Dataset Information

PIK3CA Amplification Associates with Aggressive Phenotype but Not Markers of AKT-MTOR Signaling in Endometrial Carcinoma.

ABSTRACT: PURPOSE:Amplification of PIK3CA, 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 PIK3CA amplification acts via PI3K activation. We investigated the association between PIK3CA 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 (n = 188) were analyzed by FISH to determine PIK3CA 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:PIK3CA amplifications were associated with disease-specific mortality and with other markers of aggressive disease. PIK3CA amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)-high subgroup of UCEC. Tumors with PIK3CA 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:PIK3CA amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although PIK3CA 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 PIK3CA amplification itself.

SUBMITTER: Holst F

PROVIDER: S-EPMC6384094 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

<i>PIK3CA</i> Amplification Associates with Aggressive Phenotype but Not Markers of AKT-MTOR Signaling in Endometrial Carcinoma.

Holst Frederik F Werner Henrica M J HMJ Mjøs Siv S Hoivik Erling A EA Kusonmano Kanthida K Wik Elisabeth E Berg Anna A Birkeland Even E Gibson William J WJ Halle Mari K MK Trovik Jone J Cherniack Andrew D AD Kalland Karl-Henning KH Mills Gordon B GB Singer Christian F CF Krakstad Camilla C Beroukhim Rameen R Salvesen Helga B HB

Clinical cancer research : an official journal of the American Association for Cancer Research 20181115 1

<h4>Purpose</h4>Amplification of <i>PIK3CA</i>, 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 <i>PIK3CA</i> amplification acts via PI3K activation. We investigated the association between <i>PIK3CA</i> amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens.<h4>Experimental design</h4>UCECs from 591 clinically annotated patients including ...[more]

PMID: 30442683

Similar Datasets

Project description:Dedifferentiated/undifferentiated endometrial carcinoma (DDEC/UEC) is an endometrial cancer characterized by the presence of histologically undifferentiated carcinoma. Genomic inactivation of core switch/sucrose nonfermentable (SWI/SNF) complex proteins was recently identified in approximately two-thirds of DDEC/UEC. The aim of this study was to delineate the clinical behavior of SWI/SNF-deficient DDEC/UEC in comparison to SWI/SNF-intact DDEC/UEC. The study cohort consisted of 56 SWI/SNF-deficient DDEC/UEC (2 POLE-mutated), which showed either SMARCA4 (BRG1) loss, ARID1A/1B co-loss, or SMARCB1 (INI1) loss in the undifferentiated tumor, and 26 SWI/SNF-intact DDEC/UEC (4 POLE-mutated). The average age at diagnosis was 61?years for patients with SWI/SNF-deficient tumors and 64?years for SWI/SNF-intact tumors. Mismatch repair (MMR) protein deficiency was seen in 66% of SWI/SNF-deficient and 50% of SWI/SNF-intact tumors. At initial presentation, 55% of patients with SWI/SNF-deficient tumors had extrauterine disease spread in contrast to 38% of patients with SWI/SNF-intact tumors. The 2-year disease specific survival (DSS) for stages I and II disease was 65% for SWI/SNF deficient tumors relative to 100% for SWI/SNF-intact tumors (p = 0.042). For patients with stages III and IV disease, the median survival was 4 months for SWI/SNF-deficient tumors compared to 36?months for SWI/SNF-intact tumors (p = 0.0003). All six patients with POLE-mutated tumors, including one with stage IV SWI/SNF-deficient tumor were alive with no evidence of disease. Among the patients with advanced stage SWI/SNF-deficient tumors, 68% (21 of 31) received adjuvant or neoadjuvant chemotherapy (platinum/taxane-based) and all except the patient with a POLE-mutated tumor (20 of 21) experienced disease progression either during chemotherapy or within 4 months after its completion. These findings show that core SWI/SNF-deficiency defines a highly aggressive group of undifferentiated cancer characterized by rapid disease progression that is refractory to conventional platinum/taxane-based chemotherapy. This underscores the importance of accurate clinical recognition of this aggressive tumor and the need to consider alternative systemic therapy for these tumors.

Dataset Information

PIK3CA Amplification Associates with Aggressive Phenotype but Not Markers of AKT-MTOR Signaling in Endometrial Carcinoma.

Publications

<i>PIK3CA</i> Amplification Associates with Aggressive Phenotype but Not Markers of AKT-MTOR Signaling in Endometrial Carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure