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    Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Nov 15. pii: 1078-0432.CCR-18-0452. doi: 10.1158/1078-0432.CCR-18-0452
    Amplification Associates with Aggressive Phenotype but Not Markers of AKT-MTOR Signaling in Endometrial Carcinoma.
    Holst F1,  Werner HMJ2,  Mjøs S3,  Hoivik EA4,  Kusonmano K5,  Wik E6,  Berg A7,  Birkeland E8,  Gibson WJ9,  Halle MK10,  Trovik J11,  Cherniack AD12,  Kalland KH13,  Mills GB14,  Singer CF15,  Krakstad C16,  Beroukhim R17,  Salvesen HB18
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    Abstract

    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. 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. 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. 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.


    ©2018 American Association for Cancer Research.

    Publikations ID: 30442683
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