罕见RET原癌基因Y606C突变所致家族性甲状腺髓样癌家系临床特点分析

摘要

目的：分析讨论RET原癌基因Y606C这一罕见突变所致家族性甲状腺髓样癌（familial medullary thyroid carcinoma，FMTC）的临床生物学特点。方法：对先期确诊的1个携带RET原癌基因Y606C种系突变的FMTC家系成员进行RET基因种系突变筛查，同时行血清降钙素、甲状旁腺素、颈腹部超声等相关临床检查，对患病成员和携带者给予临床干预，并总结分析上述病例临床生物学特点。结果：包括先证者在内，该家系中10例参与基因筛查，发现6例携带RET基因第10外显子Y606C突变。其中3例确诊为FMTC患者（含先证者），均为女性，平均发病年龄50.0（47～53）岁。发病成员临床均表现为甲状腺肿物伴降钙素升高，未发现甲状旁腺和肾上腺病变。2例行全甲状腺切除术，1例行患侧腺叶切除术。术后病理均确诊为甲状腺髓样癌，其中2例病理分期均属早期，术后随访期间均达生化治愈。家系中另有3例为突变携带者，平均年龄33.0（15～55）岁。其中2例颈部超声均提示甲状腺肿物（考虑良性），另1例颈部超声未见异常。除1例拒绝降钙素检测外，其余2例血清降钙素均正常范围，建议定期复查。结论：RET原癌基因Y606C突变可以导致FMTC发病，家系成员发病平均年龄较大，肿瘤分期较早，生化治愈率高，预后较好；家系成员基因检测结合颈部超声和降钙素检查有利于甲状腺髓样癌的早期诊断；对于无症状Y606C突变携带者，应根据其降钙素水平及颈部超声检查情况实施个体化临床处置。%Objective: A study was conducted to investigate the biological characteristics of familial medullary thyroid carcinoma (FMTC) caused by rare RET proto-oncogene mutation Y606C and to discuss treatment options. Methods:Systemic medical data, in-cluding RET germline mutation screening, biochemical testing, imaging examinations, clinical management, and postoperative follow-up, were obtained from 10 members of the 3-generate FMTC family. These data were confirmed previously. The clinical features of the above-mentioned cases were summed up. Results:RET screening showed heterozygous missense mutation of Y606C on exon 10 in 6 cases. Among the 6 carriers, 3 cases (including the index patient) have been affected by MTC. The mean age of these patients at the time of diagnosis was 50.0 years old (in the range of 47-53 years old). The manifestations associated with MTC included thyroid nod-ules and elevated levels of calcitonin. Two patients accepted total thyroidectomy and one patient underwent lobectomy. MTC was con-firmed by postoperative pathology and all tumors were early stage without regional lymph node metastasis. Biochemical cure was achieved during the follow-up. The mean age of three mutation carriers was 33.0 years (in the range of 15-55 years). Among the three carriers, multiple thyroid lesions have been detected by ultrasound in a 55-year-old female and a 15-year-old male. One carrier reject-ed further clinical examinations. The other two carriers' serum calcitonin levels were normal. Thus, close observation was recommend-ed. Conclusion:RET mutation of Y606C might lead to pathogenesis of FMTC, which is associated with older age of onset, earlier tumor stage, higher biochemical cure rate, and better prognosis. Molecular screening of the RET gene in FMTC family members, combined with ultrasound and thyroid calcitonin examinations, may be helpful in the early diagnosis of MTC. For asymptomatic Y606C mutation carriers, management should be individualized based on calcitonin level and neck ultrasound.