Rodrigues Raquel, Roque Lúcia, Espadinha Carla, Pinto António, Domingues Rita, Dinis Joana, Catarino Ana, Pereira Teresa, Leite Valeriano
Cytogenetic Laboratory, CIPM, Portuguese Cancer Institute, 1099-023 Lisbon, Portugal.
Oncol Rep. 2007 Oct;18(4):917-26.
Aneuploidy in papillary thyroid carcinomas (PTCs) is considered a marker of worse prognosis. Multiple genetic surveys have been performed in PTCs, however, we are not aware of any such studies in aneuploid PTCs. In order to contribute to a better comprehension of the genetic basis of this neoplasm's more aggressive behaviour in 17 aneuploid PTCs we performed a comparative genomic hybridization (CGH) analysis, studied the BRAF and RAS mutational status, searched for RET/PTC1 and RET/PTC3 rearrangements and determined their expression profile. Array results were validated by TaqMan and immunohistochemistry. CGH revealed multiple non-random chromosomal abnormalities. BRAFV600E and RAS mutations were found in 41.2% and 33% of the carcinomas respectively. None of the studied cases presented RET/PTC1 or RET/PTC3 rearrangement. When comparing array data with the chromosomal, mutational and clinical data we found that: a) loss of control of cellular transcription was of major relevance in this group of neoplasms, HMGA2 being one of the most overexpressed genes; b) gene expression correlated with the mutational status of PTCs, as in BRAF+ cases cMET and FN1 were concomitantly overexpressed; and c) death from disease and distant metastasis was associated to the overexpression of DDR2 and to the down-regulation of genes involved in immune, inflammatory response, signal transduction and cell adhesion processes. In conclusion we have identified in aneuploid PTCs a group of significantly altered molecules that may represent preferential targets for the development of new more efficient therapies in this type of cancer.
甲状腺乳头状癌（PTC）中的非整倍体被认为是预后较差的一个标志。此前已对PTC进行了多项基因调查，然而，我们尚未知晓有任何针对非整倍体PTC的此类研究。为了更好地理解这种肿瘤更具侵袭性的行为的遗传基础，我们对17例非整倍体PTC进行了比较基因组杂交（CGH）分析，研究了BRAF和RAS的突变状态，查找RET/PTC1和RET/PTC3重排情况，并确定了它们的表达谱。通过TaqMan和免疫组织化学对芯片结果进行了验证。CGH揭示了多个非随机的染色体异常。BRAFV600E和RAS突变分别在41.2%和33%的癌组织中被发现。所研究的病例均未出现RET/PTC1或RET/PTC3重排。当将芯片数据与染色体、突变及临床数据进行比较时，我们发现：a）细胞转录调控失控在这组肿瘤中具有重要意义，HMGA2是过度表达最明显的基因之一；b）基因表达与PTC的突变状态相关，如在BRAF+病例中，cMET和FN1同时过度表达；c）疾病死亡和远处转移与DDR2的过度表达以及参与免疫、炎症反应、信号转导和细胞黏附过程的基因下调有关。总之，我们在非整倍体PTC中鉴定出了一组显著改变的分子，它们可能是开发针对这类癌症更有效新疗法的优先靶点。
