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Clin Cancer Res DOI:10.1158/1078-0432.CCR-18-0452

Amplification Associates with Aggressive Phenotype but Not Markers of AKT-MTOR Signaling in Endometrial Carcinoma.

Publication TypeJournal Article
Year of Publication2019
AuthorsHolst, F, Werner, HMJ, Mjøs, iv, S, Hoivik, EA, Kusonmano, K, Wik, E, Berg, A, Birkeland, E, Gibson, WJ, Halle, MK, Trovik, J, Cherniack, AD, Kalland, K-H, Mills, GB, Singer, CF, Krakstad, C, Beroukhim, R, Salvesen, HB
JournalClin Cancer Res
Volume25
Issue1
Pages334-345
Date Published2019 Jan 01
ISSN1557-3265
KeywordsAged, Biomarkers, Tumor, Class I Phosphatidylinositol 3-Kinases, Disease-Free Survival, DNA Copy Number Variations, Endometrial Neoplasms, Female, Gene Amplification, Gene Expression Regulation, Neoplastic, Humans, Middle Aged, Mutation, Neoplasm Metastasis, Phenotype, Prognosis, Proto-Oncogene Proteins c-akt, RNA, Messenger, Signal Transduction, TOR Serine-Threonine Kinases
Abstract

PURPOSE: Amplification of , encoding the PI3K catalytic subunit alpha, is common in uterine corpus endometrial carcinoma (UCEC) and linked to an aggressive phenotype. However, it is unclear whether amplification acts via PI3K activation. We investigated the association between amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens.EXPERIMENTAL DESIGN: UCECs from 591 clinically annotated patients including 83 tumors with matching metastasis ( = 188) were analyzed by FISH to determine copy-number status. These data were integrated with mRNA and protein expression and clinicopathologic data. Results were verified in The Cancer Genome Atlas dataset.RESULTS: amplifications were associated with disease-specific mortality and with other markers of aggressive disease. amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)-high subgroup of UCEC. Tumors with amplification also demonstrated an increase in phospho-p70S6K but had decreased levels of activated phospho-AKT1-3 as assessed by Reverse Phase Protein Arrays and an mRNA signature of MTOR inhibition.CONCLUSIONS: amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although amplification associates with some surrogate measures of increased PI3K activity, markers for AKT1-3 and MTOR signaling are decreased, suggesting that this signaling is not a predominant pathway to promote cancer growth of aggressive serous-like UCEC. Moreover, these associations may reflect features of the SCNA-high subgroup of UCEC rather than effects of amplification itself.

DOI10.1158/1078-0432.CCR-18-0452
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/30442683?dopt=Abstract

Alternate JournalClin Cancer Res
PubMed ID30442683
PubMed Central IDPMC6384094
Grant ListP50 CA098258 / CA / NCI NIH HHS / United States
R01 CA188228 / CA / NCI NIH HHS / United States