title: Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation.
abstract: Although 75% of endometrial cancers are treated at an early stage, 15% to 20% of these recur. We performed an integrated analysis of genome-wide expression and copy-number data for primary endometrial carcinomas with extensive clinical and histopathological data to detect features predictive of recurrent disease. Unsupervised analysis of the expression data distinguished 2 major clusters with strikingly different phenotypes, including significant differences in disease-free survival. To identify possible mechanisms for these differences, we performed a global genomic survey of amplifications, deletions, and loss of heterozygosity, which identified 11 significantly amplified and 13 significantly deleted regions. Amplifications of 3q26.32 harboring the oncogene PIK3CA were associated with poor prognosis and segregated with the aggressive transcriptional cluster. Moreover, samples with PIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase (PI3K), a signature that was shared by aggressive tumors without PIK3CA amplification. Tumors with loss of PTEN expression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3K activation signature, high protein expression of the PI3K pathway member STMN1, and an aggressive phenotype in test and validation datasets. However, mutations of PTEN or PIK3CA were not associated with the same expression profile or aggressive phenotype. STMN1 expression had independent prognostic value. The results affirm the utility of systematic characterization of the cancer genome in clinically annotated specimens and suggest the particular importance of the PI3K pathway in patients who have aggressive endometrial cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: H B
authors.initials: HB
authors.lastname: Salvesen
authors.forename: S L
authors.initials: SL
authors.lastname: Carter
authors.forename: M
authors.initials: M
authors.lastname: Mannelqvist
authors.forename: A
authors.initials: A
authors.lastname: Dutt
authors.forename: G
authors.initials: G
authors.lastname: Getz
authors.forename: I M
authors.initials: IM
authors.lastname: Stefansson
authors.forename: M B
authors.initials: MB
authors.lastname: Raeder
authors.forename: M L
authors.initials: ML
authors.lastname: Sos
authors.forename: I B
authors.initials: IB
authors.lastname: Engelsen
authors.forename: J
authors.initials: J
authors.lastname: Trovik
authors.forename: E
authors.initials: E
authors.lastname: Wik
authors.forename: H
authors.initials: H
authors.lastname: Greulich
authors.forename: T H
authors.initials: TH
authors.lastname: Bø
authors.forename: I
authors.initials: I
authors.lastname: Jonassen
authors.forename: R K
authors.initials: RK
authors.lastname: Thomas
authors.forename: T
authors.initials: T
authors.lastname: Zander
authors.forename: L A
authors.initials: LA
authors.lastname: Garraway
authors.forename: A M
authors.initials: AM
authors.lastname: Oyan
authors.forename: W R
authors.initials: WR
authors.lastname: Sellers
authors.forename: K H
authors.initials: KH
authors.lastname: Kalland
authors.forename: M
authors.initials: M
authors.lastname: Meyerson
authors.forename: L A
authors.initials: LA
authors.lastname: Akslen
authors.forename: R
authors.initials: R
authors.lastname: Beroukhim
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D016000:Cluster Analysis; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D050777:Stathmin / Q000378:metabolism; D016019:Survival Analysis; D018631:ras Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C493995:STMN1 protein, human; D050777:Stathmin; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins