Analysis of Chemotherapeutic Response in Ovarian Cancers Using Publicly Available High-Throughput Data

Bosquet, Jesús González; Marchion, Douglas C.; Chon, Hye Sook; Lancaster, Johnathan M.; Chanock, Stephen J.

doi:10.1158/0008-5472.can-14-0186

Cited by 35 publications

(26 citation statements)

References 52 publications

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“…First, we identified a common deletion in H23, OVCAR3 and A2780 cells, induced by cisplatin treatment in chromosome 18, including two completely deleted genes, LRP1B and ITF2. A similar deletion was identified in a previous study analysing cisplatin response in ovarian cancer samples, which supports our results [16]. However, there is another study analyzing the cytogenetic alterations of CDDP-resistant A2780R cells, which shows different genomic alterations.…”

Section: Discussionsupporting

confidence: 92%

A Novel Role for the Tumor Suppressor Gene ITF2 in Lung Tumorigenesis and Chemotherapy Response

Pernía¹,

Sastre-Perona²,

Rodriguez-Antolín³

et al. 2020

Preprint

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Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyze and validated the cytogenetic alterations that arise after treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines by 1-million array-CGH and qRT-PCR methodologies. RNA-sequencing, functional transfection assays and gene-pathway activity analysis were used to identify genes with a potential role in the development of this malignancy. Results were further explored in 55 lung and ovarian primary tumors and control samples and in two extensive in silico databases. Long-term cell exposure to platinum induces the frequent deletion of ITF2 gene. Its expression re-sensitizes tumor cells to platinum and recovers the levels of Wnt/β-catenin transcriptional activity. ITF2 expression was also frequently downregulated in epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation between ITF2 and HOXD9 expression, revealing that NSCLC patients with lower expression of HOXD9 have a better overall survival rate. We define the implication of ITF2 as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. This data highlights the possible role of ITF2 and HOXD9 as novel therapeutic targets for platinum resistant tumors.

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Section: Discussionsupporting

confidence: 92%

A Novel Role for the Tumor Suppressor Gene ITF2 in Lung Tumorigenesis and Chemotherapy Response

Pernía¹,

Sastre-Perona²,

Rodriguez-Antolín³

et al. 2020

Preprint

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“…In addition to tumour infiltrating lymphocytes (TILs), effector molecules secreted by both tumour and immune cells mediate tumour progression, metastasis and/or response to therapy . Indeed, four molecular subtypes of HGSC were recently defined with the C1 and C2 molecular subtypes of HGSC showing a predominance of immune‐related gene signatures . Interestingly, the C2 subtype shows characteristic higher levels of CXCL9 , CXCL10 and CXCL11 expression as well as higher intra‐epithelial CD3 + T cell infiltration compared to C1 which has a distinct high stromal immune signature .…”

Section: Introductionmentioning

confidence: 99%

STAT1‐associated intratumoural T_H1 immunity predicts chemotherapy resistance in high‐grade serous ovarian cancer

Page

Ren

et al. 2016

The Journal of Pathology CR

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High‐grade serous ovarian carcinoma (HGSC) accounts for 70% of all epithelial ovarian cancers but clinical management is challenged by a lack of accurate prognostic and predictive biomarkers of chemotherapy response. This study evaluated the role of Signal Transducer and Activator of Transcription 1 (STAT1) as an independent prognostic and predictive biomarker and its correlation with intratumoural CD8+ T cells in a second independent biomarker validation study. Tumour STAT1 expression and intratumoural CD8+ T cell infiltration were assessed by immunohistochemistry as a multicentre validation study conducted on 734 chemotherapy‐naïve HGSCs. NanoString‐based profiling was performed to correlate expression of STAT1 target genes CXCL9, CXCL10 and CXCL11 with CD8A transcript expression in 143 primary tumours. Multiplexed cytokine analysis of pre‐treatment plasma from resistant and sensitive patients was performed to assess systemic levels of STAT1‐induced cytokines. STAT1 was validated as a prognostic and predictive biomarker in both univariate and multivariate models and its expression correlated significantly with intra‐epithelial CD8+ T cell infiltration in HGSC. STAT1 levels increased the prognostic and predictive value of intratumoural CD8+ T cells, confirming their synergistic role as biomarkers in HGSC. In addition, expression of STAT1 target genes (CXCL9, CXCL10 and CXCL11) correlated significantly with levels of, and CD8A transcripts from intratumoural CD8+ T cells within the resistant and sensitive tumours. Our findings provide compelling evidence that high levels of STAT1, STAT1‐induced chemokines and CD8+ T cells correlate with improved chemotherapy response in HGSC. These results identify STAT1 and its target genes as novel biomarkers of chemosensitivity in HGSC. These findings provide new translational opportunities for patient stratification for immunotherapies based on emerging biomarkers of inflammation in HGSC. An improved understanding of the role of interferon‐inducible genes will be foundational for developing immunomodulatory therapies in ovarian cancer.

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“…Another study reported a prognostic and response predictive 97‐gene signature using 7 transcriptomic data sets including the TCGA RNA‐Seq data (total n = 1020 patients) . Salinas et al, 2016 aimed at genetic predisposition to chemotherapy resistance and evaluated 22 007 unique SNPs in the TCGA data set, within a previously reported 422‐gene signature. A total of 19 SNPs were identified as a result of this evaluation; however, these failed validation in independent data sets.…”

Section: Omics In Action: Predicting Chemotherapy Resistancementioning

confidence: 99%

Multi‐omics in high‐grade serous ovarian cancer: Biomarkers from genome to the immunome

Clifford

Vitkin

Nersesian

et al. 2018

American J Rep Immunol

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Epithelial ovarian cancer (EOC) is a lethal gynaecological disease that imposes significant burden on health care and patient quality of life. High-grade serous carcinoma of the ovary (HGSC) is the most prevalent histological type of EOC. A vast majority of HGSC cases are diagnosed at late stages of the disease, limiting the opportunity for clinical intervention and resulting in a 10-year survival rate of <20%. Recent innovations in high-throughput molecular analysis of patient-derived specimens may address these clinical challenges by providing an enhanced understanding of the molecular aetiology of ovarian cancer, in addition to offering several opportunities for rational biomarker and targeted therapy discovery. In this review, we highlight the most significant contributions of omics approaches and how the advent of immunomics can aid in personalized combination chemo-immunotherapy in ovarian cancer treatment. We further provide insights into immunogenomic correlates of pre-treatment tumour immune microenvironment and some of the potential interpretations of immunomic data that require further validation, based on stromal and immune contributions to biomarker signatures. We believe a comprehensive integrative approach via meta-analysis of large ovarian cancer molecular profiling data sets is urgently needed to define robust prognostic and predictive classifiers of disease progression and treatment response. These investigations will inform rationalized biomarker-driven combination chemo-immunotherapy trials for improving response and survival of ovarian cancer patients.

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Analysis of Chemotherapeutic Response in Ovarian Cancers Using Publicly Available High-Throughput Data

Abstract: A third of patients with epithelial ovarian cancer (OVCA) will not respond to standard treatment.

Cited by 35 publications

References 52 publications

A Novel Role for the Tumor Suppressor Gene ITF2 in Lung Tumorigenesis and Chemotherapy Response

A Novel Role for the Tumor Suppressor Gene ITF2 in Lung Tumorigenesis and Chemotherapy Response

STAT1‐associated intratumoural T_H1 immunity predicts chemotherapy resistance in high‐grade serous ovarian cancer

Multi‐omics in high‐grade serous ovarian cancer: Biomarkers from genome to the immunome

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Analysis of Chemotherapeutic Response in Ovarian Cancers Using Publicly Available High-Throughput Data

Abstract: A third of patients with epithelial ovarian cancer (OVCA) will not respond to standard treatment.

Cited by 35 publications

References 52 publications

A Novel Role for the Tumor Suppressor Gene ITF2 in Lung Tumorigenesis and Chemotherapy Response

A Novel Role for the Tumor Suppressor Gene ITF2 in Lung Tumorigenesis and Chemotherapy Response

STAT1‐associated intratumoural TH1 immunity predicts chemotherapy resistance in high‐grade serous ovarian cancer

Multi‐omics in high‐grade serous ovarian cancer: Biomarkers from genome to the immunome

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STAT1‐associated intratumoural T_H1 immunity predicts chemotherapy resistance in high‐grade serous ovarian cancer