Title: Somatic mutations and copy number alterations as prognostic markers for primary endometrial cancer
Other Titles: Somatische mutaties en copy number veranderingen als prognostische merkers voor primaire endometriumkanker
Authors: García Dios, Diego Andrés
Issue Date: 26-Jun-2013
Abstract: During the last decade, the incidence of endometrial cancer has increased and despite the advances in surgery, mortality has not been reduced. Therefore, there is a need to offer better treatment options to these patients. Stratification of high-risk patients is a priority in order to tailor more effective and personalized treatments. The PI3K/AKT/PTEN/mTOR signaling pathway is altered in 80% of all endometrial cancer cases. Different targeted therapies directed towards its components have been introduced in several clinical trials. Despite the use of EGFR, PI3K and/or mTOR inhibitors, these trials did not take into consideration the molecular profiling of the tumors and therefore, the efficiency of the treatments could be misleading.In a first study included in this PhD thesis, we aimed to identify the mutation status of a selection of genes in a large set of primary endometrial tumors. A set of more than 100 hotspot mutations were genotyped in genes potentially acting as prognostic or predictive markers in endometrial cancer. Mutations were correlated with tumor characteristics in a discovery cohort, replicated in independent cohorts and finally, confirmed in the overall population (n=1,117). Centers from Belgium, Norway, Australia and Sweden collaborated in the study. Overall, we concluded that mutations in PIK3CA, TP53, PTEN and FBXW7 correlate, respectively, with high-grade tumors, type II tumors, type I tumors and lymph node invasion. Mutations in functional domains such as exon 20 of PIK3CA are more pathogenic than others in exons 1-7 or 9 and finally, a gene-specific mutation in PIK3CA (H1047R) correlates with faster RFS. These markers might be used for selection of high-risk patients and to predict the benefit of systemic adjuvant chemotherapy in combination with targeted therapies.In a second study, we characterized somatic copy number alterations (CNAs) in a large series of 200 endometrial tumors, including endometrioid and non-endometrioid endometrial cancers. In addition, the mutation status of the PI3K/AKT/PTEN/mTOR signaling pathway was determined in order to combine amplification and deletion data with somatic mutations in genes of interest. This international collaboration included centers from Belgium and Spain. The genome-wide screening of single-nucleotide polymorphisms allowed us to detect 15 amplified and 25 deleted regions. These are candidate regions to harbor novel tumor drivers in endometrial cancer and we demonstrated correlations with adverse clinical variables such as non-endometrioid histology, high-grade tumors, lymph nodes invasion and reduced relapse-free survival (RFS). Reduced RFS due to PTEN haplo-insufficiency and PIK3CA hyperactivation stresses the important role of the PI3K/AKT/PTEN/mTOR signalling pathway in endometrial cancer and patients should be included in future clinical trials according to the mutation and copy number status of the tumors.In a final study, we decided to further investigate mixed endometrial tumors, a specific tumortype observed in 10% of patients diagnosed with endometrial cancer. Here, we investigated a set of 42 endometrial mixed tumors including patients from Belgium, Spain and Czech Republic. We performed a detailed survival analysis as well as genotyping of the PI3K/AKT/PTEN/mTOR pathway in the separate tumor components. Mixed endometrioid and non-endometroid tumors are frequently mutated in KRAS and show a similar relapse pattern as this of EECs. We demonstrated that mixed serous and clear cell carcinomas with or without endometrioid component are high-risk endometrial tumors that relapse fast and more frequently, in a similar way to pure NEECs and show recurrent mutations in PIK3CA and FBXW7. Molecular profiling suggests that mutations PIK3CA are more frequent in mixed tumors and that these events correlate with lymph nodes invasion. After a thorough separation and genotyped of each tumor component, we determined that 66.7% of mixed tumors evolve from a common lesion, whereas 25.9% have a different clonal pattern suggesting either polyclonal origin or divergent genotype heterogeneity.In conclusion, several markers of bad prognosis for endometrial cancer patients were elucidated in this work. Mutations in PIK3CA, TP53, PTEN and FBXW7 were shown to correlate with high-grade tumors, type II tumors, type I tumors and lymph node invasion, whereas the specific mutation H1047R in PIK3CA serves as prognostic markers for relapse-free survival in EC patients. CNAs are a common event in EC and frequently amplified or deleted chromosomal regions are susceptible of harboring novel candidate cancer-related genes. Haplo-insufficiency of TSGs such as PTEN by mutation or deletion and hyperactivation of oncogenes such as PIK3CA through mutation or amplification were detected in patients with reduced RFS. In mixed endometrial turmors, mutations in PIK3CA are a frequent event, even more than in pure EECs or NEECs and correlate with lymph nodes invasion, whereas mutations in KRAS could define the group of endometrioid plus non-endometrioid mixed tumors that show better outcome. Finally, it is shown that 66.7% of mixed tumors have a common origin and 25.9% have a policlonal origin, this should be taken into account when targeted therapies are tailored towards different mixed tumors.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Gynaecological Oncology
Laboratory of Translational Genetics (Vesalius Research Center) (+)

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