title: Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients.
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.
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Berg
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Erling A
authors.initials: EA
authors.lastname: Hoivik
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Siv
authors.initials: S
authors.lastname: Mjøs
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Frederik
authors.initials: F
authors.lastname: Holst
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Henrica M J
authors.initials: HM
authors.lastname: Werner
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Ingvild L
authors.initials: IL
authors.lastname: Tangen
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Department of Cancer Biology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Department of Cancer Biology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Gibson
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.|Computational Biology Unit, University of Bergen, Norway.
authors.forename: Kanthida
authors.initials: K
authors.lastname: Kusonmano
authors.affiliation: Department of Pathology, Haukeland University Hospital, Norway.|Department of Clinical Medicine, Center for Cancer Biomarkers, University of Bergen, Norway.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wik
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Jone
authors.initials: J
authors.lastname: Trovik
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Mari K
authors.initials: MK
authors.lastname: Halle
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Microbiology, Haukeland University Hospital, Norway.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Øyan
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Microbiology, Haukeland University Hospital, Norway.
authors.forename: Karl-Henning
authors.initials: KH
authors.lastname: Kalland
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cherniack
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Department of Cancer Biology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Department of Pathology, Haukeland University Hospital, Norway.|Department of Clinical Medicine, Center for Cancer Biomarkers, University of Bergen, Norway.
authors.forename: Ingunn
authors.initials: I
authors.lastname: Stefansson
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Krakstad
authors.affiliation: Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.|Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015992:Body Mass Index; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D059472:Exome / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation; D009362:Neoplasm Metastasis; D009765:Obesity / Q000150:complications*; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins