PTEN Deficiency in Tubo-Ovarian High-Grade Serous Carcinoma is Associated with Poor Progression-Free Survival and is Mutually Exclusive with CCNE1 Amplification

Zhang, Xiaoming; Wang, Aihui; Han, Lucy; Liang, Brooke; Allard, Grace M.; Diver, Elisabeth; Howitt, Brooke E.

doi:10.1016/j.modpat.2023.100106

Cited by 4 publications

(1 citation statement)

References 79 publications

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“…PTEN is a tumour suppressor and negative regulator of the PI3K-signalling pathway. Although deleterious single nucleotide variants and deletions in PTEN are rare in HGSC 4 , inactivation through complex re-arrangements is more frequent 12 , and complete (13-59%) or partial (13-55%) PTEN protein loss is common [13][14][15][16] , suggesting transcriptional dysregulation. Furthermore, genomic alterations in the PI3K/Ras signalling pathway occur in 45% of HGSC 4 and enhanced PI3K pathway signalling is observed in the presence of PTEN protein expression 17 .…”

Section: Introductionmentioning

confidence: 99%

Heme oxygenase-1 expressing omental macrophages as a therapeutic target in ovarian high grade serous carcinoma

Spear

Saux

Mirza

et al. 2023

Preprint

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Ovarian high grade serous carcinoma (HGSC) remains a disease of poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesised aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a novel targeting strategy. We used both murine models and HGSC patient samples to study the impact of loss of Pten, a negative regulator of PI3K pathway signalling. We identified populations of resident macrophages specifically in Pten null omental tumours. These macrophages derive from peritoneal fluid macrophages and have a unique gene expression programme, marked by high levels of HMOX1 expression, the gene for the enzyme heme oxygenase-1. Targeting resident peritoneal macrophages prevents appearance of HMOX1hi macrophages and in doing so reduces tumour growth. Furthermore, direct inhibition of HMOX1 extends survival in vivo. HMOX1hi macrophages with corresponding gene expression programmes are also identified in human HGSC tumours and their presence correlates with activated tumoural PI3K pathway/mTOR signalling and poor overall survival in HGSC patients. In contrast, tumours with low number of HMOX1hi macrophages are marked by increased adaptive immune response gene expression. Our data suggest that HMOX1hi macrophages represent a potential therapeutic target and biomarker for poor prognosis HGSC.

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Section: Introductionmentioning

confidence: 99%

Heme oxygenase-1 expressing omental macrophages as a therapeutic target in ovarian high grade serous carcinoma

Spear

Saux

Mirza

et al. 2023

Preprint

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Endometrioid ovarian carcinoma landscape: pathological and molecular characterization

de Nonneville,

Kalbacher,

Cannone

et al. 2024

Molecular Oncology

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Endometrioid ovarian cancers (EOvC) are usually managed as serous tumors. In this study, we conducted a comprehensive molecular investigation to uncover the distinct biological characteristics of EOvC. This retrospective multicenter study involved patients from three European centers. We collected clinical data and formalin‐fixed paraffin‐embedded (FFPE) samples for analysis at the DNA level using panel‐based next‐generation sequencing and array‐comparative genomic hybridization. Additionally, we examined mRNA expression using NanoString nCounter® and protein expression through tissue microarray. We compared EOvC with other ovarian subtypes and uterine endometrioid tumors. Furthermore, we assessed the impact of molecular alterations on patient outcomes, including progression‐free survival (PFS) and overall survival (OS). Preliminary analysis of clinical data from 668 patients, including 86 (12.9%) EOvC, revealed more favorable prognosis for EOvC compared with serous ovarian carcinoma (5‐year OS of 60% versus 45%; P = 0.001) driven by diagnosis at an earlier stage. Immunohistochemistry and copy number alteration (CNA) profiles of 43 cases with clinical data and FFPE samples available indicated that EOvC protein expression and CNA profiles were more similar to endometrioid endometrial tumors than to serous ovarian carcinomas. EOvC exhibited specific alterations, such as lower rates of PTEN loss, mutations in DNA repair genes, and P53 abnormalities. Survival analysis showed that patients with tumors harboring loss of PTEN expression had worse outcomes (median PFS 19.6 months vs. not reached; P = 0.034). Gene expression profile analysis confirmed that EOvC differed from serous tumors. However, comparison to other rare subtypes of ovarian cancer suggested that the EOvC transcriptomic profile was close to that of ovarian clear cell carcinoma. Downregulation of genes involved in the PI3K pathway and DNA methylation was observed in EOvC. In conclusion, EOvC represents a distinct biological entity and should be regarded as such in the development of specific clinical approaches.

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The intricate dance of tumor evolution: Exploring immune escape, tumor migration, drug resistance, and treatment strategies

Guo,

Bian,

et al. 2024

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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PTEN Deficiency in Tubo-Ovarian High-Grade Serous Carcinoma is Associated with Poor Progression-Free Survival and is Mutually Exclusive with CCNE1 Amplification

Cited by 4 publications

References 79 publications

Heme oxygenase-1 expressing omental macrophages as a therapeutic target in ovarian high grade serous carcinoma

Heme oxygenase-1 expressing omental macrophages as a therapeutic target in ovarian high grade serous carcinoma

Endometrioid ovarian carcinoma landscape: pathological and molecular characterization

The intricate dance of tumor evolution: Exploring immune escape, tumor migration, drug resistance, and treatment strategies

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