Trovato M, Fraggetta F, Villari D, Batolo D, Mackey K, Trimarchi F, Benvenga S
Dipartimento di Patologia Umana, Policlinico Universitario, Messina, Italy.
J Clin Endocrinol Metab. 1999 Sep;84(9):3235-40. doi: 10.1210/jcem.84.9.5986.
Papillary thyroid cancer (PTC), but neither the follicular nor the anaplastic histotype [follicular thyroid cancer (FTC), anaplastic thyroid cancer (ATC)], overexpresses simultaneously the protooncogene HGF (hepatocyte growth factor) and its receptor HGF-R (or c-met). Because 1) HGF and c-met map to chromosome 7q21 and 7q31, respectively, 2) FTC loses genetic material at multiple loci with a frequency much higher than PTC, and 3) loss of heterozygosity (LOH) on 7q has been previously found in various tumors, we tested the hypothesis that both FTC and ATC, but not PTC, could harbor LOH in segments of 7q encompassing the loci for HGF and c-met. We screened 6 normal thyroids, 10 colloid nodules, 10 follicular hyperplasias, 10 oncocytic adenomas, 10 follicular adenomas (FA), 10 FTC, 6 ATC, 12 PTC using two microsatellite markers for HGF, and two for c-met. LOH for all 4 markers was found in 100% of FTC, 100% of ATC, and (for only 1 or 2 markers) in 10-29% of FA. This is the first demonstration of an LOH that separates both FTC and ATC from PTC, in the best possible manner: 100% vs. 0%. Clearly, each of the two segments we have probed contains at least one tumor suppressor gene, whose inactivation is crucial for the establishment of the FTC (and ATC) phenotype. This loss of genetic material explains why FTC and ATC, but not PTC, fail to express both HGF and c-met. Our findings may also have immediate diagnostic application, in the context of assisting pathologists in the often difficult task of distinguishing FA from FTC.
甲状腺乳头状癌（PTC），而非滤泡状或间变性组织学类型[滤泡状甲状腺癌（FTC）、间变性甲状腺癌（ATC）]，不会同时过表达原癌基因HGF（肝细胞生长因子）及其受体HGF-R（或c-met）。由于1）HGF和c-met分别定位于7号染色体的7q21和7q31；2）FTC在多个位点丢失遗传物质的频率远高于PTC；3）先前在各种肿瘤中已发现7号染色体上的杂合性缺失（LOH），我们检验了这样一个假设，即FTC和ATC而非PTC，可能在7号染色体上包含HGF和c-met基因座的片段中存在LOH。我们使用两个针对HGF的微卫星标记和两个针对c-met的微卫星标记，对6个正常甲状腺组织、10个胶样结节、10个滤泡增生组织、10个嗜酸细胞腺瘤、10个滤泡性腺瘤（FA）、10个FTC、6个ATC、12个PTC进行了筛查。在100%的FTC、100%的ATC以及（仅针对1个或2个标记）10%-29%的FA中发现了所有4个标记的LOH。这是以最佳方式首次证明将FTC和ATC与PTC区分开来的LOH：100%对0%。显然，我们所探测的两个片段中的每一个都至少包含一个肿瘤抑制基因，其失活对于FTC（和ATC）表型的建立至关重要。这种遗传物质的丢失解释了为什么FTC和ATC而非PTC不能同时表达HGF和c-met。我们的发现可能在协助病理学家完成区分FA与FTC这一通常困难的任务方面，具有直接的诊断应用价值。
