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

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。

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

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 exon16 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 exon11 in RET proto-oncogene were detected in the fifteen MEN2A pedigrees. They were C634W (13.3%), C634Y (46.7%), C634R (26.7%), C634F (6.7%) and C634S (6.7%); Through the analysis of the genotype-phenotype 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 overseas 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 overseas 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 than that in foreign reports.