Gaidano G, Pastore C, Santini V, Nomdedeu J, Gamberi B, Capello D, Vischia F, Resegotti L, Mazza U, Ferrini P R, Lo Coco F, Saglio G
Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Torino, Ospedale San Luigi, Orbassano, Italy.
Genes Chromosomes Cancer. 1997 Aug;19(4):250-5.
Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative disorders that may progress to acute leukemia in a subset of patients. This study aimed at investigating the genetic lesions associated with the blastic transformation of PV and ET. A panel of PV and ET cases at different stages of disease was analyzed for the presence of genetic alterations of TP53, NRAS, KRAS, and MDM2 by a combination of mutational analysis and Southern blot hybridization. The occurrence of microsatellite instability (MSI) was also tasted in selected cases. Samples of PV and ET analyzed in chronic phase disease were consistently devoid of all genetic lesions tested, suggesting that alterations of TP53, NRAS, KRAS, and MDM2 do not contribute significantly to development of chronic phase PV and ET. Conversely, mutations of TP53 were detected in 7/15 (46.6%) blastic phase cases, including 3/5 PV and 4/10 ET. In blastic phase patients for whom the corresponding chronic phase DNA was also available, it could be documented that the genetic lesion had arisen at the time of blastic transformation. In addition to TP53 mutations, cases of blastic phase PV and ET occasionally harbored mutations of NRAS (one case of blastic phase ET) or displayed MSI (one case of blastic phase PV). These data indicate that inactivation of TP53 is a relatively frequent event associated with the blastic transformation of PV and ET and may be responsible for the tumor progression of these disorders.
真性红细胞增多症（PV）和原发性血小板增多症（ET）是慢性骨髓增殖性疾病，部分患者可能会进展为急性白血病。本研究旨在调查与PV和ET急变相关的基因损伤。通过突变分析和Southern印迹杂交相结合的方法，对一组处于疾病不同阶段的PV和ET病例进行分析，以检测TP53、NRAS、KRAS和MDM2的基因改变情况。还对部分病例检测了微卫星不稳定性（MSI）的发生情况。对处于慢性期疾病的PV和ET样本进行分析，结果显示始终未检测到所有测试的基因损伤，这表明TP53、NRAS、KRAS和MDM2的改变对慢性期PV和ET的发展没有显著影响。相反，在15例急变期病例中有7例（46.6%）检测到TP53突变，其中包括3例PV和4例ET。对于那些也有相应慢性期DNA样本的急变期患者，可以证明基因损伤是在急变时出现的。除了TP53突变外，急变期PV和ET病例偶尔还存在NRAS突变（1例急变期ET）或显示微卫星不稳定性（1例急变期PV）。这些数据表明，TP53失活是与PV和ET急变相关的相对常见事件，可能是这些疾病肿瘤进展的原因。
