Charis Eng Professor/Vice Chair Ph.D. Training Faculty

Genomic Medicine Institute Lerner Research Institute Cleveland Clinic NE50 9500 Euclid Avenue Cleveland, Ohio 44195 Tel: (216) 444-3440 Fax: (216) 636-0655 E-mail: engc@ccf.org http://www.lerner.ccf.org/gmi/ http://www.lerner.ccf.org/gmi/cpgh/

About Charis Eng

Charis Eng, MD, PhD is the Chair and founding Director of the Genomic Medicine Institute of the Cleveland Clinic, founding Director and attending clinical cancer geneticist of the institute's clinical component, the Center for Personalized Genetic Healthcare, and Professor and Vice Chairman of the Department of Genetics at Case Western Reserve University School of Medicine. She holds a joint appointment as Professor of Molecular Medicine at the Cleveland Clinic Lerner College of Medicine and is a member of Cleveland Clinic's Taussig Cancer Center and of the CASE Comprehensive Cancer Center. Dr. Eng was honored with the Sondra J. and Stephen R. Hardis Endowed Chair in Cancer Genomic Medicine in 2008 and the American Cancer Society Clinical Research Professorship in 2009. More recently, she was elected to the Institute of Medicine (IOM) of the US National Academies. She continues to hold an honorary appointment at the University of Cambridge. Dr. Eng's research interests may be broadly characterized as clinical cancer genetics translational research. Her work on RET testing in multiple endocrine neoplasia type 2 and characterization of the widening clinical spectra of PTEN mutations have been acknowledged as the paradigm for the practice of clinical cancer genetics. At the clinical interface, Dr. Eng is acknowledged as one of the rare "go to" people on what is and how to implement genetic- and -omics-informed personalized healthcare.

Dr. Eng grew up in Singapore and Bristol, UK and entered the University of Chicago at the age of 16. After completing an MD and PhD at its Pritzker School of Medicine, she specialized in internal medicine at Beth Israel Hospital, Boston and trained in medical oncology at Harvard's Dana-Farber Cancer Institute. She was formally trained in clinical cancer genetics at the University of Cambridge and the Royal Marsden NHS Trust, UK, and in laboratory-based human cancer genetics by Prof Sir Bruce Ponder. At the end of 1995, Dr. Eng returned to the Farber as Assistant Professor of Medicine, and in January, 1999 was recruited by The Ohio State University as Associate Professor of Medicine and Director of the Clinical Cancer Genetics Program. In 2001, she was honored with the conferment of the Davis Professorship and appointed Co-Director of the Division of Human Genetics in the Department of Internal Medicine. In 2002, she was promoted to Professor and Division Director, and was conferred the Klotz Endowed Chair. She was recruited to the Cleveland Clinic in Sept, 2005. Dr. Eng has published over 320 peer reviewed original papers in such journals as the New England Journal of Medicine, JAMA, Lancet, Nature Genetics, Nature, Cell and Molecular Cell. She has received numerous awards and honors including election to the American Society of Clinical Investigation, to the Association of American Physicians and as Fellow of AAAS, the Doris Duke Distinguished Clinical Scientist Award and named a Local Legend from Ohio bestowed by the American Medical Women's Association in conjunction with the US Senate on women physicians who have demonstrated commitment, originality, innovation and/or creativity in their fields of medicine. Dr. Eng is the 2005 recipient of the ATA Van Meter Award at the 13^th International Thyroid Conference, the 2006 Ernst Oppenheimer Award of The Endocrine Society and the 2006 American Cancer Society John Peter Minton, MD, PhD Hero of Hope Research Medal of Honor. She was recently selected as the Editor-in-Chief of Endocrine Related Cancer (2011-2015). She was the North American Editor of the Journal of Medical Genetics (1998-2005), Senior Editor of Cancer Research (2004-09), and Associate Editor of the Journal of Clinical Endocrinology and Metabolism (2005-09) and of the American Journal of Human Genetics (2007-09). Dr. Eng completed a 3-year term on the Board of Directors of the American Society of Human Genetics, has completed a 2-year term as Chair of the Clinical Science Committee of the Personalized Medicine Coalition and is serving a 5-year term on the Board of Scientific Directors of the National Human Genome Research Institute. Dr. Eng was appointed by Kathleen Sebelius to the US Department of Health and Human Services' Secretary's Advisory Committee on Genetics, Health and Society (2009-11). She also served as co-chair of their Task Force to examine whole genome sequencing for clinical application.

Research

The optimal manner of achieving seamless translational cancer research is on a single platform of research, clinical care and education. On such a base, the broad thrust of the Eng laboratory can be characterized as clinical cancer genetics translational research, which involves the utilization and integration of multiple -omics-based platforms to identify, characterize and understand genes which cause susceptibility to high penetrance Mendelian and complex heritable cancers, to determine their role in sporadic carcinogenesis and to perform molecular epidemiologic analyses as they might relate to near-future clinical applications. Upon this framework, we are investigating the following broad topics:

Genetic and Functional Characterization of the Harmatoma-Tumor Syndromes: PTEN, KILLIN and Beyond

The translational objective of this group of projects is to obtain evidence to ensure accurate molecular diagnosis to sub-set individuals for genotype-specific risk assessment and medical management such as surveillance and prevention, as well as for family-specific gene predictive testing. Functional interrogation will then point to signaling pathways which will help inform future therapeutic and preventative targets, whether by naturally occurring compounds or by synthetic compounds.

Our prototype hamartoma-tumor syndrome is Cowden syndrome (CS), which is a difficult-to-recognize under-diagnosed autosomal dominant disorder characterized by multiple hamartomas and a high risk of breast and thyroid cancers. We mapped the CS predisposition to 10q23 and subsequently identified germline mutations in the PTEN tumor suppressor gene as associated with the majority of classic CS. Because of the difficulty in recognizing CS, despite the International Cowden Consortium Operational Diagnostic Criteria, many more (perhaps 10-100-fold more) individuals who have incomplete clinical features of CS present to be evaluated. Only 5-10% of such CS-like individuals have germline PTEN mutations. Relatedly, after analyzing 3,042 probands, we have recently created a PTEN risk calculator which is based on demographics and clinical features to come up with the most parsimonious features to predict prior probability of finding a PTEN mutation www.lerner.ccf.org/gmi/ccscore/.As another strategy of examining mutational spectra and variable clinical expression, PTEN and a series of other relevant genes are being analyzed for individuals and families presenting with different clinical features, one of which includes unexplained hamartomatous polyps.

PTEN is ubiquitously expressed and plays broad cell signaling roles, chief of which includes G1 cell cycle arrest and apoptosis. In 2000, after we noticed PTEN nuclear expression by immunohistochemistry, we demonstrated that PTEN can traffick in and out of the nucleus. PTEN has 4 nuclear localization-like signals and only works in pairs. We subsequently also showed that PTEN has two ATP-binding motifs that are required for nuclear exit. We are particularly interested in the mechanisms of nuclear entry and exit, their partitioned function and how natural compounds such as resveratrol affects intracytoplastic localization in the context of neoplasia.

In 2008, we identified germline variants of SDHB and SDHD associated with 10% of individuals with PTEN mutation negative CS and CS-like. The succinate dehydrogenase genes were first described as the susceptibility genes for pheochromocytoma-paraganglioma syndromes, which we also characterized. We are currently examining the interaction of the SDH and PTEN pathways in modifying neoplasia risks.

A novel tumor suppressor gene KILLIN which shares the same transcription start site as PTEN was recently found to be transcribed in the opposite direction. Presumably PTEN and KILLIN share the same bidirectional promoter. Recently, we found that germline methylation of the bidirectional promoter was associated with downregulation of KILLIN but not PTEN. Germline KILLIN methylation was found in ~37% of individuals with PTEN mutation negative CS and CS-like individuals. Notably, individuals with germline KILLIN methylation have a 2-3-fold increased prevalence of breast and renal carcinomas over those with germline PTEN mutations. This is important for genetic counseling and risk management between the two genes. We are currently validating the role of KILLIN in CS/CS-like and its function.

Integrative Genomic Analysis for Systems Medicine Approach to Common Cancer Risk

We are pursuing several strategies, from single platform to multiple platform integration, to obtain in point-of-care risk calculators to facilitate risk assessment and subsequently personalized medical management. We are particularly interested in homozygosity mapping and its integration with various relevant platforms to come up with low-to-moderate penetrance and eventually interaction with environment. We focus on such solid tumors as carcinomas of the breast, lung, oropharyngeal, and prostate as well as uveal melanoma.

Integrative Genomic Analysis of the Micro and Macro Environment of Solid Tumors

A solid tumor is heterogeneous comprising the carcinomatous component and its microenvironment, in which we have shown genomic and expressional alterations relevant to clinical outcome. We are utilizing single and multiple platform strategies to examine the alterations in solid tumor microenvironment in the context of clinical outcomes. Furthermore, a solid tumor does not exist in isolation and in certain sites, are exposed to its non-human macroenvironment including microbial and other populations. We are utilizing metagenomic profiling to describe microbial populations in oropharyngeal squamous cell carcinomas as they relate to other somatic alterations and clinical outcome.

Selected Publications