[p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumor aggressiveness in humans]
1Systempathologie und Labor für Hochdurchsatzgenomik, Institut für Klinische Pathologie, Universitätsspital Zürich, Schmelzberstr. 12, 8091, Zürich, Schweiz, peter.wild@usz.ch.
Abstract:
Type II endometrial carcinomas are a highly aggressive group of tumor subtypes that are frequently associated with inactivation of the TP53 tumor suppressor gene. We show that mice with endometrium-specific deletion of the Trp53 gene 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 tumors, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumor 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. The 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 combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumors.
Insights
TP53 tumor suppressor gene inactivation and mTORC1 pathway activation are key drivers in aggressive endometrial cancers. These molecular changes, impacting p53 and mTORC1, predict poor patient survival across subtypes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Type II endometrial carcinomas are aggressive and often linked to TP53 gene inactivation.
- Understanding the molecular drivers of endometrial cancer subtypes is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of Trp53 gene deletion and mTORC1 pathway activation in endometrial tumorigenesis.
- To analyze the combined impact of p53 and mTORC1 alterations on patient survival in endometrial cancer.
Main Methods:
- Utilized a mouse model with endometrium-specific Trp53 gene deletion.
- Examined histological changes, precursor lesions, and tumor development in mice.
- Analyzed mTORC1 pathway activation and p53 status in 521 human endometrial carcinomas.
- Correlated molecular alterations with patient survival data.
Main Results:
- Trp53 deletion in mice recapitulated human type II endometrial carcinoma precursor lesions and led to tumor development.
- mTORC1 pathway activation was common in precursor lesions and tumors, suggesting cooperation with Trp53 deficiency.
- mTORC1 pathway activation was prevalent in both type I and type II endometrial carcinoma subtypes.
- Both mTORC1 pathway activation and p53 status independently predicted poor patient survival.
Conclusions:
- Combined p53 inactivation and mTORC1 pathway activation represent unifying pathogenic features in aggressive, late-stage endometrial tumors.
- p53 and mTORC1 alterations play distinct roles in initiating different endometrial cancer subtypes.
- Targeting the mTORC1 pathway may offer therapeutic strategies for endometrial cancer patients with p53 alterations.
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