Are oncogenes sufficient to cause human cancer?
Are oncogenes sufficient to cause human cancer?
复制标题
致癌基因足以引起人类癌症吗？
DOI：
10.1073/pnas.1015563107
复制
发表时间：
2010
影响因子：
11.1
通讯作者：
Mills,GordonB
中科院分区：
文献类型：
--
作者：
Woodman,ScottE;Mills,GordonB
讨论 先前已在 SK 中鉴定出成纤维细胞生长因子受体 3 (FGFR3) 和磷脂酰肌醇 3 激酶催化亚基 (PIK3CA) 突变 (2, 3)。 Hafner 等人 (1) 对 25 名 SK 患者的 175 个独立 SK 病变中的 FGFR3–RAS–MAPK 和 PI3K–AKT 通路基因热点突变进行了广泛分析。他们在良性肿瘤中显示出高频率的 FGFR3 (71%)、PIK3CA (50%)、KRAS (20%)、EGFR (7%)、HRAS (3%) 和 AKT (2%) 突变 (1)。完整的序列分析可能会发现更高的突变率，这表明大多数（如果不是全部）SK 病变至少有一种，也可能有几种假定的致癌突变。引人注目的是，尽管它们缺乏恶性潜力，但 89% 的 SK 至少有一种突变，45% 的一种已明确表征的癌基因有不止一种突变。在SK中观察到的突变存在于恶性肿瘤中，并且当在转基因小鼠中表达时，足以诱发肿瘤。因此，必须有一种有效的机制来限制 SK 的恶性转化。 FGFR3 和 PIK3CA 中的突变频率与偶然预测的频率大致相同，表明它们不是共同选择的。相比之下，FGFR3 和 KRAS 或 PIK3CA 和 KRAS 中的突变频率低于偶然预测的频率，这表明要么缺乏两种突变发生的选择压力，要么每种突变的后果之间存在负相互作用。
DiscussionFibroblast growth factor receptor 3 (FGFR3) and phosphatidylinositol 3-kinase catalytic subunit (PIK3CA) mutations have been previously identified in SK (2, 3). Hafner et al.(1) perform an extensive analysis of hot spot mutations in genes in the FGFR3–RAS–MAPK and PI3K–AKT pathways in 175 independent SK lesions from 25 SK patients. They showed a high frequency of FGFR3 (71%), PIK3CA (50%), KRAS (20%), EGFR (7%), HRAS (3%), and AKT (2%) mutations in the benign tumors (1). A complete sequence analysis is likely to identify an even higher mutation rate, suggesting that most, if not all, SK lesions have at least one and likely several putative oncogenic mutations. Strikingly, despite their lack of malignant potential, 89% of SK had at least one mutation, and 45% had more than one mutation in a well-characterized oncogene. Mutations observed in SK are present in malignant tumors and when expressed in transgenic mice, are sufficient to induce tumors. Thus, a potent mechanism must constrain malignant conversion in SK. The frequency of comutations in FGFR3 and PIK3CA was approximately that predicted by chance, suggesting that they are not coselected. In contrast, the frequency of comutations in FGFR3 and KRAS or PIK3CA and KRAS was lower than predicted by chance, suggesting either a lack of selective pressure for both mutations to occur or a negative interaction between the consequences of each mutation.