GCAT|Panel, a comprehensive structural variant haplotype map of the Iberian population from high-coverage whole-genome sequencing.

The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization, and phasing of structural variants (SVs).

Somatic Hypomethylation of Pericentromeric SST1 Repeats and Tetraploidization in Human Colorectal Cancer Cells.

Somatic DNA hypomethylation and aneuploidy are hallmarks of cancer, and there is evidence for a causal relationship between them in knockout mice but not in human cancer. The non-mobile pericentromeric repetitive elements SST1 are hypomethylated in about 17% of human colorectal cancers (CRC) with some 5-7% exhibiting strong age-independent demethylation. We studied the frequency of genome doubling, a common event in solid tumors linked to aneuploidy, in randomly selected single cell clones of near-diploid LS174T human CRC cells differing in their level of SST1 demethylation.

Stimulated emission depletion (STED) super resolution imaging of RNA- and protein-containing domains in fixed cells.

Super resolution microscopy has changed our capability to visualize and understand spatial arrangements of RNA- and protein-containing domains in individual cells. In a previous study, we described a novel lncRNA, Tumor-associated NBL2 transcript (TNBL), which originates from a primate specific macrosatellite repeat. We aimed to describe several aspects of TNBL lncRNA, with one focus being pinpointing its precise location in the nucleus, as well as visualizing its interactions with proteins to deduce its functionality.

Preservation of fertility in patients with cancer (Review).

Survival rates in oncological patients have been steadily increasing in recent years due to the greater effectiveness of novel oncological treatments, such as radio‑ and chemotherapy. However, these treatments impair the reproductive ability of patients, and may cause premature ovarian failure in females and azoospermia in males. Fertility preservation in both female and male oncological patients is nowadays possible and should be integrated as part of the oncological healthcare.

Genomic profiling in advanced stage non-small-cell lung cancer patients with platinum-based chemotherapy identifies germline variants with prognostic value in SMYD2.

Objective: The aim of the study was to investigate the relationship between germline variations as a prognosis biomarker in patients with advanced Non-Small-Cell-Lung-Cancer (NSCLC) subjected to first-line platinum-based treatment.

Materials And Methods: We carried out a two-stage genome-wide-association study in non-small-cell lung cancer patients with platinum-based chemotherapy in an exploratory sample of 181 NSCLC patients from Caucasian origin, followed by a validation on 356 NSCLC patients from the same ancestry (Valencia, Spain).

Results: We identified germline variants in SMYD2 as a prognostic factor for survival in patients with advanced NSCLC receiving chemotherapy.

Multitrait genome association analysis identifies new susceptibility genes for human anthropometric variation in the GCAT cohort.

Background: Heritability estimates have revealed an important contribution of SNP variants for most common traits; however, SNP analysis by single-trait genome-wide association studies (GWAS) has failed to uncover their impact. In this study, we applied a multitrait GWAS approach to discover additional factor of the missing heritability of human anthropometric variation.

Methods: We analysed 205 traits, including diseases identified at baseline in the GCAT cohort (Genomes For Life- Cohort study of the Genomes of Catalonia) (n=4988), a Mediterranean adult population-based cohort study from the south of Europe.

A novel long non-coding RNA from NBL2 pericentromeric macrosatellite forms a perinucleolar aggregate structure in colon cancer.

Primate-specific NBL2 macrosatellite is hypomethylated in several types of tumors, yet the consequences of this DNA hypomethylation remain unknown. We show that NBL2 conserved repeats are close to the centromeres of most acrocentric chromosomes. NBL2 associates with the perinucleolar region and undergoes severe demethylation in a subset of colorectal cancer (CRC).

Methylation-Sensitive Amplification Length Polymorphism (MS-AFLP) Microarrays for Epigenetic Analysis of Human Genomes.

Somatic, and in a minor scale also germ line, epigenetic aberrations are fundamental to carcinogenesis, cancer progression, and tumor phenotype. DNA methylation is the most extensively studied and arguably the best understood epigenetic mechanisms that become altered in cancer. Both somatic loss of methylation (hypomethylation) and gain of methylation (hypermethylation) are found in the genome of malignant cells.

GCAT|Genomes for life: a prospective cohort study of the genomes of Catalonia.

Purpose: The prevalence of chronic non-communicable diseases (NCDs) is increasing worldwide. NCDs are the leading cause of both morbidity and mortality, and it is estimated that by 2030, they will be responsible for 80% of deaths across the world. The Genomes for Life (GCAT) project is a long-term prospective cohort study that was designed to integrate and assess the role of epidemiological, genomic and epigenomic factors in the development of major chronic diseases in Catalonia, a north-east region of Spain.

Analysis of Somatic DNA Methylation Alterations of Genes Encoding Cell Surface Metallopeptidases in Colorectal Cancer.

The genome of cancer cells accumulates numerous genetic and epigenetic somatic alterations ultimately conferring capabilities for unrestrained growth, invasion of local tissues, migration, and colonization of distant organs. Many of these new capabilities require the disruption of the cell-to-cell interactions between the cancer cell and its microenvironment. These interactions are mediated, among other factors, by the activity of extracellular enzymes that reshape not only the extracellular compartment of the cancer cells but also that of the neighboring non-cancerous stroma cells.

Helicase Lymphoid-Specific Enzyme Contributes to the Maintenance of Methylation of SST1 Pericentromeric Repeats That Are Frequently Demethylated in Colon Cancer and Associate with Genomic Damage.

DNA hypomethylation at repetitive elements accounts for the genome-wide DNA hypomethylation common in cancer, including colorectal cancer (CRC). We identified a pericentromeric repeat element called SST1 frequently hypomethylated (>5% demethylation compared with matched normal tissue) in several cancers, including 28 of 128 (22%) CRCs. SST1 somatic demethylation associated with genome damage, especially in tumors with wild-type Seven percent of the 128 CRCs exhibited a higher ("severe") level of demethylation (≥10%) that co-occurred with mutations.

Emerging roles of macrosatellite repeats in genome organization and disease development.

Abundant repetitive DNA sequences are an enigmatic part of the human genome. Despite increasing evidence on the functionality of DNA repeats, their biologic role is still elusive and under frequent debate. Macrosatellites are the largest of the tandem DNA repeats, located on one or multiple chromosomes.

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape.

We wanted to implement an NGS strategy to globally analyze hereditary cancer with diagnostic quality while retaining the same degree of understanding and control we had in pre-NGS strategies. To do this, we developed the I2HCP panel, a custom bait library covering 122 hereditary cancer genes. We improved bait design, tested different NGS platforms and created a clinically driven custom data analysis pipeline.

Clinical characteristics of synchronous colorectal cancers in Japan.

Background: Incidence and clinical characteristics of synchronous colorectal cancer (sCRC) patients significantly vary among studies, likely due to differences in surveillance methodology. If remain undetected, sCRC can progress to more advanced stages seriously aggravating patient prognosis. We studied the incidence and clinicopathological characteristics of Japanese patients with sCRCs who underwent surgery for primary CRC and received exhaustive perioperative surveillance.

MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells.

We aimed to elucidate the effect of JQ1, a BET inhibitor, on small cell lung cancers (SCLCs) with MYCL amplification and/or expression. Fourteen SCLC cell lines, including four with MYCL amplification, were examined for the effects of JQ1 on protein and gene expression by Western blot and mRNA microarray analyses. The sensitivity of SCLC cells to JQ1 was assessed by cell growth and apoptosis assays.

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis.

Unlabelled: Peptidyl arginine deiminases (PADI) are a family of enzymes that catalyze the poorly understood posttranslational modification converting arginine residues into citrullines. In this study, the role of PADIs in the pathogenesis of colorectal cancer was investigated. Specifically, RNA expression was analyzed and its association with survival in a cohort of 98 colorectal cancer patient specimens with matched adjacent mucosa and 50 controls from donors without cancer.

Malignant, but not benign, intraductal papillary mucinous neoplasm preferentially associates with prior extrapancreatic malignancies.

Intraductal papillary mucinous neoplasm (IPMN) has been associated with a high incidence of extrapancreatic malignancies (EPMs). However, it is controversial whether IPMN is prognostic for EPM. We aimed to help clarify the issue studying this association in patients with histologically proven IPMN.

Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation.

Small cell lung cancer (SCLC) is the most aggressive type of lung cancer with high mortality. One of the MYC family genes, MYC, MYCL or MYCN, is amplified in ~20% of the SCLCs; therefore, MYC proteins are potential therapeutic targets in SCLC patients. We investigated the therapeutic impact of Omomyc, a MYC dominant negative, in a panel of SCLC cell lines.

Tumor size is an independent risk predictor for metachronous colorectal cancer.

Non-hereditary colorectal cancer (CRC) patients are at higher risk of developing independent metachronous CRC than cancer-naïve individuals, but the reason is unknown. We studied metachronous CRC risk factors among one thousand five Japanese CRC patients who underwent surgery for CRC. Relative hazard risk of clinical and pathological features was assessed by univariate and multivariate Cox's proportional hazard regression analysis.

Quantification of unmethylated Alu (QUAlu): a tool to assess global hypomethylation in routine clinical samples.

Hypomethylation of DNA is a hallmark of cancer and its analysis as tumor biomarker has been proposed, but its determination in clinical settings is hampered by lack of standardized methodologies. Here, we present QUAlu (Quantification of Unmethylated Alu), a new technique to estimate the Percentage of UnMethylated Alu (PUMA) as a surrogate for global hypomethylation. QUAlu consists in the measurement by qPCR of Alu repeats after digestion of genomic DNA with isoschizomers with differential sensitivity to DNA methylation.

Epigenetic inactivation of the extracellular matrix metallopeptidase ADAMTS19 gene and the metastatic spread in colorectal cancer.

Background: ADAMTS19 encodes a member of the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) protein family with emerging roles in carcinogenesis and metastasis. ADAMTS shares several distinct protein modules including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. In a previous work, we found ADAMTS19 frequently hypermethylated in colorectal cancer (CRC).

Somatic DNA Hypomethylation in H. pylori-Associated High-Risk Gastritis and Gastric Cancer: Enhanced Somatic Hypomethylation Associates with Advanced Stage Cancer.

Objectives: Helicobacter pylori-related high-risk gastritis (HRG) is a severe risk factor for gastric cancer (GC). The link between HRG and long-term risk for GC may involve genetic and epigenetic alterations underlying a field defect, i.e.

Second German-Catalan workshop on epigenetics & cancer.

The Second German-Catalan Workshop on Epigenetics and Cancer was held in Barcelona on November 19-21, 2014. The workshop brought together, for the second time, scientists from 2 German and 2 Catalan research institutions: the DKFZ, from Heidelberg, the CRCME, from Freiburg, and the IMPPC and PEBC/IDIBELL, both from Barcelona. The German-Catalan Workshops are intended to establish the framework for building a Research School to foster collaborations between researchers from the different institutions.

Mycoplasma CG- and GATC-specific DNA methyltransferases selectively and efficiently methylate the host genome and alter the epigenetic landscape in human cells.

Aberrant DNA methylation is frequently observed in disease, including many cancer types, yet the underlying mechanisms remain unclear. Because germline and somatic mutations in the genes that are responsible for DNA methylation are infrequent in malignancies, additional mechanisms must be considered. Mycoplasmas spp.

Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans.

Somatic hypermethylation of the O6-methylguanine-DNA methyltransferase gene (MGMT) was previously associated with G > A transition mutations in KRAS and TP53 in colorectal cancer (CRC). We tested the association of MGMT methylation with G > A mutations in KRAS and TP53 in 261 CRCs. Sixteen cases, with and without MGMT hypermethylation, were further analyzed by exome sequencing.