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BCRF Grantee Since

2007

Donor Recognition

The von Mandl Family Award

Charis Eng, MD, PhD, FACP

Sondra J. and Stephen P. Hardis Chair in Cancer Genomic Medicine
Chair and Director, Genomic Medicine Institute
Cleveland Clinic
Professor and Vice Chairman
Department of Genetics and Genome Sciences
Case Western Reserve University School of Medicine
Cleveland, Ohio

Current Research

In November 2009, Charis Eng, MD, PhD, Chair and Director of Cleveland Clinic Lerner Research Institute's Genomic Medicine Institute, was appointed to the U.S. Department of Health and Human Services Secretary's Advisory Committee on Genetics, Health and Society (SACGHS) to serve a three-and-a-half year term. The committee advises HHS Secretary Kathleen Sebelius on the medical, ethical, legal, and social implications of integrating genetic technologies into clinical and public health practice.

Heritable alterations (mutations) in the PTEN tumor suppressing (cancer fighting) gene are associated with a subset, but not all, individuals and families with Cowden syndrome (CS), who are predisposed to breast and thyroid cancers. Other genes must also predispose to breast and thyroid cancer. Dr. Eng and colleagues have now validated with a very large number of patients that heritable mutations in mitochondrial (energy-warehouse of a cell) genes SDHB, SDHC, and SDHD (SDHx) accounts for a subset of CS and CS-like (CSL) individuals independent of their PTEN mutation status. Patients with SDHx alterations have increased prevalence of breast cancers compared to those with PTEN mutations. Dr. Eng has found that these SDHx variants likely shut down cancer-fighting functions of PTEN by oxidizing PTEN protein and shifting its subcellular localization. Both vitamin E and resveratrol (found in red wine) antioxidant interventions showed partial rescue of the cancer phenotype in cells from patients with SDHx alterations. Dr. Eng will continue to address their broad hypothesis that SDHx variants could be absolute modifiers of PTEN germline mutations for breast cancer risk via patient-oriented research, and in vitro functional interrogation, that is, why and how.

In the last year, Dr. Eng’s team has added to their initial exciting pilot data to suggest that a new gene KLLN, sharing a bidirectional promoter with PTEN and also sharing p53 as a transcription factor, may be a new low-moderate penetrance predisposition gene for breast cancer. In addition, they also identified that individuals without PTEN or SDH alterations had a new way of shutting down a cancer suppressing gene KLLN (which is next to PTEN but reads backwards).. In the upcoming year, they wish to examine a large number of CS/CS-like individuals to validate KLLN as a new breast cancer-predisposition gene. Dr. Eng plans to explore whether KLLN methylation modifies breast cancer risk in individuals with PTEN mutations.

Mid-Year Summary

Heritable alterations (mutations) in the PTEN tumor suppressing (cancer fighting) gene are associated with a subset, but not all, individuals and families with Cowden syndrome (CS), who are predisposed to breast and thyroid cancers. Other genes must also predispose to breast and thyroid cancer. Dr. Eng and her team have now validated with a very large number of patients that heritable mutations in genes encoding mitochondrial complex II subunits (energy-warehouse of a cell) SDHB, SDHC, and SDHD (SDHx) accounts for a subset of CS and CS-like (CSL) individuals independent of their PTEN mutation status. Patients with SDHx alterations have increased prevalence of breast cancers compared to those with PTEN mutations. SDHx variants likely compromise mitochondrial respiration and increase glycolysis, shut down cancer-fighting functions of PTEN by oxidizing PTEN protein and shifting its subcellular localization. Both vitamin E and resveratrol (found in red wine) antioxidant interventions showed partial rescue of the cancer phenotype in cells from patients with SDHx alterations. In addition, the researchers also identified that individuals without PTEN or SDH alterations had a new way of shutting down a cancer suppressing gene KLLN (which is next to PTEN but reads backwards). They identified significantly increased KLLN promoter methylation in CS individuals, which is associated with increased risks of all CS-associated malignancies, especially breast cancer, compared to the general population. This will facilitate breast cancer risk assessment and management and genetic counseling.

Bio

Dr. Charis Eng is the Chair and founding Director of the Genomic Medicine Institute of the Cleveland Clinic, as well as the 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 of Sciences for her achievements and leadership in genetics- and genomics-based research and personalized healthcare. 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-enabled personalized healthcare.

After completing an MD and PhD at its Pritzker School of Medicine at the University of Chicago, 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 in the United Kingdom and in laboratory-based human cancer genetics by Professor Sir Bruce Ponder. At the end of 1995, Dr. Eng returned to Dana-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 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.

Dr. Eng was recruited to the Cleveland Clinic in September 2005 where she founded and leads the Genomic Medicine Institute, a single platform for research, academic clinical activities and education in genomics medicine as it enables healthcare. Dr. Eng has published over 330 peer reviewed original papers in such journals as the New England Journal of Medicine, Journal of American Medical Association, 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 completed a three-year term on the Board of Directors of the American Society of Human Genetics, has completed a two-year term as Chair of the Clinical Science Committee of the Personalized Medicine Coalition and is serving a five-year term on the Board of Scientific Directors of the National Human Genome Research Institute. Recently, 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 (2009-2011). She also is co-chair of their Task Force to examine whole genome sequencing for clinical application, and serves on the Expert Panel of the WHO Grand Challenges Project on Public Health Genomics in Developing Countries. She has just been named to the US News and World Report Top Doctors List and to MedCity’s List of Cleveland Clinic’s Top 50 Doctors-Ever.