Publications

Supplementary Figure S3 from Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas

<p>(A) Aspartate/glutamate ratios assessed by LC-MS in GOT2 KD Hela cells transfected with empty vector (EV), GOT2 wild-type (WT) cDNA, GOT2- c.223T>G cDNA, and GOT2- c.357A>T cDNA. The ratios were reported as means (n=3). Error bars represent standard deviations. A t-test was applied to test for differences between GOT WT and GOT2- c.223T>G and - c.357A>T transfected cells. n.s.: not significant. (B) Succinate/fumarate ratios assessed by LC-MS in OGDHL KD Hela cells transfected with EV, OGDHL WT cDNA, and OGDHL- c.750G>T cDNA. The ratios were reported as means (n=3). Error bars represent standard deviations. A t-test was applied to test for differences. n.s.: not significant</p>

Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder Cancer Study: a case–control study

Figure S6 from ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms

<p>Expression levels of surface ERBB4 and pERBB4 was measured by FACS (A) and immunoblotting (B) in Karpas1718 parental and resistant. (A) Two independent experiments were performed: exp1 (left panel) and exp2 (right panel). Density plots show the median MFI values of two replicates from each experiment: negative control (dotted black), parental (grey), resistant (red). Results are presented from Welch Two Sample test performed on MFI values of the two experiments. (B) Immunobloting for total (grey) and phospho (red) ERBB4 in parental (left) and resistant (right) Karpas1718 cells. Representative image of two independent experiments. Data on the barplot represents the mean of two experiments, errors bars represent standard deviation of the mean. * for p<0.05 from a t-test.</p>

Supplementary Figure 1 from The PDGFRβ–AKT Pathway Contributes to CDDP-Acquired Resistance in Testicular Germ Cell Tumors

<p>PDF file - 242K, In Figure S1 we present the results obtained on PDGFR expression analysis by flow cytometry, were we show how this receptor is expressed in the cell surface at higher levels in GCT27R cells than in GCT27S cells.</p>

Fiscal Transparency

Abstract Quality of governance is a key for political accountability, hence, the importance of identifying its determinants. Here, we focus on one dimension of quality of governance: fiscal transparency. Drawing on a sample of 691 Catalan municipalities (2001–7), we estimate the factors determining levels of budgetary transparency. Political competition and decentralization are the most important determinants of fiscal transparency. By contrast, budgetary variables do not appear to play any role.

Data from The Inescapable Influence of Noncoding RNAs in Cancer

<div>Abstract<p>This report summarizes information presented at the 2015 Keystone Symposium on “MicroRNAs and Noncoding RNAs in Cancer.” Nearly two decades after the discovery of the first miRNA, the role of noncoding RNAs in developmental processes and the mechanisms behind their dysregulation in cancer has been steadily elucidated. Excitingly, miRNAs have begun making their way into the clinic to combat diseases such as hepatitis C and various forms of cancer. Therefore, at this Keystone meeting, novel findings were presented that enhance our view on how small and long noncoding RNAs control developmental timing and oncogenic processes. Recurring themes included (i) how miRNAs can be differentially processed, degraded, and regulated by ribonucleoprotein complexes, (ii) how particular miRNA genetic networks that control developmental process, when disrupted, can result in cancer disease, (iii) the technologies available to therapeutically deliver RNA to combat diseases such as cancer, and (iv) the elucidation of the mechanism of actions for long noncoding RNAs, currently a poorly understood class of noncoding RNA. During the meeting, there was an emphasis on presenting unpublished findings, and the breadth of topics covered reflected how inescapable the influence of noncoding RNAs is in development and cancer. <i>Cancer Res; 75(24); 5206–10. ©2015 AACR</i>.</p></div>

Abstract 4252: Redefining the DNA methylome of prostate cancer using DNA methylation arrays.

Abstract Prostate cancer (PCa) is the most common noncutaneous malignancy and a leading cause of cancer death among men. Clinically localized disease might be successfully treated whereas disseminated disease remains mostly lethal. During prostate cancer development and progression, tumor cells undergo abnormal epigenetic modifications, including DNA methylation alterations. DNA methylation is the most studied epigenetic alteration in human cancer, and is associated with transcriptional repression of both coding and non-coding regions of the genome. Aberrant DNA methylation is gaining force in the fields of cancer risk assessment, diagnosis and therapy monitoring in different cancer types, including prostate cancer. Importantly, aberrant hypermethylation is widespread during neoplastic alteration of prostate cells, suggesting that restoration of a normal prostate epigenome through treatment with demethylating drugs could be clinically beneficial. The main aim of this work was to identify new epigenetically downregulated CpG's in PCa, using the 450K cytosine microarray-based approach, followed by validation in a larger set of clinical samples. We used the Infinium HumanMethylation450 BeadChip (Illumina) to consistently and significantly detect CpG methylation changes in prostate cancer tissues in comparison with morphological normal prostate tissue. The selected genomic regions were validated by pyrosequencing. The methylation data were subsequently confirmed at mRNA level using qRT-PCR. To prove the functional role of aberrant DNA methylation, we also performed a treatment with 5-Aza-2′-Deoxycytidine in PCa cell lines. Our work might provide new translational applications to the clinical management of PCa patients, based on of DNA methylation changes in PCa. Citation Format: Joao Ramalho-Carvalho, Rui Henrique, Sergi Sayols, Antonio Gomez, Carmen Jerónimo, Manel Esteller. Redefining the DNA methylome of prostate cancer using DNA methylation arrays. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4252. doi:10.1158/1538-7445.AM2013-4252

Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming

Figure S1 from Single-cell Multiomics Analysis of Myelodysplastic Syndromes and Clinical Response to Hypomethylating Therapy

<p>Mutational burden at diagnosis across patients and correlation between single-cell and bulk VAFs</p>

An Adenine Code for DNA: A Second Life for N6-Methyladenine

Table S4 from ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms

<p>Sequences of sgRNAs used for induction of ERBB4 transcription by CRISPR activation technique.</p>

Spontaneous subgaleal haematoma presenting as an alteration in platelet function

Epitranscriptomics in Hematopoiesis and Hematologic Malignancies

Abstract Since the 1960s, a large number of chemical modifications have been identified in RNA molecules, establishing the RNA epigenetics field named “epitranscriptomics.” These chemical marks participate in several RNA metabolic processes; however, the biological relevance of many of these modifications and the many enzymes involved in their function is not completely understood. Emerging knowledge of the epitranscriptome (pseudouridine, N6-methyladenosine, and A-to-I editing) in hematopoiesis and hematologic malignancies reveals the requirement of these modifications in normal development and their alteration in disorders, leading to the development of new molecules and strategies to target the epitranscriptome as a novel therapeutic approach. RNA modifications are required for the correct development of hematopoietic cells, and their alteration can promote the development of malignancies or the transition from a low-grade to an aggressive disease. While we are expanding our understanding of the epitranscriptome of normal and malignant hematopoiesis, the number of potential new therapeutic interventions is rising.

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus

Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.

Non‐CpG island promoter hypomethylation and miR‐149 regulate the expression of <i>SRPX2</i> in colorectal cancer

Gene silencing by DNA hypermethylation of CpG islands is a well-characterized phenomenon in cancer. The effect of hypomethylation in particular of non-CpG island genes is much less well described. By genome-wide screening, we identified 105 genes in microsatellite stable (MSS) colorectal adenocarcinomas with an inverse correlation (Spearman's ρ ≤ -0.40) between methylation and expression. Of these, 35 (33%) were hypomethylated non-CpG island genes and two of them, APOLD1 (Spearman's ρ = -0.82) and SRPX2 (Spearman's ρ = -0.80) were selected for further analyses. Hypomethylation of both genes were localized events not shared by adjacent genes. A set of 662 FFPE DNA samples not only confirmed that APOLD1 and SRPX2 are hypomethylated in CRC but also revealed hypomethylation to be significantly (p <0.01) associated with tumors being localized in the left side, CpG island methylator phenotype negative, MSS, BRAF wt, undifferentiated and of adenocarcinoma histosubtype. Demethylation experiments supported SRPX2 being epigenetically regulated via DNA methylation, whereas other mechanisms in addition to DNA methylation seem to be involved in the regulation of APOLD1. We further identified miR-149 as a potential novel post-transcriptional regulator of SRPX2. In carcinoma tissue, miR-149 was downregulated and inversely correlated to SRPX2 (ρ = -0.77). Furthermore, ectopic expression of miR-149 significantly reduced SRPX2 transcript levels. Our study highlights that in colorectal tumors, hypomethylation of non-CpG island-associated promoters deregulate gene expression nearly as frequent as do CpG-island hypermethylation. The hypomethylation of SRPX2 is focal and not part of a large block. Furthermore, it often translates to an increased expression level, which may be modulated by miR-149.

Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers and Therapeutic Targets?

Cancer Epigenetics: Dna Methylation and Chromatin Alterations in Human Cancer

96 INVITED Human Cancer Epigenetics