relationship between different RET mutations and the aggressiveness of hereditary medullary thyroid cancer （HMTC） or the presentation of other endocrine disorders in patients with multiple endocrine neoplasia type 2 （MEN2）.Methods A total of 73 thyroid medullary carcinoma patients from 22 Chinese kindreds who were treated in our center from 2010 to 2015 were enrolled.RET genes in the patients and their relatives were screened.Results According to the clinical data and 2015 American Thyroid Association （ATA） guidelines,patients were classified into 3 RET mutation risk groups：Modest,24 cases;High,48 cases;and Highest,1 case.Multivariate analysis showed an increased likelihood of MTC stage Ⅲ or Ⅳ at diagnosis with increasing of age and risk.The likelihood increased 11.6% per year of age at surgery （95% confidence interval,1.040-1.198;P =0.002）.The likelihood in patients with high risk was 7.9 times higher than patients with modest risk （95% confidence interval,1.607-38.717;P =0.003）.Aside from one patient with MEN2B,other 72 patients were MEN2A,of them,28 cases from 7 kindreds with classical MEN2A （codon 634 ＆amp; 618）,14 cases from 3 kindreds with cutaneous lichen amyloidosis （codon 634）,4 cases from 1 kindred with Hirschsprung＇s disease （codon 620）,and 26 cases from 10 kindreds with familial MTC.Conclusion The aggressiveness of HMTC and the presentation of other endocrine diseases are related to specific RET mutations.For RET mutation carriers,MTC and other endocrine diseases should be diagnosed and treated early based on the RET genotypes.