p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

Abstract

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.

The impact of microRNA-mediated PI3K/AKT signaling on epithelial-mesenchymal transition and cancer stemness in endometrial cancer

“…Consistent with this, recent molecular researches have shown that dysregulation of the PI3K/AKT signaling was found in all subtypes of EC, and associated with more aggressive disease [17-19]. Therefore, effective blocking of the PI3K/AKT pathway may be therapeutically valuable in the treatment of EC.…”

High-Throughput Mutation Profiling of Primary and Metastatic Endometrial Cancers Identifies KRAS, FGFR2 and PIK3CA to Be Frequently Mutated

“…In endometrial carcinomas, the oncogenes CTNNB1 and tumor suppressor genes PTEN and P53 have also been reported to be frequently mutated [34], [35] but were not included in the present sceen and can therefore not be accounted for. Among the included genes and mutations, we have identified and validated KRAS , PIK3CA and FGFR2 to be the most frequently mutated oncogenes in endometrial cancer.…”

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

“…The ability to identify patients with excellent prognosis who may not require chemotherapy or radiotherapy would conserve resources, but, more importantly, would spare these women from overtreatment and unnecessary toxic side effects. Last, we updated the survival metaanalysis (11) of POLE-mutated endometrial carcinomas to include results from eight different studies (6,(10)(11)(12)(24)(25)(26)(27) including our own results. The overall findings significantly strengthen the growing body of evidence that POLE mutations are highly favorable prognostic markers in endometrial carcinomas, and will change how we manage women with this disease.…”