Restricted 12p amplification and RAS mutation in human germ cell tumors of the adult testis
Restricted 12p amplification and RAS mutation in human germ cell tumors of the adult testis
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DOI：
10.1016/s0002-9440(10)64631-7
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发表时间：
2000-10-01
影响因子：
6
通讯作者：
Looijenga, LHJ
中科院分区：
文献类型：
--
作者：
Roelofs, H;Mostert, MC;Looijenga, LHJ
青年人睾丸生殖细胞瘤（tgct），包括精原细胞瘤和非精原细胞瘤，均以12p过代表为特征，多数为同染色体，其生物学和临床意义尚不清楚。有限数量的tgct已被鉴定为12p受限区域的额外高水平扩增，包括K-RAS原癌基因。在这里，我们发现这些限制性12p扩增的发生率在原代tgct中类似于8%，在单个细胞形成中，i（12p）和限制性12p扩增是相互排斥的。扩增子的边缘聚集在短区域内，在邻近的原位癌细胞中从未发现过扩增子。12p扩增受限的精原细胞瘤几乎没有凋亡，肿瘤细胞与RAS基因突变的精原细胞瘤细胞一样，在体外存活时间延长。然而，不同精原细胞瘤组间的增殖指数没有差异。尽管含有同质限制性12p扩增的精原细胞瘤患者的年龄明显低于缺乏该扩增的患者，但限制性12p扩增/RAS突变的存在并不能预测临床表现时的疾病阶段和原发性精原细胞瘤的治疗反应，在来自44名失败的顺铂化疗患者的55例原发性和转移性肿瘤中，限制性12p扩增和RAS突变的发生率与连续的应答患者相同。这些数据支持tgct中12p的增加与侵袭性生长有关的模型。它允许肿瘤细胞，特别是那些表现出早期生殖细胞特征的细胞（精原细胞），在其特定的微环境外存活，12p上某些基因的过度表达可能会抑制这些肿瘤细胞的凋亡。然而，12p和K-RAS突变有限扩增的拷贝数并不能预测对治疗的反应和患者的生存。
Human testicular germ-cell tumors of young adults (TGCTs), both seminomas and nonseminomas, are characterized by 12p overrepresentation, mostly as isochromosomes, of which the biological and clinical significance is still unclear. A limited number of TGCTs has been identified with an additional high-level amplification of a restricted region of 12p including the K-RAS proto-oncogene. Here we show that the incidence of these restricted 12p amplifications is similar to 8% in primary TGCTs, Within a single cell formation of i(12p) and restricted 12p amplification is mutually exclusive. The borders of the amplicons cluster in short regions, and the amplicon was never found in the adjacent carcinoma in situ cells. Seminomas with the restricted 12p amplification virtually lacked apoptosis and the tumor cells showed prolonged in vitro survival like seminoma cells with a mutated RAS gene. However, no differences in proliferation index between these different groups of seminomas were found. Although patients with a seminoma containing a homogeneous restricted 12p amplification presented at a significantly younger age than those lacking it, the presence of a restricted 12p amplification/RAS mutation did not predict the stage of the disease at clinical presentation and the treatment response of primary seminomas, In 55 primary and metastatic tumors from 44 different patients who failed cisplatinum-based chemotherapy, the restricted 12p amplification and RAS mutations had the same incidence as in the consecutive series of responding patients. These data support the model that gain of 12p in TGCTs is related to invasive growth. It allows tumor cells, in particular those showing characteristics of early germ cells tie, the seminoma cells), to survive outside their specific microenvironment, Overexpression of certain genes on 12p probably inhibits apoptosis in these tumor cells. However, the copy numbers of the restricted amplification of 12p and K-RAS mutations do not predict response to therapy and survival of the patients.