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

// Anna Berg 1,2 , Erling A. Hoivik 1,2 , Siv Mjøs 1,2 , Frederik Holst 1,2 , Henrica M. J. Werner 1,2 , Ingvild L. Tangen 1,2 , Amaro Taylor-Weiner 7,8,9 , William J. Gibson 7,8,9 , Kanthida Kusonmano 1,2,3 , Elisabeth Wik 4,5 , Jone Trovik 1,2 , Mari K. Halle 1,2 , Anne M. Øyan 1,6 , Karl-Henning Kalland 1,6 , Andrew D. Cherniack 7 , Rameen Beroukhim 7,8,9 , Ingunn Stefansson 4,5 , Gordon B. Mills 10 , Camilla Krakstad 1,2 and Helga B. Salvesen 1,2* 1 Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway 2 Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway 3 Computational Biology Unit, University of Bergen, Norway 4 Department of Pathology, Haukeland University Hospital, Norway 5 Department of Clinical Medicine, Center for Cancer Biomarkers, University of Bergen, Norway 6 Department of Microbiology, Haukeland University Hospital, Norway 7 The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America 8 Department of Cancer Biology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America 9 Harvard Medical School, Boston, Massachusetts, United States of America 10 Department of Systems Biology, MD Anderson Cancer Center, Houston Texas Correspondence: Helga B. Salvesen, email: // Keywords : endometrial carcinoma, endometrial hyperplasia, metastasis, body mass index, PI3Kinase Received : August 20, 2014 Accepted : November 04, 2014 Published : November 04, 2014 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 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.