Publications

<p>Clinical information on the series of serum samples from CLL clinical patients exposed to idelalisib or to ibrutinib. Samples were longitudinally acquired at different time points. Patients were paired according to similar clinical features.</p>

Supplementary Figure 1 from Discovery of Epigenetically Silenced Genes by Methylated DNA Immunoprecipitation in Colon Cancer Cells

We have with enthusiasm taken the challenge from Begell House, the publisher, to reintroduce Critical Reviews in Oncogenesis (CRO) to an audience of scientists, students, and health personnel.The last issue of CRO was published in 2000, and the following year, the first draft of the human genome sequence was published. 1,2Those latter publications are among the most important ones following the identification of the DNA helix more than 50 years ago. 3The biological breakthroughs, combined with the tremendous technological developments, state that modern biomedical research and advanced medicine are truly dependent on competences across sciences.With this in mind, we believe that the new CRO should attempt to grasp the interest of a broad range of readers, from those dedicated to cancer research to those with educational interests, or with the wish to be updated in the latest research and to obtain easily accessible overviews of cancer relevant themes.We will seek to cover basic research, translational, and clinical issues, as well as epidemiological studies, all of which are cornerstones in any comprehensive cancer center.In this first issue, we present six review articles covering a broad range of aspects of cancer science.The article by Mesquita et al., beginning on page 3, 4 reviews the interesting topic of tissue transdifferentiation with focus on a naturally occurring process -gastric intestinal metaplasia.The authors challenge the conservative textbook definition and provide an update on the molecular regulation mechanisms of this phenomenon.This article reviews a topic of interest to a wide range of sciences, including stem cell research.The challenge of molecular mechanisms explaining complex morphological tissue patterns are also discussed by Torlacovic and Snover, beginning on page 27. 5 These authors present a useful overview of classification of colorectal polyps with emphasis on the spectrum of serrated polyps.The latter is an unfamiliar term to many and is often, and wrongly, included in the subgroup of hyperplastic polyps.The identification of the serrated pathway will not only aid in understanding the tumor etiology, but also have clinical consequences for the patients.The group of Guldberg from the University of Copenhagen has long experience in mutational analyses in cancers, as well as in other diseases.Their article by Dahl et al., beginning on page 41, 6 provides an in-depth critical review of the benefits and limitations of some of the most used methods for detection of unknown mutations, as well as for diagnostic analyses of known mutations.Germline mutations that predispose individuals to a variable extent of risk to develop breast cancer are summarized in a review on familial breast cancer by Margolin and Lindblom beginning on page 75. 7This article also covers the clinical implications of gene testing in breast cancer as well as strategies for prevention and treatment.Another clinical challenge for one of the major cancer diseases in the Western world, carcinomas in the large bowel, is dealt with in the article from

Sirtuins are key players of metabolic stress response. Originally described as deacetylases, some sirtuins also exhibit poorly understood mono-adenosine 5'-diphosphate (ADP)-ribosyltransferase (mADPRT) activity. We report that the deacetylase SirT7 is a dual sirtuin, as it also features auto-mADPRT activity. SirT7 mADPRT occurs at a previously undefined active site, and its abrogation alters SirT7 chromatin distribution. We identify an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions. SirT7 promotes mH2A1 enrichment in a subset of nearby genes, many of them involved in second messenger signaling, resulting in their specific up- or down-regulation. The expression profile of these genes under calorie restriction is consistently abrogated in SirT7-deficient mice, resulting in impaired activation of autophagy. Our work provides a novel perspective on sirtuin duality and suggests a role for SirT7/mH2A1.1 axis in glucose homeostasis and aging.

1UCD Conway Institute of Biomolecular and Biomedical Research University College Dublin, Ireland 2CNIO, Madrid, Spain Abstracts of the Perspectives in Melanoma X and The Third Annual International Melanoma Research Congress, 14–16 September 2006, Noordwijk, The Netherlands

<p>Fisher exact test for each mutated gene, comparing responders vs. non-responders at diagnosis</p>

Somatic epigenetic inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) is frequent in colorectal cancer (CRC); however, its involvement in CRC predisposition remains unexplored. We assessed the role and relevance of MGMT germline mutations and epimutations in familial and early-onset CRC. Mutation and promoter methylation screenings were performed in 473 familial and/or early-onset mismatch repair-proficient nonpolyposis CRC cases. No constitutional MGMT inactivation by promoter methylation was observed. Of six rare heterozygous germline variants identified, c.346C > T (p.H116Y) and c.476G > A (p.R159Q), detected in three and one families respectively, affected highly conserved residues and showed segregation with cancer in available family members. In vitro, neither p.H116Y nor p.R159Q caused statistically significant reduction of MGMT repair activity. No evidence of somatic second hits was found in the studied tumors. Case-control data showed over-representation of c.346C > T (p.H116Y) in familial CRC compared to controls, but no overall association of MGMT mutations with CRC predisposition. In conclusion, germline mutations and constitutional epimutations in MGMT are not major players in hereditary CRC. Nevertheless, the over-representation of c.346C > T (p.H116Y) in our familial CRC cohort warrants further research.

Abstract DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D-susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits.

<p>Supplementary Figures and Tables combined</p>

Abstract In 2013, the ALFA (ALzheimer and FAmilies) project was established to investigate pathophysiological changes in preclinical Alzheimer’s disease (AD), and to foster research on early detection and preventive interventions. Since then, it has prospectively followed cognitively unimpaired late/middle-aged participants, most of whom are adult children of AD patients. Risk stratification of cognitively unimpaired individuals, including genetic factors is key for implementing AD prevention strategies. Here, we report the genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers, emphasizing amyloid/tau status and gender differences. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic risk of AD. It is, therefore, well-suited to study early pathophysiological changes in the preclinical AD continuum . Highlights Prevalence of ε4 carriers in ALFA is higher than in the general European population. The ALFA study is highly enriched in AD genetic risk factors beyond APOE . AD genetic profiles in ALFA are similar to clinical groups along the continuum . ALFA has succeeded in establishing a cohort of CU individuals at high genetic AD risk. ALFA is well suited to study pathogenic events/early pathophysiological changes in AD.

Systemic lupus erythematosus (SLE) is characterised by systemic inflammation involving various immune cell types. Monocytes, pivotal in promoting and regulating inflammation in SLE, differentiate from classic monocytes into intermediate and non-classic monocytes, assuming diverse roles and changing their proportions in inflammation. In this study, we investigated the epigenetic and transcriptomic profiles of these and novel monocyte subsets in SLE in relation to activity and progression.