Bergant Damijan, Hocevar Marko, Besic Nikola, Glavac Damjan, Korosec Branka, Caserman Simon
Department of Surgical Oncology, Institute of Oncology, Zaloska 2, 1000 Ljubljana, Slovenia.
Wien Klin Wochenschr. 2006 Jul;118(13-14):411-6. doi: 10.1007/s00508-006-0636-8.
Medullary thyroid cancer (MTC) is a rare endocrine tumor that may be sporadic or inherited in settings of MEN2A, MEN2B and FMTC. Germline point mutations in the RET proto-oncogene are responsible for tumor occurrence, inheritance and great clinical variability. The aim of this study was to correlate the genotype and phenotype of patients with hereditary MTC (age at diagnosis, sex, TNM classification and clinical features).
Between 1997 and 2003 genetic testing was performed in 69 out of 98 patients with "sporadic" MTC. Carriage of mutation was found in 14 (20.2%) patients (index patients) and in 16 out of 31 (51.6%) of their relatives. One patient with MEN2B and codon 918 mutation was excluded from further analysis.
Genomic DNA was isolated from peripheral blood leukocytes. Exons 10, 11, 13, 14, 15 and 16 of the RET proto-oncogene were amplified in polymerase chain reactions. Point mutations of the RET gene were detected with single-strand conformation analysis and DNA sequencing. Detected mutations were confirmed with restriction enzyme analysis.
Codon 634 mutations were detected in 15 patients (50%; aged 18-76 years; 6 families), codon 618 in nine patients (30%; aged 12-65 years; 4 families) and codon 790 in five patients (16.6%; aged 16-74 years; 3 families). The median age at diagnosis was 31 +/- 17.3, 33 +/- 15.9 and 36 +/- 23.8 years for patients with codon 618, 634 and 790 mutations. Selected by sex, females with codon mutations 618 and 634 versus 790 had median age at diagnosis of 34.5 +/- 15.6 years and 43.5 +/- 22.9 years, whereas the inverse result was observed in males (26.5 +/- 18.0 versus 16 years). The male/female ratio was 1:2 for patients with codon 618 and 634 mutations and 1:4 for patients with codon 790 mutations. Some of the data suggested correlation between specific genotypes, tumor size, stage of MTC and age at diagnosis. Pheochromocytoma (12 out of 15 patients) and primary hyperparathyroidism (6 out of 15 patients) were diagnosed solely in patients with codon 634 mutations. One patient with FMTC and Hirschprung disease was found in a family with codon 618 mutations.
Correlation between tumor size, stage of MTC at diagnosis in view of patient's age, and specific genotype were indicated in our limited series and were more evident in female patients with codon 790 mutations. Later onset and a probably less aggressive course of MTC in these patients than in patients with other mutations should be considered in planning prophylactic thyroid surgery. MEN2A syndrome was related solely to codon 634 mutations.
甲状腺髓样癌（MTC）是一种罕见的内分泌肿瘤，可散发或在MEN2A、MEN2B和FMTC综合征中遗传。RET原癌基因中的种系点突变是肿瘤发生、遗传及显著临床变异性的原因。本研究旨在关联遗传性MTC患者的基因型与表型（诊断年龄、性别、TNM分期及临床特征）。
1997年至2003年间，对98例“散发”MTC患者中的69例进行了基因检测。在14例（20.2%）患者（索引患者）及其31例亲属中的16例（51.6%）中发现了突变携带者。1例患有MEN2B且密码子918突变的患者被排除在进一步分析之外。
从外周血白细胞中分离基因组DNA。通过聚合酶链反应扩增RET原癌基因的第10、11、13、14、15和16外显子。采用单链构象分析和DNA测序检测RET基因的点突变。通过限制性酶切分析确认检测到的突变。
在15例患者（50%；年龄18 - 76岁；6个家系）中检测到密码子634突变，9例患者（30%；年龄12 - 65岁；4个家系）中检测到密码子618突变，5例患者（16.6%；年龄16 - 74岁；3个家系）中检测到密码子790突变。密码子618、634和790突变患者的诊断中位年龄分别为31±17.3岁、33±15.9岁和36±23.8岁。按性别选择，密码子618和634突变的女性患者与密码子790突变的女性患者相比，诊断中位年龄分别为34.5±15.6岁和43.5±22.9岁，而男性患者情况相反（分别为26.5±18.0岁和16岁）。密码子618和634突变患者的男女比例为1:2，密码子790突变患者的男女比例为1:4。一些数据表明特定基因型、肿瘤大小、MTC分期与诊断年龄之间存在关联。仅在密码子634突变的患者中诊断出嗜铬细胞瘤（15例患者中的12例）和原发性甲状旁腺功能亢进（15例患者中的6例）。在一个密码子618突变的家系中发现1例患有FMTC和先天性巨结肠的患者。
在我们的有限病例系列中，提示了肿瘤大小、基于患者年龄的MTC诊断分期与特定基因型之间的关联，在密码子790突变的女性患者中更为明显。在计划预防性甲状腺手术时，应考虑这些患者的MTC发病较晚且病程可能比其他突变患者侵袭性小。MEN2A综合征仅与密码子634突变相关。
