15个多发性内分泌腺瘤2A型家系的临床和RET基因突变研究  

The clinical patterns and RET proto-oncogene in fifteen multiple endocrine neoplasia type 2A pedigrees

作　　者：周瑜琳[1] 朱绍兴[2] 李建军 刘静波 殷民[5] 肖步云 虞朝黎[7] 王立明[8] 顾丽群[1] 崔斌[1] 宁光[1] 李小英[1] 赵咏桔[1] 

机构地区：[1]上海交通大学医学院附属瑞金医院内分泌代谢病科 [2]福建协和医院泌尿外科 [3]浙江省温岭市第二人民医院外科 [4]陕西省电子中心医院心脏科 [5]宁波大学医学院附属李惠利医院泌尿外科 [6]广东省中山市广济医院普外科 [7]浙江台州医院内分泌科 [8]大连医科大学附属第二医院外科

出　　处：《中华内科杂志》2007年第6期466-470,共5页Chinese Journal of Internal Medicine

基　　金：国家自然科学基金(30370666)

摘　　要：目的研究15例多发性内分泌腺瘤2A 型(MEN2A)先证者及其家系成员的临床表型和 RET 原癌基因突变情况。方法收集15例 MEN2A 先证者家系的共119名家系成员,提取其外周血基因组 DNA,分别对 RET 原癌基因第8、10、11、13、14、15、16外显子进行 PCR 产物直接测序。结果在15个 MEN2A 家系中,共有49例检出 RET 原癌基因突变。其中37例有 MEN2A 临床表型,另12例为基因携带者,前者诊断 MEN2A 的年龄显著晚于后者[(43.0±13.9)岁比(9.8±7.4)岁,P<0.01];37例 MEN2A 患者中甲状腺髓样癌(MTC)、嗜铬细胞瘤(PCC)和甲状旁腺增生或腺瘤(HPT)的发生率分别为91.9%,56.8%和10.8%;在15个 MEN2A 家系中,共检出5种基因突变类型,均位于 RET 原癌基因第11外显子634位点,分别为:C634W(13.3%),C634Y(46.7%),C634R(26.7%),C634F(6.7%),C634S(6.7%)。结论 15个 MEN2A 家系中,37例有临床表型的 MEN2A患者平均确诊年龄高于国外相关报道;MEN2A 患者 MTC 和 PCC 的发病率和国外文献报道的基本一致,而 HPT 则较低;所有 MEN2A 患者的 RET 原癌基因突变均位于634位点,较国外文献报道的单一。Objective To detect the phenotype and rearranged mutations during transfection of RET proto-oncogene in fifteen multiple endocrine neoplasia type 2A （MEN2A） probands and their family members. Methods Totally 119 family members of the fifteen MEN2A pedigrees were recruited. Total genomic DNA was extracted from peripheral blood for PCR. PCR products of exon 8,10,11,13,14,15 and exonl6 of the RET proto-oncogene were purified and direct gene sequencing was performed. Results The germline mutations of RET proto-oncogene were detected in 49 members of the fifteen MEN2A pedigrees. Among them, 37 patients had MEN2A phenotype and the remaining 12 were gene carriers. The mean age at which the members of the former group were diagnosed as MEN2A was significantly later than those of the latter group [ （ 43.0 ±13.9 ） yr vs （ 9.8 ±7. 4 ） yr, P 〈 0. 01 ] ; The incidences of medullary thyroid carcinoma（MTC）, pheochromocytoma（PCC） and hyperparathyroidism（HPT） in 37 MEN2A patients were 91.9%, 56. 8% and 10. 8%; Five germline mutations which all located in codon 634 of exonll in RET proto-oncogene were detected in the fifteen MEN2A pedigrees. They were C634W （13. 3% ）, C634Y （46. 7 % ）, C634 R （ 26. 7 % ）, C634 F （ 6. 7 % ） and C634 S （ 6. 7 % ） ; Through the analysis of the genotypephenotype of the 37 MEN2A patients, no statistic significance was found in the age of diagnose for MEN2A,the incidence of PCC, the percentage of cervical lymph node metastasis and the five different genotypes. Conclusion The mean age at which the 37 patients of the fifteen MEN2A pedigrees were diagnosed was older than that reported in the oversea literatures. The occurrence of MTC in MEN2A patients is earlier than that of PCC and HPT. The incidences of MTC and PCC are basically consistent with those in the oversea archives, while the incidence of HPT is lower than that in the corresponding report. The detected mutations of RET proto-oncogene in MEN2A patients were all located in codon 634, being simpler th

关 键 词：多内分泌腺瘤形成2a型 甲状腺肿瘤 原癌基因 点突变 

分 类 号：R736[医药卫生—肿瘤]