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Proc Natl Acad Sci U S A DOI:10.1073/pnas.0806514106

Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation.

Publication TypeJournal Article
Year of Publication2009
AuthorsSalvesen, HB, Carter, SL, Mannelqvist, M, Dutt, A, Getz, G, Stefansson, IM, Raeder, MB, Sos, ML, Engelsen, IB, Trovik, J, Wik, E, Greulich, H, Bø, TH, Jonassen, I, Thomas, RK, Zander, T, Garraway, LA, Oyan, AM, Sellers, WR, Kalland, KH, Meyerson, M, Akslen, LA, Beroukhim, R
JournalProc Natl Acad Sci U S A
Volume106
Issue12
Pages4834-9
Date Published2009 Mar 24
ISSN1091-6490
KeywordsBiomarkers, Tumor, Cluster Analysis, Endometrial Neoplasms, Enzyme Activation, Female, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, Loss of Heterozygosity, Phosphatidylinositol 3-Kinases, Prognosis, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), ras Proteins, Stathmin, Survival Analysis
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.

URLhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=19261849
DOI10.1073/pnas.0806514106
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/19261849?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID19261849
PubMed Central IDPMC2660768
Grant ListK08 CA122833 / CA / NCI NIH HHS / United States
K08CA122833 / CA / NCI NIH HHS / United States