Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
EMBO Mol Med. 2012 Aug;4(8):808-24. doi: 10.1002/emmm.201101063. Epub 2012 Jun 8.
Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours.
II 型子宫内膜癌是一组侵袭性很强的肿瘤亚型，通常与 TP53 肿瘤抑制基因失活有关。我们发现，子宫内膜特异性缺失 Trp53 的小鼠最初表现出与人类 II 型子宫内膜癌已知前体病变完全相同的组织学变化，随后发展为代表所有 II 型亚型的癌。这些前体病变和肿瘤中经常激活 mTORC1 信号通路，提示该通路与肿瘤起始时 Trp53 缺失存在遗传合作。与这一观点一致，对 521 例人类子宫内膜癌的分析表明，I 型和 II 型子宫内膜癌亚型中经常激活 mTORC1 通路。mTORC1 通路激活和 p53 表达或突变状态均可独立预测患者预后不良。我们认为，p53 和 mTORC1 通路中的分子改变在不同子宫内膜癌亚型的起始中发挥不同的作用，但联合的 p53 失活和 mTORC1 通路激活是组织学不同的晚期侵袭性子宫内膜肿瘤亚型的统一致病特征。
