CA: A Cancer Journal for Clinicians13 Dec 2022, . Epub 13 Dec 2022
Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome. Whereas genetic changes disrupt the DNA sequence, epigenetic alterations contribute to the acquisition of hallmark tumor capabilities by regulating gene expression programs that promote tumorigenesis. Shifts in DNA methylation and histone mark patterns, the two main epigenetic modifications, orchestrate tumor progression and metastasis. These cancer-specific events have been exploited as useful tools for diagnosis, monitoring, and treatment choice to aid clinical decision making. Moreover, the reversibility of epigenetic modifications, in contrast to the irreversibility of genetic changes, has made the epigenetic machinery an attractive target for drug development. This review summarizes the most advanced applications of epigenetic biomarkers and epigenetic drugs in the clinical setting, highlighting commercially available DNA methylation-based assays and epigenetic drugs already approved by the US Food and Drug Administration.
van der Strate I, Kazemzadeh F, Nagtegaal ID, Robbrecht D, van de Wouw A, Padilla CS, Duijts S, Esteller M, Greco FA, Pavlidis N, Qaseem A, Snaebjornsson P, van Zanten SV, Loef C
International consensus on the initial diagnostic workup of cancer of unknown primary.
Crit Rev Oncol Hematol23 Nov 2022, 181103868. Epub 23 Nov 2022
Although the incidence of Cancer of Unknown Primary (CUP) is estimated to be 1-2 % of all cancers worldwide, no international standards for diagnostic workup are yet established. Such an international guideline would facilitate international comparison, provide adequate incidence and survival rates, and ultimately improve care of patients with CUP.
Genetic and epigenetic defects of the RNA modification machinery in cancer.
Trends Genet12 Nov 2022, . Epub 12 Nov 2022
Cancer was initially considered to be an exclusively genetic disease, but an interplay of dysregulated genetic and epigenetic mechanisms is now known to contribute to the cancer phenotype. More recently, chemical modifications of RNA molecules - the so-called epitranscriptome - have been found to regulate various aspects of RNA function and homeostasis. Specific enzymes, known as RNA-modifying proteins (RMPs), are responsible for depositing, removing, and reading chemical modifications in RNA. Intensive investigations in the epitranscriptomic field in recent years, in conjunction with great technological advances, have revealed the critical role of RNA modifications in regulating numerous cellular pathways. Furthermore, growing evidence has revealed that RNA modification machinery is often altered in human cancers, highlighting the enormous potential of RMPs as pharmacological targets or diagnostic markers.
PRC2 Loss and DNMT Inhibition Boost Viral Mimicry in Cancer.
Cancer Discov2 Sep 2022, 12(9)2020-2022.
In this issue of Cancer Discovery, Patel and colleagues explore the synergistic lethality of PRC2 inactivation and DNMT inhibition in malignant peripheral nerve sheath tumor cells. Reactivation of retrotransposons under this dual control suggests that the viral mimicry response contributes to enhanced cytotoxicity with potential clinical implications. See related article by Patel et al., p. 2120 (5).
R. S. Joshi, M. Rigau, C.A. García-Prieto, M. Castro de Moura, D. Piñeyro, S. Moran, V. Davalos, P. Carrion, M. Ferrando-Bernal, I. Olalde, C. Lalueza-Fox, A. Navarro, C. Fernández-Tena, D. Aspandi, F. M. Sukno, X. Binefa, A. Valencia, M. Esteller
Look-alike humans identified by facial recognition algorithms show genetic similarities
Cell Reports30 Aug 2022, .
The human face is one of the most visible features of our unique identity as individuals. Interestingly, mono-zygotic twins share almost identical facial traits and the same DNA sequence but could exhibit differences in other biometrical parameters. The expansion of the world wide web and the possibility to exchange pictures of humans across the planet has increased the number of people identified online as virtual twins or doubles that are not family related. Herein, we have characterized in detail a set of ‘‘look-alike’’ humans, defined by facial recognition algorithms, for their multiomics landscape. We report that these individuals share similar genotypes and differ in their DNA methylation and microbiome landscape. These results not only provide in-sights about the genetics that determine our face but also might have implications for the establishment of other human anthropometric properties and even personality characteristics.
Lucas Pontel, Alberto Bueno-Costa, Agustín E. Morellato, Juliana Carvalho Santos, Gaël Roué, Manel Esteller
Ferroptosis is a form of cell death triggered by phospholipid hydroperoxides (PLOOH) generated from the iron-dependent oxidation of polyunsaturated fatty acids (PUFAs). To prevent ferroptosis, cells rely on the antioxidant glutathione (GSH), which serves as cofactor of the glutathione peroxidase 4 (GPX4) for the neutralization of PLOOHs. Some cancer cells can also limit ferroptosis through a GSH-independent axis, centered mainly on the ferroptosis suppressor protein 1 (FSP1). The significance of these two anti-ferroptosis pathways is still poorly understood in cancers from hematopoietic origin. Here, we report that blood-derived cancer cells are selectively sensitive to compounds that block the GSH-dependent anti-ferroptosis axis. In T and B acute lymphoblastic leukemia (ALL) cell lines and patient biopsies, the promoter of the gene coding for FSP1 is hypermethylated, silencing the expression of FSP1 and creating a selective dependency on GSH-centered anti-ferroptosis defenses. In-trans expression of FSP1 increases the resistance of leukemic cells to compounds targeting the GSH-dependent anti-ferroptosis pathway. FSP1 over-expression also favors ALL-tumor growth in an in vivo chick chorioallantoic membrane (CAM) model. Hence, our results reveal a metabolic vulnerability of ALL that might be of therapeutic interest.
A timely, user-friendly analysis of the mouse DNA methylome
Mouse models are widely used in biomedical sciences and in epigenetic studies, yet a simple way to interrogate the mouse DNA methylation was lacking. In this issue of Cell Genomics, Zhou et al.1 describe a mouse DNA methylation microarray to simplify epigenomic analysis.
Jan Bińkowski, Olga Taryma-Leśniak, Karolina Łuczkowska, Anna Niedzwiedź, Kacper Lechowicz, Dominik Strapagiel, Justyna Jarczak, Veronica Davalos, Aurora Pujol, Manel Esteller, Katarzyna Kotfis, Bogusław Machaliński, Miłosz Parczewski, Tomasz K. Wojdacz
Epigenetic activation of antiviral sensors and effectors of interferon response pathways during SARS-CoV-2 infection
Biomedicine & Pharmacotherapy11 Jul 2022, .
Recent studies have shown that methylation changes identified in blood cells of COVID-19 patients have a potential to be used as biomarkers of SARS-CoV-2 infection outcomes. However, different studies have reported different subsets of epigenetic lesions that stratify patients according to the severity of infection symptoms, and more importantly, the significance of those epigenetic changes in the pathology of the infection is still not clear. We used methylomics and transcriptomics data from the largest so far cohort of COVID-19 patients from four geographically distant populations, to identify casual interactions of blood cells’ methylome in pathology of the COVID-19 disease. We identified a subset of methylation changes that is uniformly present in all COVID-19 patients regardless of symptoms. Those changes are not present in patients suffering from upper respiratory tract infections with symptoms similar to COVID-19. Most importantly, the identified epigenetic changes affect the expression of genes involved in interferon response pathways and the expression of those genes differs between patients admitted to intensive care units and only hospitalized. In conclusion, the DNA methylation changes involved in pathophysiology of SARS-CoV-2 infection, which are specific to COVID-19 patients, can not only be utilized as biomarkers in the disease management but also present a potential treatment target.
M. Casado-Pelaez, A. Bueno-Costa, M. Esteller
Single cell cancer epigenetics
Trends in Cancer9 Jul 2022, .
The epigenome encompasses several mechanisms controlling gene expression that can be aberrantly regulated during cancer development and progression. Tumors are highly complex and heterogeneous biological systems that require the study of epigenetic alterations at a single cell resolution.
Several single cell technologies developed to study different layers of the epigenome, such as chromatin accessibility or histone modifications, have been developed and applied in cancer research over the past few years, improving our understanding of the mechanisms driving tumorigenesis.
Although these techniques are promising, most are still nascent and present limitations, such as low throughput and limited coverage. In addition, the analysis and integration of the various single cell epigenomic data modalities have challenges and require the development of new computational tools.
Bulk sequencing methodologies have allowed us to make great progress in cancer research. Unfortunately, these techniques lack the resolution to fully unravel the epigenetic mechanisms that govern tumor heterogeneity. Consequently, many novel single cell-sequencing methodologies have been developed over the past decade, allowing us to explore the epigenetic components that regulate different aspects of cancer heterogeneity, namely: clonal heterogeneity, tumor microenvironment (TME), spatial organization, intratumoral differentiation programs, metastasis, and resistance mechanisms. In this review, we explore the different sequencing techniques that enable researchers to study different aspects of epigenetics (DNA methylation, chromatin accessibility, histone modifications, DNA–protein interactions, and chromatin 3D architecture) at the single cell level, their potential applications in cancer, and their current technical limitations.
Veronica Davalos, Carlos A. García-Prieto, Gerardo Ferrer, Sergio Aguilera-Albesa, Juan Valencia-Ramos, Agustí Rodríguez-Palmero, Montserrat Ruiz, Laura Planas-Serra, Iolanda Jordan, Iosune Alegría, Patricia Flores-P erez, Veronica Cantarín, Victoria Fumado, Maria Teresa Viadero, Carlos Rodrigo, Maria Méndez-Hernández, Eduardo Lopez-Granados, Roger Colobran, Jacques G. Riviere, Pere Soler-Palacín, Aurora Pujol, Manel Esteller
Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study
Lancet eClinicalMedicine25 Jun 2022, 50 .
Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C.
Peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants.
The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C.
We have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder.