Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients

Anna Berg, Erling A. Hoivik, Siv Mjøs, Frederik Holst, Henrica M.J. Werner, Ingvild L. Tangen, Amaro Taylor-Weiner, William J. Gibson, Kanthida Kusonmano, Elisabeth Wik, Jone Trovik, Mari K. Halle, Anne M. Øyan, Karl Henning Kalland, Andrew D. Cherniack, Rameen Beroukhim, Ingunn Stefansson, Gordon B. Mills, Camilla Krakstad, Helga B. Salvesen

    Research output: Contribution to journalArticle

    39 Scopus citations

    Abstract

    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 wholeexome 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.

    Original languageEnglish (US)
    Pages (from-to)1327-1339
    Number of pages13
    JournalOncotarget
    Volume6
    Issue number2
    DOIs
    StatePublished - 2015

    Keywords

    • Body mass index
    • Endometrial carcinoma
    • Endometrial hyperplasia
    • Metastasis
    • PI3Kinase

    ASJC Scopus subject areas

    • Oncology

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  • Cite this

    Berg, A., Hoivik, E. A., Mjøs, S., Holst, F., Werner, H. M. J., Tangen, I. L., Taylor-Weiner, A., Gibson, W. J., Kusonmano, K., Wik, E., Trovik, J., Halle, M. K., Øyan, A. M., Kalland, K. H., Cherniack, A. D., Beroukhim, R., Stefansson, I., Mills, G. B., Krakstad, C., & Salvesen, H. B. (2015). Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients. Oncotarget, 6(2), 1327-1339. https://doi.org/10.18632/oncotarget.2675