scholarly journals Disentangling heterogeneity of Malignant Pleural Mesothelioma through deep integrative omics analyses

2021 ◽  
Author(s):  
Lise Mangiante ◽  
Nicolas Alcala ◽  
Alex Di Genova ◽  
Alexandra Sexton-Oates ◽  
Abel Gonzalez-Perez ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Malignant Pleural Mesothelioma ◽  
Cell Morphology ◽  
Cpg Island ◽  
Adaptive Immune Response ◽  
Whole Genome Sequencing Data ◽  
Pleural Mesothelioma ◽  
Sequencing Data ◽  
Cpg Island Methylator Phenotype ◽  
Sources Of Variation

Malignant Pleural Mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Using the largest series of whole-genome sequencing data integrated with transcriptomic and epigenomic data using multi-omic factor analysis, we demonstrate that MPM heterogeneity arises from four sources of variation: tumor cell morphology, ploidy, adaptive immune response, and CpG island methylator phenotype. Previous genomic studies focused on describing only the tumor cell morphology factor, although we robustly find the three other sources in all publicly available cohorts. We prove how these sources of variation explain the biological functions performed by the cancer cells, and how genomic events shape MPM molecular profiles. We show how these new sources of variation help understand the heterogeneity of the clinical behavior of MPM and drug responses measured in cell lines. These findings unearth the interplay between MPM functional biology and its genomic history, and ultimately, inform classification, prognostication and treatment.

Profiling of Aberrant DNA Methylation In AML Reveals Subclasses of CpG Islands with Epigenetic or Genetic Association

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2498-2498
Author(s):  
Claudia Gebhard ◽  
Mohammed Sadeh ◽  
Dagmar Glatz ◽  
Lucia Schwarzfischer ◽  
Rainer Spang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Cpg Island ◽  
Cpg Islands ◽  
Sequencing Data ◽  
Cpg Island Methylator Phenotype ◽  
Chip Sequencing ◽  
Aberrant Dna Methylation ◽  
Methylation Patterns

Abstract Abstract 2498 CpG islands show frequent and often disease-specific epigenetic alterations during malignant transformation, however, the underlying mechanisms are poorly understood. We used methyl-CpG immunoprecipitation (MCIp) to generate comparative DNA methylation profiles of 30 patients with acute myeloid leukemia for human CpG islands across the genome. DNA methylation profiles across 23.000 CpG islands revealed highly heterogeneous methylation patterns in AML with over 6000 CpG islands showing aberrant de novo methylation in AML. Based on these profiles we selected a subset of 380 CpG islands (covering 15.000 individual CpGs) for detailed fine-mapping analyses of aberrant DNA methylation in 185 patients with AML (50% normal karyotype). We found that a proportion of patients (5/185) displayed a concerted hypermethylation at almost all studied loci, representing the rare CpG island methylator phenotype (CIMP) in AML. Meta analysis of methylation profiling and published ChIP sequencing data separated CpG islands in two groups. A highly correlated subgroup of CpG island regions was strongly associated with histone H3 lysine 27 trimethylation in human hematopoietic progenitor cells, suggesting that disease-related de novo DNA methylation at these CpG islands is linked with polycomb group protein (PcG)-mediated repression. The group of mainly non-PcG target CpG islands showed heterogeneous methylation patterns across patients and unsupervised hierarchical clustering revealed a correlation of methylation profiles with genetic disease markers, including oncofusion proteins as well as CEBPA- and NPM1-mutations. Our study suggests that both epigenetic as well as genetic aberrations may underlay AML-related changes in CpG island DNA methylation states. Disclosures: No relevant conflicts of interest to declare.

Circulating tumor cell (CTC) as a significant clinical marker in epithelioid-type malignant pleural mesothelioma (MPM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7080-7080
Author(s):  
Kazue Yoneda ◽  
Fumihiro Tanaka ◽  
Shunichi Fukuda ◽  
Hayato Orui ◽  
Masaki Hashimoto ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Tumor Cell ◽  
Malignant Pleural Mesothelioma ◽  
Poor Prognosis ◽  
Circulating Tumor Cell ◽  
Independent Prognostic Factor ◽  
Pleural Mesothelioma ◽  
Roc Curve Analysis ◽  
Clinical Marker ◽  
Significant Difference

7080 Background: Circulating tumor cell (CTC) is a surrogate of distant metastasis, and our preliminary study suggested that CTC detected by an EpCAM-based immuno-magnetic separation system (“CellSearch”) was a useful clinical marker in the diagnosis of malignant pleural mesothelioma (MPM) (Tanaka F. et al ASCO 2008). Methods: Patients who presented at our institute to receive pleural biopsy with suspicion of MPM were prospectively enrolled. CTCs in 7.5mL of peripheral blood were quantitatively evaluated with the CellSearch system. Results: Among 136 eligible patients, 104 were finally diagnosed with MPM, and 32 were with non-malignant diseases (NM). CTC was positive (CTC≥1) in 32.7% (37/104) of MPM pts, and in 9.4% (3/32) of NM pts (p=0.011). CTC-count was significantly higher in MPM (range, 0-9) than in NM (range, 0-1; p=0.007). According to a ROC curve analysis, the CTC-test provided a significant diagnostic performance in discrimination between MPM and NM (AUC= 0.623; P=0.036). Among MPM pts, CTC-positivity and CTC-count were significantly increased with tumor progression (p=0.026 and p=0.008, respectively). For all MPM pts, there was no significant difference in overall survival between CTC-positive and negative pts. However, in a planned subset analysis, CTC was a significant factor to predict poor prognosis (median survival time, 8.0 months for CTC-positive pts, and 20.3 months for negative pts; p=0.012) in pts with epithelioid-type MPM in which CTC was exclusively positive; a multivariate analysis confirmed that CTC, along with PS, was an independent prognostic factor (HR=2.38; P=0.006). Conclusions: CTC was a significant diagnostic marker in discrimination between MPM and NM. CTC-positivity was a significant and independent prognostic factor to predict a poor prognosis of epithelioid MPM. [Table: see text]

Genomic landscape and immune phenotype of malignant pleural mesothelioma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9056-9056 ◽  
Author(s):  
Meera Patel ◽  
Andrew Elliott ◽  
Stephen V. Liu ◽  
Chul Kim ◽  
Luis E. Raez ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Specific Gene ◽  
Pleural Mesothelioma ◽  
Sequencing Data ◽  
Age And Gender ◽  
Gene Pathway ◽  
Immune Biomarkers ◽  
Genomic Landscape ◽  
Whole Transcriptome Sequencing ◽  
And Gender

9056 Background: Malignant pleural mesothelioma (MPM) is a relatively uncommon malignancy with poor prognosis and no major therapeutic breakthroughs over the past decade. Better understanding of the genomic landscape and distribution of immune biomarkers in this disease has the potential to enable development of novel therapies. Methods: We analyzed molecular profiles of 222 MPM tumors using next-generation sequencing of 592 genes utilizing Caris Life Sciences platform. Genes were grouped into pathways: DNA damage repair (DDR) ( ATM, BRCA2, BRIP1, BAP1, CHEK2, ERCC2, FANCA/D2/E/L, MLH1, MSH6, MUTYH, NBN, PMS2, RAD50/51B, WRN), cell cycle regulation including TP53 ( RB1,CCNE1, CDKN2A, CCND1, CCND3, CDKN1B), chromatin remodeling (CR) ( ARID2, ASXL1, DNMT3A, EP300, EZH2, KDM6A, KMT2C, KMT2D, NSD3, PBRM1, SMARCB1/A4, SETD2), RAS/MAPK ( KRAS, MAP2K1, NF1, NF2), and PI3K/AKT ( AKT, PIK3CA, PIK3R1/R2, PTEN, RICTOR, TSC1, TSC2, ZNF703). Tumor mutational burden (TMB), PD-L1 expression (SP142 IHC, tumor staining), and MSI/MMR were analyzed. Seventy-two cases also had whole transcriptome sequencing data. Differences in alterations were compared for age, gender, and pathways. Results: Median age of patients (pts) was 72 yr (range, 37-90), 73% were male. Gene pathway alterations were seen in 81% of cases. DDR, specifically homologous recombination (HR), was the most commonly mutated pathway (36.9%), followed by RAS (25.2%) and CR (18.9%). Genes mutated in ≥5% of cases included BAP1 (26.3%), NF2 (23.5%), TP53 (15.5%), SETD2 (10.2%). PD-L1 was high (≥50% tumor cells positive) in 11.4% (n = 24), intermediate (1-49%) in 31.4% (n = 66), and negative ( < 1%) in 57.1% (n = 120) pts. TMB was high (≥10 mutations/Mb) in 9.6% of tumors (n = 20). None of the tumors were dMMR/MSI-H. HR gene BAP1 and CR gene SETD2 mutations trended to be more prevalent in pts ≥70 yo (p = 0.02). CR trended to be more commonly mutated in females (p = 0.02). No other significant differences were found in specific gene/pathway alterations, PD-L1 expression, or TMB in the context of age and gender. Distribution of PD-L1 expression was not different among various pathways. No highly recurrent, targetable fusion isoforms were seen among the 85 identified (mean 1.1 fusions/tumor), which have not yet been characterized for pathogenicity. Conclusions: The majority of MPM tumors harbor alteration in one of the key cellular pathways. HR pathway mutations are the most common. The majority of tumors were PD-L1 negative and carry low TMB indicating low immunogenicity. No age and gender specific differences exist except for BAP1 and SETD2 mutations.

scholarly journals Detection of Circulating Tumor Cells (CTCs) in Malignant Pleural Mesothelioma (MPM) with the “Universal” CTC-Chip and An Anti-Podoplanin Antibody NZ-1.2

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 888
Author(s):  
Taiji Kuwata ◽  
Kazue Yoneda ◽  
Masataka Mori ◽  
Masatoshi Kanayama ◽  
Koji Kuroda ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Malignant Pleural Mesothelioma ◽  
Circulating Tumor Cell ◽  
Microfluidic System ◽  
Clinical Implications ◽  
Pleural Mesothelioma ◽  
Rare Tumor ◽  
Podoplanin Expression ◽  
Higher Sensitivity

Circulating tumor cell (CTC) is a potentially useful surrogate of micro-metastasis, but detection of rare tumor cells contaminated in a vast majority of normal hematologic cells remains technical challenges. To achieve effective detection of a variety of CTCs, we have developed a novel microfluidic system (CTC-chip) in which any antibody to capture CTCs is easily conjugated. In previous studies, we employed an antibody (clone E-1) against podoplanin that was strongly expressed on mesothelioma cells. The CTC-chip coated by the E-1 antibody (E1-chip) provided a modest sensitivity in detection of CTCs in malignant pleural mesothelioma (MPM). Here, to achieve a higher sensitivity, we employed a novel anti-podoplanin antibody (clone NZ-1.2). In an experimental model, MPM cells with high podoplanin expression were effectively captured with the CTC-chip coated by the NZ-1.2 antibody (NZ1.2-chip). Next, we evaluated CTCs in the peripheral blood sampled from 22 MPM patients using the NZ1.2-chip and the E1-chip. One or more CTCs were detected in 15 patients (68.2%) with the NZ1.2-chip, whereas only in 10 patients (45.5%) with the E1-chip. Of noted, in most (92.3%, 12/13) patients with epithelioid MPM subtype, CTCs were positive with the NZ1.2-chip. The CTC-count detected with the NZ1.2-chip was significantly higher than that with the E1-chip (p = 0.034). The clinical implications of CTCs detected with the NZ1.2-chip will be examined in a future study.

Circulating tumor cell (CTC) as a clinical marker in malignant pleural mesothelioma (MPM).

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 10572-10572 ◽  
Author(s):  
F. Tanaka ◽  
K. Yoneda ◽  
N. Kondo ◽  
M. Hashimoto ◽  
T. Takuwa ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Malignant Pleural Mesothelioma ◽  
Circulating Tumor Cell ◽  
Pleural Mesothelioma ◽  
Clinical Marker
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