Charis Eng, MD, PhD, FACP

2007-2008 BCRF Project:
All breast cancers have a genetic component. Tumor suppressor genes mastermind tumor suppressor proteins that act like automobile brakes to prevent cell overgrowth. Dr. Eng's lab studies a vital tumor suppressor gene called PTEN. Germline (in every cell of the body; can be passed on) gene mutations represent faults or alterations in DNA (which is the stuff of genes), resulting in the cells' brakes to fail. Germline mutations of PTEN cause Cowden syndrome (CS). CS, which was believed to be rare, is actually under-recognized, particularly by non-cancer genetics professionals, and therefore, diagnoses are not made.

This is rather dangerous because CS is a hereditary condition with a high risk of breast and thyroid cancers. One way to objectively make a diagnosis is by a gene test. 80-85% of obvious CS individuals have been found to have PTEN mutations but the remaining 15-20% and the majority of those with some features of CS (CS-like) do not have PTEN mutations, thus diminishing the advantage of gene testing for diagnosis and cancer risk management and screening. Because of a small pilot, Dr. Eng's team has potentially uncovered new genes, SDHB-D, for CS and CS-like disorders, and hence, new breast cancer susceptibility genes. These genes direct proteins involved in energy production in the mitochondria, the powerhouses of our cells.

The researchers' first objective seeks to examine the frequency of germline mutations in 3 related genes, SDHB-D, in 1,000 further CS/CS-like individuals. They also plan to determine if mutations in these genes relate to and hence objectively predict for risk of breast and/or thyroid cancer in these patients. Their second objective seeks to determine what these mutations precisely do within cells to cause breast and thyroid cancers to develop, which will contribute to novel treatment and preventative strategies.

Mid-Year Progress Report:
A subset of all breast cancers are heritable, ie, can be passed on in a 50-50 fashion, to the next generation. When altered (mutated), breast cancer susceptibility genes predispose an individual to breast, and usually other types of cancers. One of the goals of good practice is to differentiate heritable cancers from sporadic (not inherited) ones.

Cowden syndrome (CS) is an excellent model of a difficult to recognize breast cancer susceptibility syndrome. Although the classic description of CS is multiple hamartomas (benign growths) and a high risk of breast (up to 50% lifetime risk) and thyroid (10% lifetime risk) cancers, it is still difficult to recognize, and hence, likely to be under-diagnosed, because the expression is broad and the many features a CS individual has can also occur in the general population. PTEN is a ubiquitous tumor suppressor (like the brakes of a car that normally prevents cells from becoming cancerous) that plays a role in both heritable and sporadic cancers. Mutations of the PTEN gene cause CS. PTEN mutations have been found in 82-85% of those with CS while 15-18% are mutation negative despite extensive analyses.

This project seeks to find mutations in 3 candidate susceptibility genes, SDHB, C and D, which play a role in mitochondria (powerhouse of cells, energy production) in CS/CS-like individuals without PTEN mutations. In the last three months, Dr. Eng and her team have been able to obtain 350 samples from 350 CS and CS-like individuals. They have filled out checklists of clinical features and cancers related or possibly related to CS for each of these individuals. Their DNA, RNA and protein are being extracted, with the latter being analyzed for a protein that is related to mitochondrial function. The researchers are optimizing a new technology to be able to quickly look for mutations in the 3 SDHx genes of those individuals with elevated MnSOD.

Bio:
Charis Eng is the Chair and founding Director of the Genomic Medicine Institute of the Cleveland Clinic Foundation, 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. 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 the characterization of the widening clinical spectra of PTEN gene mutations as they relate to breast and thyroid cancer risks have been acknowledged as the paradigm for the practice of clinical cancer genetics. She was also the first to demonstrate genomic alterations in the normal-appearing stromal cells surrounding breast cancers and she believes that they may be vital in clinical outcome.

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 laboratory-based human cancer genetics and clinical cancer genetics at the University of Cambridge and the Royal Marsden NHS Trust, UK. At the end of 1995, Dr. Eng was recruited back 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 2002, she was promoted to Professor and Director of the Division of Human Genetics, and was conferred the Klotz Endowed Chair. She moved to the Cleveland Clinic in Sept, 2005.

Dr. Eng has published over 260 peer reviewed original papers in such journals as the New England Journal of Medicine, JAMA, Lancet, Nature Genetics, Nature 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, the 2006 Ernst Oppenheimer Young Investigator Award of The Endocrine Society and the 2006 American Cancer Society John Peter Minton, MD, PhD Hero of Hope Research Medal of Honor. She is Senior Editor of Cancer Research and Associate Editor of the Journal of Clinical Endocrinology and Metabolism and of the American Journal of Human Genetics. Dr. Eng is serving a 3-year term on the Board of Directors of the American Society of Human Genetics and will serve a 5-year term on the Board of Scientific Directors of the National Human Genome Research Institute beginning in Autumn, 2007.