TCGC: Clinical Genome ConferenceTCGC: Clinical Genome ConferenceTCGC: Clinical Genome Conference

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Wednesday, June 26

7:30 am Conference Registration

 Genetic & Epigenetic Interplay in Cancer 

8:30 Chairperson’s Opening Remarks

Lucy A. Godley, M.D., Ph.D., Associate Professor, Department of Medicine, Section of Hematology/Oncology, Cancer Research Center, The University of Chicago


Spontaneous and Therapy-Induced Evolution of Tumor Genomes and Epigenomes

Joesph CostelloJoseph Costello, Ph.D., Professor in Residence, Department of Neurological Surgery; Director, Epigenetics Division, Cell Cycling and Signaling Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco

This presentation will focus on results from a longitudinal analysis of brain tumor genomes and epigenomes using next-generation sequencing. The impact of chemotherapy on induction of driver mutations and their functional effects will also be discussed.



9:25 Distinguishing between Driver and Passenger Epigenetic Modifications in Cancer

Daniel De CarvalhoDaniel De Carvalho, Ph.D., Principal Investigator, Ontario Cancer Institute, University Health Network; Assistant Professor, Medical Biophysics, Faculty of Medicine, University of Toronto

Cancer cells typically exhibit aberrant DNA methylation patterns that can drive malignant transformation. Whether cancer cells are dependent on these abnormal epigenetic modifications remains elusive. We used experimental and bioinformatic approaches to unveil genomic regions that require DNA methylation for survival of cancer cells, suggesting these are key epigenetic events associated with tumorigenesis.


10:00 FFPE-ChIP-Seq Enables the Genome-Wide Analysis of Chromatin Modifications in Long-Term Stored FFPE Samples

Active MotifTerry KellyTerry Kelly, Ph.D., R&D Manager, Active Motif

This talk will focus on Active Motif's newly developed FFPE assays, enabling ChIP and ChIP- seq in long term stored FFPE samples for the investigation of epigenetic alterations in normal and diseased primary tissue. The FFPE Chromatin Preparation protocol is capable of extracting high quality chromatin from FFPE tissues at least 10 years old. Using this methodology we have generated interpretable and reproducible results with antibodies against active and repressive histone marks as well as transcription factors on chromatin from rat brain as well as normal and cancerous human colon, lung and kidney FFPE samples.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing


11:00 BAF Complexes in Human Malignancy

Diana HargreavesDiana Hargreaves, Ph.D., Research Fellow, Pathology, Stanford University School of Medicine

Subunits of mammalian SWI/SNF (BAF) complexes have recently been implicated as tumor suppressors in human malignancies. To understand the full extent of their involvement, we conducted an analysis demonstrating that BAF subunits are mutated in 19.6% of all human tumors. Further analysis revealed several features of BAF subunit mutant cancers, including the frequency of mutation to each subunit, the subunit specificity with regard to cancer type, the likelihood of mutations to more than one subunit, and the co-occurrence with other mutations. Our analyses suggest that BAF subunits will be important biomarkers for more personalized therapeutic treatment.


11:35 The DNA Methylome of Prostate Cancer Teaches a Lesson about Cholesterol Homeostasis

Angela TingAngela Ting, Ph.D., Assistant Professor, Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic; Assistant Professor, Genetics, School of Medicine, Case Western Reserve University

In our efforts to understand the impact of epigenetic changes in prostate cancer development, we set out to map the DNA methylome profiles for benign prostates, prostate cancers of different clinicopathological features, and common prostate cell line models using next-generation sequencing. This global analysis revealed many novel cellular pathways and regulators that are aberrantly disrupted by DNA methylation. I will discuss in particular our findings on the cellular cholesterol efflux pathway and how dysregulation of a key efflux transporter may impact the clinical management of prostate cancer.

12:10 pm Close of Session


12:15 Lunch on Your Own


Mechanisms in (De)Methylation Underlying Development of Disease 

1:30 Chairperson’s Opening Remarks

Angela Ting, Ph.D., Assistant Professor, Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic

1:35 Family Proteins and 5-Hydroxymethylcytosine in Stem Cells, Development and Cancer

Yujiang Geno ShiYujiang Geno Shi, Ph.D., Associate Biochemist, Division of Endocrinology, Brigham and Women’s Hospital; Assistant Professor, Medicine, Harvard Medical School

Recent studies have shown that ten-eleven translocation (Tet) proteins can catalyze 5mC oxidation and generate 5mC derivatives, including 5-hydroxymethylcytosine (5hmC). Not only are Tet family proteins and 5hmC critical for the identity and normal function of embryonic stem cells and early embryonic process of development, but dysregulation of these newly identified epigenetic factors also plays a major role in cancer development. Here we report an essential role of Tet3 in animal development, and define 5hmC as a potential biomarker for tumor progression. These studies will significantly increase our current understanding of the biological functions of Tet proteins and 5hmC while providing mechanistic insight into the development of epigenetic therapeutics.


2:10 Defining the Epigenetic Landscape during Normal and Malignant Hematopoiesis

Lucy GodleyLucy A. Godley, M.D., Ph.D., Associate Professor, Department of Medicine, Section of Hematology/Oncology, Cancer Research Center, The University of Chicago

Hematopoietic stem cell commitment and differentiation involves silencing of self-renewal genes and induction of a specific transcriptional program, which is controlled in part through dynamic changes in covalent cytosine modifications. We have studied how the abundance and distribution of these derivatized bases influences hematopoietic stem cell commitment during normal erythropoiesis as well as during leukemia development. The identification of recurrent mutations in several genes important in epigenetic pathways as well as mouse modeling suggest that the balance of covalent cytosine modifications is a key driver of normal blood cell development. I will also discuss how these findings impact our understanding of the activity of the 'hypomethylating drugs', now in common use for the treatment of myeloid malignancies.


2:45 DNA Methylation Changes in Pre-B Cell Development and Childhood Leukemia

Joseph WiemelsJoseph Wiemels, Ph.D., Associate Professor, Cancer Epidemiology, Epidemiology and Biostatistics, University of California, San Francisco

We sought to define the epigenetic aberrations of pre-B cell leukemia by first exploring the normal patterns of DNA methylation in B cells. Pre-B cells were sorted from normal human bone marrow and typed using whole genome methylation arrays. Pre-B cells exhibit a demethylation phenotype at CpG sites closely allied with pre-B cell transcription factors. Leukemia genomes exhibit a large array of demethylation and de novo DNA methylation events from the normal, which display a profound polycomb signature. We will present this data along with an examination of DNA methylation changes caused by environmental exposures thought to affect childhood leukemia risk.


3:20 DNA Methylation Alterations in Lung Adenocarcinoma

Ite LairdIte A. Laird-Offringa, Ph.D., Associate Professor, Departments of Surgery, Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California

I will discuss our research on integrated genome-scale DNA methylation and mRNA expression data from microdissected lung adenocarcinoma and matched non-tumor lung. We have identified 164 hypermethylated genes showing concurrent downregulation, and 57 hypomethylated genes showing increased expression. Integrated pathways analysis and detailed examination of individual genes suggests mechanistic contributions of several of these genes to lung adenocarcinoma development and/or progression. I will present information on a number of candidate epigenetic driver genes for lung adenocarcinoma.

3:55 Refreshment Break in the Exhibit Hall with Poster Viewing


Whole Genome Phasing and Analysis of a Personal Methylome

Michael SnyderMichael Snyder, Ph.D., Professor and Chair, Genetics; Director, Stanford Center for Genomics and Personalized Medicine, Stanford University

Differences in DNA methylation patterns between paternal and maternal chromosomes have been shown to influence the allelic expression of a number of important genes. In spite of their important role, a global analysis of all allelic differential methylated regions (DMRs) has not yet been performed in humans.This is largely due to the fact that few haplotypes have been accurately mapped at the genome level. Here, we describe a novel method to accurately determine the phased genome of a single individual without a priori parental information, and then perform allelic MethylC-Seq analysis to generate the first genome-wide allele-specific DNA methylation map in humans. We identify 539 DMRs, and find that 90% of them lie in proximal or distal cis-regulatory regions. Many DMR-marked enhancers are associated with allele-specific transcription factor binding, open chromatin sites, and expression of neighboring genes. Moreover, DMRs are enriched for variants associated with human diseases. Our study introduces a novel approach for defining phased haplotypes and allele-specific DNA methylation, and demonstrates its importance for the functional analysis of personal genomes.

5:15 Close of Day

5:30 Dinner Short Course and TCGC: The Business of Integration and Implementation Registration

6:00 – 9:00 Dinner Short Courses

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