title: PTEN loss is a context-dependent outcome determinant in obese and non-obese endometrioid endometrial cancer patients.
abstract: Endometrial cancer incidence is increasing, due in part to a strong association with obesity. Mutations in the phosphatidylinositol 3-kinase (PI3K) pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid adenocarcinomas, the most common form of endometrial cancer. We sought to determine the impact of PI3K pathway alterations on progression free survival in a cohort of endometrioid endometrial cancers. Prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss by immunohistochemistry, was explored in the context of patient body mass index. Reverse-phase protein arrays were utilized to assess protein expression based on PTEN status. Among 187 endometrioid endometrial cancers, there were no statistically significant associations between PFS and PIK3CA, PIK3R1, PTEN mutation or loss. When stratified by body mass index, PTEN loss was associated with improved progression free survival (P < 0.006) in obese (body mass index ≥ 30) patients. PTEN loss resulted in distinct protein changes: Canonical PI3K pathway activation was observed only in the non-obese population while decreased expression of β-CATENIN and phosphorylated FOXO3A was observed in obese patients. These data suggest the impact of PTEN loss on tumor biology and clinical outcomes must be interpreted in the context of body mass index, and provide a potential explanation for discrepant reports on the effect of PTEN status and obesity on prognosis in endometrial cancer. This reveals a clinically important interaction between metabolic state and tumor genetics that may unveil the biologic underpinning of obesity-related cancers and impact ongoing clinical trials with PI3K pathway inhibitors.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. Electronic address: swestin@mdanderson.org.
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Westin
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Ju
authors.affiliation: Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Krakstad
authors.affiliation: Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Navdeep
authors.initials: N
authors.lastname: Pal
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.affiliation: Beaumont Hospital and Royal College of Surgeons of Ireland, Dublin, Ireland.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
authors.affiliation: Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Klempner
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Henrica M J
authors.initials: HM
authors.lastname: Werner
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.affiliation: Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Myers
mesh_terms: D015992:Body Mass Index; D018269:Carcinoma, Endometrioid / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D015536:Down-Regulation / Q000235:genetics; D016889:Endometrial Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056865:Ideal Body Weight; D007150:Immunohistochemistry; D009765:Obesity / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Endometrial cancer; Obesity; PI3K/AKT pathway; PTEN loss; Survival