MOLECULAR MECHANISMS DISTINGUISH FOLLICULAR ADENOMA/FOLLICULAR CARCINOMA/THYROID

我们检测了31例滤泡性肿瘤，20例滤泡性肿瘤的基因组DNA 癌(FC)和11个滤泡性腺瘤(FA) 利用微卫星聚合酶链式反应进行基因杂合性分析 所有的染色体臂。尽管FC有一种趋势是展示 在某些染色体臂上有比FA更高的LOH百分比， PA中的LOH在统计学上没有显著差异。 然而，当我们更仔细地检查滤泡性肿瘤时，我们 发现Hurthle细胞与 滤泡癌的变异型和滤泡的Hurthle细胞型 腺瘤。因此，我们进一步调查发现，赫斯勒 细胞癌(RC)有明显更大的染色体异常 而染色体a=Iq和2p上的Hurthle细胞腺瘤(HA)和所有 Hurthle细胞肿瘤(HN)有更高的频率 与正常甲状腺相比，染色体臂LP的改变。 为了进一步评估这些基因改变的作用 在Hurthle细胞肿瘤发生中，我们检查了染色体臂Lp、IQ和 在19HC和32KA中为2p。超过15个位于CA-Repeat两侧的引物 每条染色体臂上的区域都被放射性标记。DNA是聚合酶链式反应- 用放射性标记的引物进行扩增，扩增产物 用6%变性尿素-聚丙烯酰胺凝胶电泳法分离。 如果一个等位基因的信号强度在 提供信息的病例在肿瘤DNA中至少减少了50% 与相应的正常DNA进行比较；等位基因的增加如果 还注意到了更多的乐队。等位基因改变的差异是 根据费舍尔精确检验(p&lt；0.05)，HC显著大于HA 6个1p基因座：D1S224、D1S207)(智商：D1SI660)(2p：D2S1240、D2S1788、D2S1394)。 这些结果有力地支持了甲状腺肿瘤进展模型和 染色体臂Lp、Lq和2p与Hurthle的肿瘤发生有关 细胞肿瘤。需要对这些区域进行其他映射，以 进一步阐明潜在的分子遗传机制 负责任。 最后，由于滤泡性肿瘤的鉴别诊断 仍然是一个临床难题，没有解决办法，我们又寻求了另一个 分子市场，也就是端粒酶，来决定它是否 将FA与PC区分开来。11例患者中检测到端粒酶活性 在11例癌中，在23例良性滤泡性腺瘤中有5例，在 22例匹配的正常甲状腺组织。在本系列中，端粒酶分析 其特异度为74%，敏感度为100%。正因为如此 初步数据我们已经建立了一项多机构研究，希望 AT端粒酶活性在卵泡细胞癌鉴别诊断中的价值 肿瘤。最后，由于Hurthle cell的数据前景看好 对于肿瘤，我们计划进一步绘制出具有 Hurthle细胞癌Lp、IQ和2p的异常

We examined genomic DNA from 31 follicular neoplasms, 20 follicular carcinomas (FC) and 11 follicular adenomas (FA) for loss of heterozygosity (LOH) using PCR-based microsatellite polymorphisms for all chromosomal arms. Although there was a tendency for FC to exhibit a greater percent LOH on certain chromosomal arms than the FA, there was no statistically significant difference between LOH seen in PA. However, when we examined more closely the follicular neoplasms we found that there was a significant difference between the Hurthle cell variant of follicular carcinoma and Hurthle cell variant of follicular adenoma. We, therefore, further pursued this and found that Hurthle cell carcinomas (RC) had significantly greater chromosomal abnormalities than Hurthle cell adenomas (HA) on chromosomal a=Iq and 2p and that all Hurthle cell neoplasms (HN) had a significantly greater frequency of alterations on chromosomal arm lp compared to normal thyroid glands. In an attempt to further evaluate the role of these genetic alterations in Hurthle cell tumorigenesis, we examined chromosomal arms lp, Iq and 2p in 19 HC and 32 KA. More than 15 primers that flanked CA-repeat regions on each chromosomal arm were radiolabelled. DNA was PCR- amplified using the radiolabelled primers, and PCR products were separated by electrophoresis on 6% denaturing urea-polyacrylamide gels. Allelic loss was recorded if the signal intensity of one allele in informative cases was at least 50% decreased in the tumor DNA as compared to corresponding normal DNA; allelic gain was considered if additional bands were noted. Differences in allelic alterations were significantly greater in HC than HA by Fisher's exact test (p<0.05) at six loci 1p:D1S224,D1S207)(Iq:D1SI660)(2p:D2S1240,D2S1788,D2S1394). These results strongly support the thyroid tumor progression model and implicate chromosomal arms lp,lq,and 2p in the tumorigenesis of Hurthle cell neoplasms. Additional mapping of these regions is needed to further elucidate the underlying molecular genetic mechanisms responsible. Finally, because the differential diagnosis of follicular neoplasms still posed a clinical dilemma without solution, we pursued another molecular market, namely telomerase, to determine whether or not it would distinguish FA from PC. Telomerase activity was detected in 11 of 11 carcinomas, in 5 of 23 benign follicular adenomas and in none of 22 matched normal thyroid tissues. In this series the telomerase assay had a specificity of 74% and a sensitivity of 100%. Because of this preliminary data we have instituted a multi-institutional study looking at telomerase activity in the differential diagnosis of follicular neoplasms. And finally, because of the promising data with Hurthle cell neoplasms, we plan to further map the chromosomal regions that have abnormalities on lp, Iq and 2p in Hurthle cell carcinomas.