Genetics and epigenetics of 1q rearrangements in hematological malignancies

Recently, we and others have described a novel class of chromosome aberrations that involves constitutive heterochromatin on human chromosome 1 (cytogenetic band 1q12). These anomalies are particularly frequent in B cell non-Hodgkins lymphoma (NHL) and multiple myeloma (MM) and, remarkably, almost invariably involve partial or total gain of chromosome 1q (including 1q12 heterochromatin) and the formation of novel heterochromatin/euchromatin junctions. This review discusses the pathological significance of these anomalies in light of i) recent integrated gene expression and array comparative genomic hybridisation (aCGH) profiling in MM and ii) increasing evidence of a key role for heterochromatin in the control of normal and pathological gene silencing.     

Genetics and epigenetics of facio-scapulohumeral progressive (Landouzy-Dejerine) muscular dystrophy

Landouzy-Dejerine muscular dystrophy is a rare hereditary disease with prevalence of 0.9 to 1.4 in 100,000. Clinically the disease is characterized by weakness and atrophy of the facial and shoulder girdle muscles. It is caused by partial deletion of the 3.3-kb subtelomeric D4Z4 repeat on chromosome 4 (locus 4q35). This paper presents a critical review of the literature data and hypotheses explaining molecular mechanisms of progressive fascioscapulohumeral muscular dystrophy.     

German-Catalan workshop on epigenetics and cancer

In the First German-Catalan Workshop on Epigenetics and Cancer held in Heidelberg, Germany (June 17–19, 2013), cutting-edge laboratories (PEBC, IMPPC, DKFZ, and the Collaborative Research Centre Medical Epigenetics of Freiburg) discussed the latest breakthroughs in the field. The importance of DNA demethylation, non-coding and imprinted genes, metabolic stress, and cell transdifferentiation processes in cancer and non-cancer diseases were addressed in several lectures in a very participative and dynamic atmosphere.

The meeting brought together leading figures in the field of cancer epigenetics to present their research work from the last five years. Experts in different areas of oncology described important advances in colorectal, lung, neuroblastoma, leukemia, and lymphoma cancers. The workshop also provided an interesting forum for pediatrics, and focused on the need to improve the treatment of childhood tumors in order to avoid, as far as possible, brain damage and disruption of activity in areas of high plasticity. From the beginning, the relevance of “omics” and the advances in genome-wide analysis platforms, which allow cancer to be studied in a more comprehensive and inclusive way, was very clear. Modern “omics” offer the possibility of identifying metastases of uncertain origin and establishing epigenetic signatures linked to a specific cluster of patients with a particular prognosis. In this context, invited speakers described novel tumor-associated histone variants and DNA-specific methylation, highlighting their close connection with other processes such as cell-lineage commitment and stemness.     

The epigenetics of the cell

A report on the 42nd Annual Meeting of the American Society for Cell Biology, San Francisco, 14-18 December 2002.     

Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer

The KEAP1/Nrf2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumor cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 non-small cell lung cancer tissues and normal specimens. Promoter methylation analysis was performed using a quantitative methylation specific PCR assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSCLCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumors (15%) and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumors had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR = 3.62; 95% CI 1.24–10.65, p = 0.02). This result was confirmed by Kaplan-Meier analysis, which demonstrated an association between worst outcome and KEAP1 double alterations (p = 0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP1 system could play a pivotal role in the cancerogenesis of NSCLC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients.     

Proteomic approaches for cancer epigenetics research

Introduction: Epigenetic dysregulation drives or supports numerous human cancers. The chromatin landscape in cancer cells is often marked by abnormal histone post-translational modification (PTM) patterns and by aberrant assembly and recruitment of protein complexes to specific genomic loci. Mass spectrometry-based proteomic analyses can support the discovery and characterization of both phenomena.

Areas covered: We broadly divide this literature into two parts: ‘modification-centric’ analyses that link histone PTMs to cancer biology; and ‘complex-centric’ analyses that examine protein–protein interactions that occur de novo as a result of oncogenic mutations. We also discuss proteomic studies of oncohistones. We highlight relevant examples, discuss limitations, and speculate about forthcoming innovations regarding each application.

Expert commentary: ‘Modification-centric’ analyses have been used to further understanding of cancer’s histone code and to identify associated therapeutic vulnerabilities. ‘Complex-centric’ analyses have likewise revealed insights into mechanisms of oncogenesis and suggested potential therapeutic targets, particularly in MLL-associated leukemia. Proteomic experiments have also supported some of the pioneering studies of oncohistone-mediated tumorigenesis. Additional applications of proteomics that may benefit cancer epigenetics research include middle-down and top-down histone PTM analysis, chromatin reader profiling, and genomic locus-specific protein identification. In the coming years, proteomic approaches will remain powerful ways to interrogate the biology of cancer.     

Genetics of epithelial tumors of the renal parenchyma in adults and renal cell carcinoma in children.

The classification of renal cell carcinomas has been affected by both the delineation of new histologic subtypes and the understanding that recognized histomorphologic patterns are reflective of specific sets of cytogenetic abnormalities. In fact, standard methods of clinicopathologic study and cytogenetic analysis have been cooperatively contributory in the evolution of current concepts regarding the biologic nature and classification of renal parenchymal epithelial tumors. In this review, the current classification scheme for these tumors is discussed from the perspective of both the defining histologic and cytogenetic features. Limited molecular data are described as well.     

Long non-coding RNAs and their implications in cancer epigenetics

LncRNAs (long non-coding RNAs) have emerged as key molecular players in the regulation of gene expression in different biological processes. Their involvement in epigenetic processes includes the recruitment of histone-modifying enzymes and DNA methyltransferases, leading to the establishment of chromatin conformation patterns that ultimately result in the fine control of genes. Some of these genes are related to tumorigenesis and it is well documented that the misregulation of epigenetic marks leads to cancer. In this review, we highlight how some of the lncRNAs implicated in cancer are involved in the epigenetic control of gene expression. While very few lncRNAs have already been identified as players in determining the cancer-survival outcome in a number of different cancer types, for most of the lncRNAs associated with epigenetic regulation only their altered pattern of expression in cancer is demonstrated. Thanks to their tissue-specificity features, lncRNAs have already been proposed as diagnostic markers in specific cancer types. We envision the discovery of a wealth of novel spliced and unspliced intronic lncRNAs involved in epigenetic networks or in highly location-specific epigenetic control, which might be predominantly altered in specific cancer subtypes. We expect that the characterization of new lncRNA (long non-coding RNA)–protein and lncRNA–DNA interactions will contribute to the discovery of potential lncRNA targets for use in therapies against cancer.     

Chromosome 3 translocations and familial renal cell cancer

Renal cell carcinomas (RCCs) occur in both sporadic and familial forms. In a subset of families the occurrence of RCCs co-segregates with the presence of constitutional chromosome 3 translocations. Previously, such co-segregation phenomena have been widely employed to identify candidate genes in various hereditary (cancer) syndromes. Here we survey the translocation 3-positive RCC families that have been reported to date and the subsequent identification of its respective candidate genes using positional cloning strategies. Based on allele segregation, loss of heterozygosity and mutation analyses of the tumors, a multi-step model for familial RCC development has been generated. This model is relevant for (i) understanding familial tumorigenesis and (ii) rational patient management. In addition, a high throughput microarray-based strategy is presented that will enable the rapid identification of novel positional candidate genes via a single step procedure. The functional consequences of the (fusion) genes that have been identified so far, the multi-step model and its consequences for clinical diagnosis, the identification of persons at risk and genetic counseling in RCC families are discussed.     

ABO blood group and risk of renal cell cancer

Background: The genetic determinants of sporadic renal cell cancer (RCC) are largely unknown. Previous studies have suggested associations between ABO blood group and risk of various cancers. However, its relationship to RCC remains unclear and no prospective data are available. Methods: We prospectively followed up 77,242 women in the Nurses’ Health Study and 30,071 men in the Health Professionals Follow-Up Study from 1996 to 2008. The information on the ABO blood group was collected from participants’ self-reports in 1996. Incidence of pathology-confirmed RCC was compared using hazard ratios (HRs) and 95% confidence intervals (CIs) derived from Cox proportional hazards models. Results: During 12 years of follow-up, 163 cases of incident RCC were documented in women and 88 cases in men. The multivariate HRs between non-O blood group (combined group of A, AB, and B) vs. blood group O were 1.51 (95% CI 1.09–2.09) in women, 1.08 (95% CI 0.70–1.66) in men, and 1.32 (95% CI 0.95–1.82) in the pooled cohorts. The associations between ABO blood group and RCC were consistent across strata of known risk factors for RCC including age, obesity, smoking, and history of hypertension (Pinteraction ≥ 0.32). Conclusions: We found a suggestive non-significant association between non-O blood group and increased risk of RCC in the pooled cohorts of men and women, and this association was significant in women. Our findings need to be replicated by other prospective studies.     

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. Exchange programs for graduate students are among the activities of the future School. The topics presented and discussed in 33 talks were diverse and included work on DNA methylation, histone modifications, chromatin biology, characterization of imprinted regions in human tissues, non-coding RNAs, and epigenetic drug discovery. Among novel developments from the previous Workshop are the report of the epigenetics angle of the Warburg effect and the long-range trans-acting interaction of DNA methylation and of nucleosome remodeling. A shift in the view on DNA methylation became apparent by the realization of the intertwined interplay between hyper- and hypo-methylation in differentiation and cancer.