bims-ovdlit 2022-01-02 papers

Issue of 2022–01–02
seven papers selected by
Lara Paracchini, Humanitas Research

Epigenomes. 2021 Apr 09. pii: 8. [Epub ahead of print]5(2):

Cell-Free DNA Methylation as Blood-Based Biomarkers for Pancreatic Adenocarcinoma-A Literature Update.

Stine Dam Henriksen, Ole Thorlacius-Ussing.

Pancreatic adenocarcinoma has a horrible prognosis, which is partly due to difficulties in diagnosing the disease in an early stage. Additional blood-born biomarkers for pancreatic adenocarcinoma are needed. Epigenetic modifications, as changes in DNA methylation, is a fundamental part of carcinogenesis. The aim of this paper is to do an update on cell-free DNA methylation as blood-based biomarkers for pancreatic adenocarcinoma. The current literature including our studies clearly indicates that cell-free DNA methylation has the potential as blood-based diagnostic and prognostic biomarkers for pancreatic adenocarcinoma. However, still no clinical applicable biomarker for pancreatic adenocarcinoma based on DNA methylation do exist. Further well-designed validation studies are needed.

Keywords: DNA methylation; cell-free DNA; diagnostic biomarker; epigenetic; pancreatic cancer; pancreatic ductal adenocarcinoma; prognostic biomarker

DOI: https://doi.org/10.3390/epigenomes5020008

Anticancer Res. 2022 Jan;42(1): 349-353

Correlation Between Clinical Outcomes and Serum CA-125 Levels After Standard Treatment for Epithelial Ovarian Cancer.

Juhun Lee, Jong Mi Kim, Yoon Hee Lee, Gun Oh Chong, Dae Gy Hong.

BACKGROUND/AIM: To analyze the relationship between clinical outcomes for epithelial ovarian cancer and serum CA-125 levels after chemotherapy in Korean women.
PATIENTS AND METHODS: This study included 183 patients who underwent the standard treatment regimen for epithelial ovarian cancer. They were divided into early- (I, II) and advanced-stage (III, IV) groups. Serum CA-125 level after adjuvant chemotherapy completion (post-chemotherapy; PC-CA-125) was measured. Overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI), and platinum resistance were evaluated.
RESULTS: In advanced-stage group, OS, PFS, PFI, and platinum resistance were significantly correlated with PC-CA-125. In early-stage group, PFS and platinum resistance differed significantly. Cutoff value for platinum resistance was 10.45 U/ml, 10.40 U/ml, and 15.80 U/ml for study population, early stage, and advanced groups, respectively. Accuracy was 71.1%-77.1%.
CONCLUSION: PC-CA-125 is correlated with clinical outcomes in ovarian cancer. Thus, CA-125 can be used to predict platinum resistance in ovarian cancer treatment.

Keywords: CA-125; Ovarian cancer; chemotherapy; clinical outcomes; overall survival; platinum resistance; platinum-free interval; progression-free survival

DOI: https://doi.org/10.21873/anticanres.15492

Front Oncol. 2021 ;11 795547

Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1.

Laure Chardin, Alexandra Leary.

Ovarian cancer (OC) is the most lethal gynecologic malignancy, affecting approximately 1 in 70 women with only 45% surviving 5 years after diagnosis. This disease typically presents at an advanced stage, and optimal debulking with platinum-based chemotherapy remains the cornerstone of management. Although most ovarian cancer patients will respond effectively to current management, 70% of them will eventually develop recurrence and novel therapeutic strategies are needed. There is a rationale for immune-oncological treatments (IO) in the managements of patients with OC. Many OC tumors demonstrate tumor infiltrating lymphocytes (TILs) and the degree of TIL infiltration is strongly and reproducibly correlated with survival. Unfortunately, results to date have been disappointing in relapsed OC. Trials have reported very modest single activity with various antibodies targeting PD-1 or PD-L1 resulting in response rate ranging from 4% to 15%. This may be due to the highly immunosuppressive TME of the disease, a low tumor mutational burden and low PD-L1 expression. There is an urgent need to improve our understanding of the immune microenvironment in OC in order to develop effective therapies. This review will discuss immune subpopulations in OC microenvironment, current immunotherapy modalities targeting these immune subsets and data from clinical trials testing IO treatments in OC and its combination with other therapeutic agents.

Keywords: PD-L1; immunosuppression; immunotherapy; ovarian cancer; tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2021.795547

Adv Exp Med Biol. 2021 ;1342 193-232

Immuno-Oncology for Gynecologic Malignancies.

Jeffrey A How, Ami Patel, Amir A Jazaeri.

Patients with advanced and/or recurrent gynecologic cancers derive limited benefit from currently available cytotoxic and targeted therapies. Successes of immunotherapy in other difficult-to-treat malignancies such as metastatic melanoma and advanced lung cancer have led to intense interest in clinical testing of these treatments in patients with gynecologic cancers. Currently, in the realm of gynecologic oncology, the FDA-approved use of immune checkpoint inhibitors is limited to microsatellite instability-high cancers, cancers with high tumor mutational burden, and PD-L1-positive cervical cancer. However, there has been an exponential growth of clinical trials testing immunotherapy approaches both alone and in combination with chemotherapy and/or targeted agents in patients with gynecologic cancers. This chapter will review some of the major reported and ongoing immunotherapy clinical trials in patients with endometrial, cervical, and epithelial ovarian cancer.

Keywords: Adoptive cell transfer; Cancer vaccines; Cervical cancer; Endometrial cancer; Immune checkpoint inhibitors; Immunotherapy; Ovarian cancer

DOI: https://doi.org/10.1007/978-3-030-79308-1_6

Anticancer Res. 2022 Jan;42(1): 1-12

Prospects of Improving Early Ovarian Cancer Diagnosis Using Cervical Cell Swabs.

Edyta Biskup, Regitze Solling Wils, Claus Hogdall, Estrid Hogdall.

Ovarian cancer (OC) has the poorest prognosis and the highest mortality rate among gynecological malignancies, which is largely due to delayed diagnosis. Therefore, an effective detection strategy is a compelling need. Here, we review the potential use of cervical cell swabs (Pap specimens, liquid) for early detection of OC. It has been shown, that malignant cells exfoliate from the ovaries and may be detected in Pap specimens, routinely collected through cervical cancer screening. Using Medical Subject Headings (MeSH) for searching the PubMed database we identified eight studies reporting the use of Pap specimen in early detection of OC. Six focused on detection of gene mutations, using gene panels or analysis of TP53 variants. Two studies reported analysis of methylation profiles. Seven studies were published in 2018 or later. Additionally, we found one study without MeSH terms assigned yet, which postulated using peptide biomarkers present in Pap-test fluid. In this review we present their main findings, discuss challenges this approach presents and include ideas for improved detection.

Keywords: Ovarian cancer; Pap test; cervical swab; liquid Pap specimen; review

DOI: https://doi.org/10.21873/anticanres.15451

Front Immunol. 2021 ;12 768115

Significance of CD47 and Its Association With Tumor Immune Microenvironment Heterogeneity in Ovarian Cancer.

Lan Yu, Yi Ding, Ting Wan, Ting Deng, He Huang, Jihong Liu.

Background: It was reported that tumor heterogeneity and the surrounding tumor microenvironment (TME) in ovarian cancer affects immunotherapy efficacy and patient outcomes. And the TME of ovarian cancer is intrinsically heterogeneous. CD47 plays vital roles in cell functional behavior and immune homeostasis relating to cancer prognosis. But how it affects TME and its contribution to heterogeneity in ovarian cancer has not been fully illustrated. Therefore, we aimed to identify a prognostic biomarker which may help explain tumor immune microenvironment heterogeneity of ovarian cancer.
Methods: Cancer single-cell state atlas (CancerSEA) was used to evaluate functional role of CD47. Several bioinformatics database including Oncomine, Gene Expression Profiling Interaction Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), The Human Protein Atlas (HPA), Ualcan and Kaplan-Meier plotter (KM plotter) were applied to illustrate correlation of CD47 with ovarian cancer prognosis and immune infiltration. Tumor Immune Single-cell Hub (TISCH) single cell database was employed to evaluate correlation of CD47 with tumor microenvironment. GeneMANIA was implemented to identify regulation networks of CD47. Differentially expressed genes (DEGs) between CD47 high and low expression groups were analyzed with R package DESeq2. Kyoto encyclopedia of genes and genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were utilized to explore how CD47 affect the immune related cell signaling pathway.
Results: CD47 expression was upregulated and connected to worse OS and PFS in ovarian cancer. Close relation was found between CD47 expression level and immune infiltration in ovarian cancer, especially with Treg cells, Monocytes, Macrophages and T cell exhaustion (P<0.05). The CD47 expression level was relatively low in plasma cells, dendritic cells and Mono/Macro cells of OV_GSE115007, in myofibroblasts, fibroblasts and endothelial cells of OV_GSE118828, compared to malignant cells of OV_GSE118828 dataset. The cell components and distribution in primary and metastatic ovarian cancer are quite distinct, which may lead to TME heterogeneity of ovarian cancer.
Conclusion: Our results indicated that CD47 is closely correlated to ovarian cancer immune microenvironment and might induce ovarian cancer heterogeneity. Therefore, CD47 may be used as a candidate prognostic biomarker and provide us with new insights into potential immunotherapy in ovarian cancer patients.

Keywords: CD47; heterogeneity; ovarian cancer; scRNA-seq; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2021.768115

Epigenomes. 2021 Feb 19. pii: 6. [Epub ahead of print]5(1):

Ultra-Low DNA Input into Whole Genome Methylation Assays and Detection of Oncogenic Methylation and Copy Number Variants in Circulating Tumour DNA.

Celina Whalley, Karl Payne, Enric Domingo, Andrew Blake, Susan Richman, Jill Brooks, Nikolaos Batis, Rachel Spruce, S-Cort Consortium, Hisham Mehanna, Paul Nankivell, Andrew D Beggs.

BACKGROUND: Abnormal CpG methylation in cancer is ubiquitous and generally detected in tumour specimens using a variety of techniques at a resolution encompassing single CpG loci to genome wide coverage. Analysis of samples with very low DNA inputs, such as formalin fixed (FFPE) biopsy specimens from clinical trials or circulating tumour DNA is challenging at the genome-wide level because of lack of available input. We present the results of low input experiments into the Illumina Infinium HD methylation assay on FFPE specimens and ctDNA samples.
METHODS: For all experiments, the Infinium HD assay for methylation was used. In total, forty-eight FFPE specimens were used at varying concentrations (lowest input 50 ng); eighteen blood derived specimens (lowest input 10 ng) and six matched ctDNA input (lowest input 10 ng)/fresh tumour specimens (lowest input 250 ng) were processed. Downstream analysis was performed in R/Bioconductor for quality control metrics and differential methylation analysis as well as copy number calls.
RESULTS: Correlation coefficients for CpG methylation were high at the probe level averaged R2 = 0.99 for blood derived samples and R2 > 0.96 for the FFPE samples. When matched ctDNA/fresh tumour samples were compared, R2 > 0.91 between the two. Results of differential methylation analysis did not vary significantly by DNA input in either the blood or FFPE groups. There were differences seen in the ctDNA group as compared to their paired tumour sample, possibly because of enrichment for tumour material without contaminating normal. Copy number variants observed in the tumour were generally also seen in the paired ctDNA sample with good concordance via DQ plot.
CONCLUSIONS: The Illumina Infinium HD methylation assay can robustly detect methylation across a range of sample types, including ctDNA, down to an input of 10 ng. It can also reliably detect oncogenic methylation changes and copy number variants in ctDNA. These findings demonstrate that these samples can now be accessed by methylation array technology, allowing analysis of these important sample types.

Keywords: circulating tumour DNA; epigenome; formalin fixed paraffin embedded

DOI: https://doi.org/10.3390/epigenomes5010006