Tumour immune cell infiltration and survival after platinum-based chemotherapy in high-grade serous ovarian cancer subtypes: A gene expression-based computational study

Ovarian carcinoma (OV) is a lethal gynecological malignancy. Most OV patients develop resistance to platinum-based chemotherapy and recurrence. Peroxisome proliferator-activated receptors (PPARs) are the ligand activating transcription factor of the nuclear receptor superfamily. PPARs as important transcriptional regulators regulate important physiological processes such as lipid metabolism, inflammation, and wound healing. Several reports point out that PPARs can also have an effect on the sensitivity of tumor cells to platinum-based chemotherapy drugs. However, the role of PPAR-target related genes (PPAR-TRGs) in chemotherapeutic resistance of OV remains unclear. The present study is aimed at optimizing candidate genes by integrating platinum-chemotherapy expression data and PPAR family genes with their targets. The gene expression profiles were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database. A total of 4 genes (AP2A2, DOCK4, HSDL2, and PDK4) were the candidate differentially expressed genes (DEGs) of PPAR-TRGs with platinum chemosensitivity. After conducting numerous survival analyses using different cohorts, we found that only the upexpression of DOCK4 has important significance with the poor prognosis of OV patients. Meanwhile, DOCK4 is detected in plasma and enriched in neutrophil and monocyte cells of the blood. We further found that there were significant correlations between DOCK4 expression and the levels of CD4+ T cell infiltration, dendritic cell infiltration, and neutrophil infiltration in OV. In addition, we verified the expression level of DOCK4 in OV cell lines treated with platinum drugs and found that DOCK4 is potentially responsive to platinum drugs. In conclusion, DOCK4 is potentially associated with immune cell infiltration and represents a valuable prognostic biomarker in ovarian cancer patients.

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Prognostic gene expression signature for high-grade serous ovarian cancer

Annals of Oncology ◽

10.1016/j.annonc.2020.05.019 ◽

2020 ◽

Vol 31 (9) ◽

pp. 1240-1250 ◽

Cited By ~ 1

Author(s):

J. Millstein ◽

T. Budden ◽

E.L. Goode ◽

M.S. Anglesio ◽

A. Talhouk ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Gene Expression Signature ◽

High Grade ◽

Serous Ovarian Cancer ◽

Expression Signature ◽

Prognostic Gene

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Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1804506115 ◽

2018 ◽

Vol 115 (50) ◽

pp. E11701-E11710 ◽

Cited By ~ 42

Author(s):

Yoong Wearn Lim ◽

Haiyin Chen-Harris ◽

Oleg Mayba ◽

Steve Lianoglou ◽

Arthur Wuster ◽

...

Keyword(s):

Gene Expression ◽

Cancer Immunotherapy ◽

Genetic Variants ◽

Immune Cell ◽

Response To Therapy ◽

Cell Infiltration ◽

Cancer Type ◽

Immune Cell Infiltration ◽

Durable Response ◽

The Impact

Cancer immunotherapy has emerged as an effective therapy in a variety of cancers. However, a key challenge in the field is that only a subset of patients who receive immunotherapy exhibit durable response. It has been hypothesized that host genetics influences the inherent immune profiles of patients and may underlie their differential response to immunotherapy. Herein, we systematically determined the association of common germline genetic variants with gene expression and immune cell infiltration of the tumor. We identified 64,094 expression quantitative trait loci (eQTLs) that associated with 18,210 genes (eGenes) across 24 human cancers. Overall, eGenes were enriched for their being involved in immune processes, suggesting that expression of immune genes can be shaped by hereditary genetic variants. We identified the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene as a pan-cancer type eGene whose expression levels stratified overall survival in a subset of patients with bladder cancer receiving anti–PD-L1 (atezolizumab) therapy. Finally, we identified 103 gene signature QTLs (gsQTLs) that were associated with predicted immune cell abundance within the tumor microenvironment. Our findings highlight the impact of germline SNPs on cancer-immune phenotypes and response to therapy; and these analyses provide a resource for integration of germline genetics as a component of personalized cancer immunotherapy.

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Colon Cancer and SARS-CoV-2: Impact of ACE2 Expression in Susceptibility to COVID-19

10.1101/2020.06.11.146878 ◽

2020 ◽

Cited By ~ 1

Author(s):

Mohsen Ahmadi ◽

Negin Saffarzadeh ◽

Mohammad Amin Habibi ◽

Fatemeh Hajiesmaeili ◽

Nima Rezaei

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Immune Cell ◽

Expression Patterns ◽

Methylation Status ◽

Functional Enrichment ◽

Cell Infiltration ◽

Survival Outcomes ◽

Immune Cell Infiltration ◽

Ace2 Gene

AbstractNovel coronavirus disease (COVID-19) pandemic has become a global health emergency. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with angiotensin-converting enzyme 2 (ACE2) to enter the cells and infects diverse human tissues. It has been reported that a few conditions, including cancer, predispose individuals to SARS-CoV-2 infection and severe form of COVID-19. These findings led us to evaluate the susceptibility of colon adenocarcinoma (COAD) patients to SARS-CoV-2 infection by investigation of ACE2 expression in their tumor tissues. The expression analysis revealed that both mRNA and protein levels of ACE2 had increased in colon cancer samples than normal group. Next, the prognosis analysis has indicated that the upregulation of ACE2 was not correlated with patient survival outcomes. Further assessment displayed the hypomethylation of the ACE2 gene promoter in COAD patients. Surprisingly, this methylation status has a strong negative correlation with ACE2 gene expression. The functional enrichment analysis of the genes that had similar expression patterns with ACE2 in colon cancer tissues demonstrated that they mainly enriched in Vitamin digestion and absorption, Sulfur relay system, and Fat digestion and absorption pathways. Finally, we found that ACE2 gene expression had a significant association with the immune cell infiltration levels in COAD patients. In conclusion, it has plausible that COAD patients are more likely to be infected with SARS-CoV-2 and experience severe injuries. Moreover, COVID-19 would bring unfavorable survival outcomes of patients with colon cancer by the way of immune cell infiltration linked process. The present study highlights the importance of preventive actions for COAD patients during the COVID-19 pandemic.

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Development of a Genomic Signatures-Based Predictor of Initial Platinum-Resistance in Advanced High-Grade Serous Ovarian Cancer Patients

Frontiers in Oncology ◽

10.3389/fonc.2020.625866 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yuan Li ◽

Xiaolan Zhang ◽

Yan Gao ◽

Chunliang Shang ◽

Bo Yu ◽

...

Keyword(s):

Ovarian Cancer ◽

Predictive Accuracy ◽

Predictive Performance ◽

Platinum Resistance ◽

High Grade ◽

Serous Ovarian Cancer ◽

Single Nucleotide Variants ◽

Tissue Samples ◽

Platinum Sensitive ◽

Platinum Based Chemotherapy

BackgroundHigh grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet.MethodsNinety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients.ResultsA high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1–100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%.ConclusionsA multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.

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Role of discoidin domain receptor 2 (DDR2) and microRNA-182 in survival of women with high-grade serous ovarian cancer

Tumor Biology ◽

10.1177/1010428318823988 ◽

2019 ◽

Vol 41 (1) ◽

pp. 101042831882398

Author(s):

Susana Ramalho ◽

Liliana AL De Angelo Andrade ◽

Cássio Cardoso Filho ◽

Rodrigo de Andrade Natal ◽

Marina Pavanello ◽

...

Keyword(s):

Ovarian Cancer ◽

Residual Disease ◽

Figo Stage ◽

Stage I ◽

High Grade ◽

Serous Ovarian Cancer ◽

Discoidin Domain Receptor ◽

Post Surgery ◽

Platinum Based Chemotherapy ◽

Discoidin Domain Receptor 2

The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (DDR2) and miR-182 expression with response to platinum-based chemotherapy and survival in women with high-grade serous ovarian cancer (HGSOC). We evaluated 78 women with HGSOC stages I-IV, diagnosed between 1996 and 2013, and followed up until 2016. DDR2 expression was assessed using immunohistochemistry on tissue microarray slides. The microRNAs were evaluated by qRT-PCR. DDR2 expression was high in 11 (14.1%) women. PFS was significantly lower in women with FIGO stage I/II – versus III/IV, post-surgery residual disease and high expression of DDR2. Women with postsurgery residual disease, FIGO stage I/II – versus III/IV and DDR2 expression had worse OS, but only post-surgery residual disease remained an independent prognostic factor for worse OS in multivariable analysis. miR-182 expression levels were significantly lower in patients harboring tumors with higher expression of DDR2 (p < 0.001). In this relatively large cohort of women with HSGOC, higher DDR2 expression was associated with lower miR-182 levels and worse PFS, suggesting that these molecules may be associated with mechanisms of HGSOC progression.

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