DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma

Cugliari, Giovanni; Catalano, Chiara; Guarrera, Simonetta; Allione, Alessandra; Casalone, Elisabetta; Russo, Alessia; Grosso, Federica; Ferrante, Daniela; Viberti, Clara; Aspesi, Anna; Sculco, Marika; Pirazzini, Chiara; Libener, Roberta; Mirabelli, Dario; Magnani, Corrado; Dianzani, Irma; Matullo, Giuseppe

doi:10.3390/cancers12113470

Cited by 9 publications

(10 citation statements)

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“…Since the methylation of TM promoter has been associated with survival and given the role of PARP1 in the methylation mechanism, this marker may be of interest for further investigation for therapeutic development. In 2019, Cugliari et al analyzed the peripheral blood of 159 MPMs and identified the CpG dinucleotide cg03546163 region associated with the gene FKBP5 as a significant marker for prognosis (205). This is very interesting as FKBP5 increases chemosensitivity to the AKT pathway, which is druggable in mesothelioma as previously described.…”

Section: Epigenetic Alterations As Promising Prognostic Biomarkersmentioning

confidence: 92%

“…In 2019, Cugliari et al. analyzed the peripheral blood of 159 MPMs and identified the CpG dinucleotide cg03546163 region associated with the gene FKBP5 as a significant marker for prognosis ( 205 ). This is very interesting as FKBP5 increases chemosensitivity to the AKT pathway, which is druggable in mesothelioma as previously described.…”

Section: Epigenetic Alterations As Promising Prognostic Biomarkersmentioning

confidence: 99%

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Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

et al. 2021

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Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

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Section: Epigenetic Alterations As Promising Prognostic Biomarkersmentioning

confidence: 92%

Section: Epigenetic Alterations As Promising Prognostic Biomarkersmentioning

confidence: 99%

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

et al. 2021

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“…Epigenetic changes have been associated with tumor progression and poor outcomes in a diverse array of tumors (28)(29)(30), and in MPM have been linked to alterations of the tumor-infiltrating immune cells. Epigenome-wide association analyses of a cohort of 159 asbestosexposed patients with MPM identified the methylation of the single-CpG marker, cg03546163, located in the 5' untranslated region of the FKBP5 gene, as associated to survival (31). This marker showed better performance compared with the traditional inflammation scores, lymphocyte-to-monocyte ratio (32), generally used as a prognostic biomarker in MPM.…”

Section: Genetic and Epigenetic Effects On The Immune Responsementioning

confidence: 99%

Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma

2021

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Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options beyond surgery and cytotoxic chemotherapy. The success of immune checkpoint inhibition has been found to correlate with expression of immune-related genes such as CD274 (PD-L1) in lung and other solid cancers. However, only a small subset of MPM patients respond to checkpoint inhibition, and this response has been varied and unpredictable across several clinical trials. Recent advances in next-generation sequencing (NGS) technology have improved our understanding of the molecular features of MPM, also with respect to its genetic signature and how this impacts the immune microenvironment. This article will review current evidence surrounding the interplay between MPM genetics, including epigenetics and transcriptomics, and the immune response.

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“…According to recent papers, both DNAm and genetic alterations may contribute to MPM tumorigenesis [ 10 , 11 , 12 , 13 , 14 , 15 ]. Whereas the genome remains consistent throughout one’s lifetime, factors like ageing, lifestyle, environmental exposures and diseases can modify DNAm.…”

Section: Introductionmentioning

confidence: 99%

“…Fischer et al examined serum DNAm of nine gene-specific promoters from MM cases [ 23 ]. A more recent paper identified hypomethylation of a single CpG in FKBP5 in whole blood cells as a predictor of overall survival in MPM cases [ 13 ]. Guarrera et al evaluated methylation levels in DNA from whole blood leukocytes as potential diagnostic markers for MPM and found a differential methylation between asbestos-exposed MPM cases and controls, mainly in genes related to the immune system [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment

Cugliari

Allione

Russo

et al. 2021

Cancers

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Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (>0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = −0.09, 95% CI = −0.12|−0.06, p = 1.2 × 10−7), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10−6). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10−11) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10−8) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 × 10−7; BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 × 10−8. Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects.

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DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma

Cited by 9 publications

References 50 publications

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma

New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment

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