Mutations and gene amplifications in Endometrial Carcinomas. “Clinical characteristics and potential targets for therapy related to KRAS, MYC, ATAD2, PIK3CA and FGFR2 alterations”
Doctoral thesis, Peer reviewed
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Background: Incidence of endometrial cancer is increasing in industrialised countries. Despite early diagnosis and generally good prognosis, around one fourth of cases follow an aggressive path with few effective treatment alternatives in a systemic disease setting. Key clinical challenges today are to (1) improve the identification of these patients with high risk for developing systemic disease to individualize surgery and conventional adjuvant treatment; (2) identify targets for new treatment strategies in the systemic setting. Main objectives: The main objective was to explore the potential of mutations and gene copy number alteration as biomarkers in endometrial carcinomas and to relate these genetic alterations to changes in transcriptional signatures and link to clinical phenotype. The goal was to improve the understanding of molecular changes identified by a distinct biomarker to promote clinical implementation of prognostic biomarkers and further exploration of potential predictive biomarkers in clinical trials. Materials and methods: To explore the role of KRAS (paper I) the most frequently genes included in 8q24 amplifications (paper III) in endometrial cancer, we analysed the relation between copy number variations and gene expression using FISH, SNP-arrays, q-PCR and microarrays. We also performed a high-throughput mutation profiling using mass-spectrometric genotyping of 28 known oncogenes (paper II). In total primary tumour samples from 464 patients and 61 metastatic lesions were included in the various analysis. Results: Amplification and gain of KRAS present in 3% and 18% of metastatic lesions was significantly related to poor prognosis (paper I). ATAD2 expression was most associated with the 8q24 amplification, and related to poor prognosis in MYC dependent endometrial cancers (paper III). FGFR2, KRAS and PIK3CA were the most frequently mutated oncogenes in primary tumours, and metastatic lesions. Conclusions: KRAS amplifications increasing from primary to metastatic lesions are relevant for endometrial cancer progression (paper I). High ATAD2 expression is indicative of poor prognosis and is suggested treated by HDAC inhibitors (paper III). FGFR2, KRAS and PIK3CA are frequent in endometrial cancer, with a potential for development of novel therapeutic strategies (paper III).
Består avPaper I: Even Birkeland, Elisabeth Wik, Siv Mjøs, Erling A. Hoivik, Jone Trovik, Henrica M.J Werner, Kanthida Kusonmano, Kjell Petersen, Maria B. Raeder, Frederik Holst, Anne Margrete Oyan, Karl-Henning Kalland, Lars A. Akslen, Ronald Simon, Camilla Krakstad,Helga B. Salvesen (2012). KRAS gene amplification and overexpression but not mutation associates with aggressive and metastatic endometrial cancer. British Journal of Cancer, 2012 Dec 4;107(12):1997-2004. The article is available at: http://hdl.handle.net/1956/7671
Paper II: Camilla Krakstad, Even Birkeland, Danila Seidel, Kanthida Kusonmano, Kjell Petersen, Siv Mjøs, Erling A. Hoivik, Mari Kyllesø Halle, Anne M. Øyan, Karl Henning Kalland, Jone Trovik, Henrica Maria Johanna Werner, and Helga Salvesen (2013). High-throughput mutation profiling of primary and metastatic endometrial cancers identifies KRAS, FGFR2 and PIK3CA to be frequently mutated. PLoS ONE 2012;7(12):e52795. The article is available at: http://hdl.handle.net/1956/6521
Paper III: Maria B. Raeder, Even Birkeland, Jone Trovik, Camilla Krakstad, Shyemaa Shehata, Steven Schumacher, Travis I. Zack, Antje Krohn, Henrica M.J Werner, Susan E. Moody, Elisabeth Wik, Ingunn M. Stefansson, Frederik Holst, Anne Marie Oyan, Pablo Tamayo, Jill P. Mesirov, Karl Henning Kalland, Lars A Akslen, Ronald Simon, Rameen Beroukhim, and Helga B. Salvesen (2013). Integrated genomic analysis of the 8q24 amplification in endometrial cancers identifies ATAD2 as essential to MYC-dependent cancers. PLoS ONE 2013;8(2):e54873. The article is available at: http://hdl.handle.net/1956/7672