Purpose: We hypothesized that estrogen receptor-a (ER-a) status in endometrial carcinomas, associated with poor prognosis, is reflected in transcriptional signatures suggesting targets for new therapy.Experimental Design: Endometrial carcinoma samples in a primary investigation cohort (n ¼ 76) and three independent validation cohorts (n ¼ 155/286/111) were analyzed through integrated molecular profiling. Biomarkers were assessed by immunohistochemistry (IHC), DNA oligonucleotide microarray, quantitative PCR (qPCR), single-nucleotide polymorphism (SNP) array, and Sanger sequencing in the cohorts, annotated for comprehensive histopathologic and clinical data, including follow-up.Results: ER-a immunohistochemical staining was strongly associated with mRNA expression of the receptor gene (ESR1) and patient survival (both P < 0.001). ER-a negativity associated with activation of genes involved in Wnt-, Sonic Hedgehog-, and TGF-b signaling in the investigation cohort, indicating epithelial-mesenchymal transition (EMT). The association between low ER-a and EMT was validated in three independent datasets. Furthermore, phosphoinositide 3-kinase (PI3K) and mTOR inhibitors were among the top-ranked drug signatures negatively correlated with the ER-a-negative tumors. Low ER-a was significantly associated with PIK3CA amplifications but not mutations. Also, low ER-a was correlated to high expression of Stathmin, a marker associated with PTEN loss, and a high PI3K activation signature.Conclusion: Lack of ER-a in endometrial cancer is associated with EMT and reduced survival. We present a rationale for investigating ER-a's potential to predict response to PI3K/mTOR inhibitors in clinical trials and also suggest EMT inhibitors to ER-a-negative endometrial carcinomas.
Background:Three quarter of endometrial carcinomas are treated at early stage. Still, 15 to 20% of these patients experience recurrence, with little effect from systemic therapies. Homo sapiens v-Ki-ras2 Kirsten rat sarcoma viral oncogenes homologue (KRAS) mutations have been reported to have an important role in tumorigenesis for human cancers, but there is limited knowledge regarding clinical relevance of KRAS status in endometrial carcinomas.Methods:We have performed a comprehensive and integrated characterisation of genome-wide expression related to KRAS mutations and copy-number alterations in primary- and metastatic endometrial carcinoma lesions in relation to clinical and histopathological data. A primary investigation set and clinical validation set was applied, consisting of 414 primary tumours and 61 metastatic lesions totally.Results:Amplification and gain of KRAS present in 3% of the primary lesions and 18% of metastatic lesions correlated significantly with poor outcome, high International Federation of Gynaecology and Obstetrics stage, non-endometrioid subtype, high grade, aneuploidy, receptor loss and high KRAS mRNA levels, also found to be associated with aggressive phenotype. In contrast, KRAS mutations were present in 14.7% of primary lesions with no increase in metastatic lesions, and did not influence outcome, but was significantly associated with endometrioid subtype, low grade and obesity.Conclusion:These results support that KRAS amplification and KRAS mRNA expression, both increasing from primary to metastatic lesions, are relevant for endometrial carcinoma disease progression.
Obesity is linked to increased incidence of endometrioid endometrial cancer (EEC) and complex atypical hyperplasia (CAH). We here explore pattern and sequence of molecular alterations characterizing endometrial carcinogenesis in general and related to body mass index (BMI), to improve diagnostic stratification and treatment strategies. We performed molecular characterization of 729 prospectively collected EEC and CAH. Candidate biomarkers were identified in frozen samples by whole-exome and Sanger sequencing, oligonucleotide gene expression and Reverse Phase Protein Arrays (investigation cohort) and further explored in formalin fixed tissues by immunohistochemistry and Fluorescent in Situ Hybridization (validation cohort). We here demonstrate that PIK3CA mutations, PTEN loss, PI3K and KRAS activation are early events in endometrial carcinogenesis. Molecular changes related to KRAS activation and inflammation are more common in obese CAH patients, suggesting different prevention and systemic treatment strategies in obese and non-obese patients. We also found that oncoprotein Stathmin might improve preoperative diagnostic distinction between premalignant and malignant endometrial lesions.
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