26 Human Cancer Epigenetics

26 Human Cancer Epigenetics

S6 european journal of cancer 48, suppl. 5 (2012) S5–S12 Sunday 8 July 2012 diversity of human cancers and for which detailed genetic and pharmacol...

50KB Sizes 0 Downloads 29 Views

S6

european journal of cancer 48, suppl. 5 (2012) S5–S12

Sunday 8 July 2012

diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE), a comprehensive resource of human cancer models for basic and translational research that encompasses gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines spanning many tumor types. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity through systematic integration of the genomic and pharmacologic datasets. In addition to rediscovering molecular features known to predict response to several drugs, we uncovered novel potential biomarkers of sensitivity and resistance to both targeted agents and chemotherapy drugs. For instance, our analysis revealed new in vitro markers associated with sensitivity to MEK inhibitors in NRAS-mutant cell lines. Also, we found that response to topoisomerase 1 inhibitors seems to be predicted largely by expression of a single gene. Finally, we observed that tissue lineage is a key predictor for sensitivity to certain compounds, providing rationale for clinical trials of these drugs in particular cancer types. Together, our results indicate that large, annotated cell-line collections may help to identify biomarkers that allow the stratification of patients for appropriate drug treatment at the preclinical stage. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.

human origin (Sweet-Cordero et al, Nat. Genetics 2005). Detailed analysis of these signatures has revealed a subset of genes expressed in T1 lesions that are silenced in K-RasG12V clusters with a T2 signature. Indeed, Dnmt1 along with various Ras epigenetic silencing elements are up-regulated in T2 lesions, suggesting a putative epigenetic contribution during the initial stages of tumor development. Bisulfite sequencing analysis has revealed that the promoters of several genes expressed in the T1 hyperplastic regions and downregulated in the T2 lesions such as SerpinB5, Runx1t1 and Necdin are hypermethylated, suggesting widespread epigenetic inactivation in tumor initiating cells. Conclusions: 1. Only a limited subset of K-RasG12V -expressing SPC+ lung cells progress to yield hyperplastic areas, some of which eventually develop into adenomas and adenocarcinomas. 2. Morphologically indistinguishable hyperplastic areas display two distinct expression profiles (T1 and T2 signatures). 3. Whereas the T1 signature is closer to normal lung epithelial cells, the T2 signature overlaps with that of aggressive NSCLCs. Thus, tumor aggressiveness might be programmed during the early steps of clonal expansion. 4. The T1 and T2 signatures are characterized by different methylation patterns suggesting that epigenetics could play a role in determining the aggressiveness of KRasG12V lesions during early stages of tumor development. 5. The tumor suppressor SerpinB5 is hypermethylated in the T2 population.

Sunday 8 July 2012

M. Esteller1 . 1 Bellvitge Biomedical Research Institute (IDIBELL), Cancer Epigenetics and Biology Program (PEBC), Barcelona, Spain

26 Human Cancer Epigenetics

10:15−12:00

Symposium

Epigenetics 23 Current Views of the Cancer Epigenome and the Translational Implications No abstract received. 24 Epigenetic Changes in Cancer: From Discovery to Deployment J. Herman1 . 1 Johns Hopkins University School of Medicine, Baltimore Maryland, USA Epigenetic changes represent common and functionally important alterations that contribute to carcinogenesis. The ability to assess changes, particularly in DNA methylation, at the genome level provides both a comprehensive look at these alterations as well as hundreds of potential tumor specific alterations which could be used for the detection of cancer or a determinant of outcome. This talk will focus on the discovery of alterations in DNA methylation in cancer and development of such discoveries towards early detection biomarkers using sensitive molecular approaches, as well as the role specific alterations of DNA methylation may play as prognostic and/or predictive biomarkers. 25 Proffered Paper: Involvement of Epigenetics in the Early Stages of NSCLC Development C. Ambrogio1 , F.J. Carmona2 , D. Santamaria1 , G. Gomez3 , M. Lozano4 , S. Mainardi1 , P. Nieto1 , O. Kocher5 , M. Esteller2 , M. Barbacid1 . 1 CNIO, Molecular Oncology, Madrid, Spain;, 2 IDIBELL, Cancer Epigenetics, Barcelona, Spain;, 3 CNIO, Structural Biology and Biocomputing Programme, Madrid, Spain;, 4 CNIO, Biotechnology Programme, Madrid, Spain;, 5 BIDMC, Department of Pathology, Boston, USA; Introduction: K-RAS oncogenes are involved in about 30% of Non Small Cell Lung Cancer (NSCLC), one of the tumors with worst prognosis. We undertook these studies to identify the nature of the cancer initiating cells in these tumors as well as the underlying mechanisms that drive the earliest steps of tumor development. Materials and Methods: We developed a genetically modified mouse model of NSCLC driven by the controlled expression of a resident K-RasG12V oncogene (Guerra et al., Cancer Cell, 2003). This strain also expresses a bicistronic color marker that allows identification of K-RasG12V expressing cells. This strategy has allowed us to identify and isolate very early lesions (up to 500 cells) and to analyze them by gene expression profiling. We have also used bisulfite sequencing on a subset of differentially expressed genes to assess their methylation status. Results and Discussion: Induction of K-RasG12V expression takes place in all known lung cell types. However, only SPC+ alveolar type II cells progress to form small hyperplastic clusters. Surprisingly, these areas, in spite of being morphologically indistinguishable, display two distinct expression profiles designated as T1 and T2. Whereas the T1 signature has significant similarities to that of normal areas not expressing K-RasG12V , the T2 signature correlates with the gene expression profiling of aggressive NSCLCs of both mouse and

For the last twenty-five years an increasing amount of evidence has shown the relevance of epigenetics in cell biology and tissue physiology, being DNA methylation aberrations in cancer the flag-ship for the recognition of its disturbance in human diseases. From the candidate gene approaches, new powerful technologies such as comprehensive DNA methylation microarrays and whole genome bisulfite sequencing has recently emerged that have reinforced the notion of epigenetic disruption in the crossroad of many sickness. From the poster-boy cases of MGMT and GSTP1 hypermethylation in the prediction of alkylating drug response and prostate cancer detection, respectively, to the personalized treatment of leukemia with small molecules targeted to fusion proteins involving histone modifiers such as DOT1L and MLL, the field has walked a long path. The current talk will focus in the epigenetic profiling, basically at the level of DNA methylation and histone modifications, that is starting to provide clinical value in the diagnosis, prognosis and prediction of response to drug therapies, with an emphasys in neoplasia, but without forgetting the novel advances in other human disorders. For cancer, we have already a wide view of the undergoing DNA methylation events that expand beyond classical promoter CpG islands of tumor suppressor genes and we have a growing list of mutated chromatin remodeler genes that contributes to the tumorigenesis process. It is time to apply this knowledge in practical clinical situations like the diagnosis of cancers of unknown primary, the screening of malignancies in high-risk populations or a biomarker selection of the patients that should receive treatment with epigenetic drugs.

Sunday 8 July 2012

10:15−12:00

Symposium

Viruses and Cancer 27 Hepatitis C Virus − Pathogenesis, Replication and Treatment C. Rice1 . 1 The Rockefeller University, New York, USA An estimated 200 million people have been infected with hepatitis C virus (HCV) with a majority unable to clear the virus. Chronic HCV infection can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. It is generally believed that disease results at least in part from immune mediated inflammation. Since HCV’s discovery in 1989 significant progress has been made in establishing experimental systems and unraveling the details of the virus lifecycle. Examples include infectious molecular clones, RNA replicons and a robust cell culture system based on an HCV isolate from a rare case of acute fulminant hepatitis. Definition of the human factors required for HCV entry and blunting innate immune response pathways has led to the development of a mouse model that supports HCV entry, replication and virus production. Together these tools have increased our understanding of the HCV lifecycle and revealed multiple steps for therapeutic intervention. In 2011, two direct acting antivirals targeting the HCV serine protease were approved in combination with the previous standard of care, pegylated type I interferon and ribavirin. Even for the most difficult to treat HCV genotype (genotype I),