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 and Genome Sciences 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. In 2010, she was elected to the National Academy of Medicine [then 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, and an important scientific basis for precision oncology. 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 470 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 13th International Thyroid Conference, the 2006 Ernst Oppenheimer Award of The Endocrine Society, the 2006 American Cancer Society John Peter Minton, MD, PhD Hero of Hope Research Medal of Honor, the 2014 James Ewing Lecturership of the Society for Surgical Oncology, the 2014 AACR WICR-Charlotte Friend Memorial Lectureship, 2015 and 2017 University of Chicago Medical Alumni Distinguished Service Award and Alumni Professional Achievement Award. She serves as the Editor-in-Chief of Endocrine Related Cancer (2011-2020). 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 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.
My research is a multidisciplinary approach to modifying PTEN-related cancer versus autism risks, murine models of Pten-autism, and microbiome in cancer.
We use multidisciplinary approaches to identify and characterize genes which cause susceptibility to inherited cancer syndromes, to determine their role in sporadic carcinogenesis and to perform molecular epidemiologic analyses as they relate to clinical applications. Upon this framework, we are examining PTEN and SDH in Cowden syndrome, which has a high risk of breast, thyroid and endometrial cancers, and SDH-related heritable neuroendocrine neoplasias. PTEN, encoding a dual specificity phosphatase on 10q23.3, is being examined in Cowden and other hamartoma syndromes and isolated cancers. Diverse mechanisms of PTEN inactivation are being pursued for various sporadic cancers, including those of the breast, thyroid and endometrium. Gene-gene interactions and gene-environment interactions are being explored. Functional studies are performed to understand the non-traditional mechanisms of somatic PTEN inactivation in breast cancer, chief of which involves nuclear-cytoplasmic trafficking. This fundamental research is aimed at not only mechanism resolution but also hopes to identify novel targets for therapy and prevention. The role of genetic alterations in the microenvironment of sporadic and heritable breast carcinomas and other solid tumors are being examined as they relate to clinical outcome. This may have broad implications not only for pathogenesis but may reveal novel compartments germane for diagnosis, prognosis, therapy and prevention. Finally, the Eng lab is searching for Barrett esophagus-predisposing genes.
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 to enable the practice of precision medicine. Upon this framework, we are investigating the following:
Genetic and Functional Characterization of PTEN Hamartoma Tumor Syndrome (PHTS): My lifelong work is to identify, characterize, and understand genes that cause susceptibility to inherited cancer syndromes and to determine how these genes can be used to develop new clinical applications. My independent career began in late 1995, when the heritable hamartoma neoplasias were a mystery and very difficult to recognize clinically and no genetic etiologies had been identified. Leading a multi-national team, we mapped the predisposition gene for Cowden syndrome (CS), a difficult to recognize, under-diagnosed hamartoma syndrome then characterized as having high risks of breast and thyroid cancers, to 10q22-q23. Subsequently, we identified that gene as PTEN, the first time a phosphatase gene was shown to be a cancer-predisposition gene. Shortly thereafter, we also showed that germline PTEN mutations cause a subset of a seemingly clinically disparate (from CS) and rare syndrome called Bannayan-Riley-Ruvalcaba syndrome (BRRS). We have delineated the PTEN mutation spectra in CS and BRRS, adding previously unknown clinical phenotypes such as autism and colonic (mixed) polyposis and colon cancer risk. We also completed multi-national a multi-institutional prospective study to build a clinical risk calculator which predicts a priori probability of a PTEN mutation for easier recognition of these patients for referral to genetics professionals. When we identified PTEN as the Cowden and BRRS predisposition gene, the known malignancy risks were breast and follicular thyroid cancers. We performed a multi-national multi-institutional prospective study to delineate the PTEN-associated neoplasias and lifetime risks. The latter led to adding endometrial, renal and colon cancer and melanoma to the PTEN-clinical phenotypic spectrum. We have also performed a first pass prospective study of second primary malignancies (SMN) in individuals with germline PTEN mutations, showing markedly elevated SMN risks for all associated cancers, especially those of the breast. All these observations have led to more precise cancer risk assessment and clinical management, as well as predictive testing of as yet unaffected family members, which we have shown to be cost-effective as well.
Our current PTEN research foci are three-fold. First, we are investigating genomic and non-genomic modifiers of cancer risk in PHTS. While individuals with PHTS have an 85% lifetime risk of female breast cancer, 35% of thyroid cancer, and so on, it is not possible to accurately predict which single individual will or will not develop a specific cancer. More recently, we have found germline SDHD variants increasing breast cancer risk in those with germline PTEN mutations. Succinate dehydrogenase subunit D is part of mitochondrial complex II, and we have shown that SDHD variants lead to increased ROS and HIF1alpha signaling and destabilization of p53 via non-canonical NQ01 downregulation secondary to NAD/FAD imbalance, leading to apoptosis resistance and oxidative stress. As such, we are currently searching for further modifiers of cancer risk in PHTS utilizing broad genomics, computational biophysics and functional approaches.
Second, we are using PHTS as a model for sporadic thyroid and breast cancer initiation, given that PTEN plays a major somatic role in many sporadic malignancies and that germline mutations are the earliest, hence, initiating event in heritable disease, ie, PHTS. Here, we are interrogating the crosstalk between PTEN and SDHx using genomic, cell (in vitro) and murine models.
Third, although the Eng lab has uncovered several predisposition genes in PTEN mutations PHTS, there remain almost half of CS and CS-like individuals who have no mutations in these known genes. Therefore, we are continuing to search for as yet identified susceptibility genes for CS/CS-like syndromes.
Dissecting the PTEN "Switch" of Developing Cancer versus Autism: Why and how germline mutation in a single gene PTEN results in such disparate phenotypes as cancer and autism is a conundrum. A major thrust of my lab is to determine the mechanistic "switch(s)" which differentiates the two clinical outcomes. Because of the complexity of our overall goal, we will use an interdisciplinary approach. First, we will leverage computational biophysics modeling and bioinformatics approaches. What we find computationally will be structurally validated. Second, we are utilizing genomics and gene expression approaches leveraging our collection of patient materials and our PTEN mouse model of intracellularly mislocalized PTEN. Finally, we will utilize functional, including immunologic, interrogation of cellular and animal models, which will be validated with patient samples.
In order to understand the PTEN "switch," it is important to characterize our PTEN mouse model with autism-like phenotypes. In following our CS/CS-like cohort with PTEN germline mutations, I noted autism amongst many kindreds. We therefore performed a pilot study prospectively accruing individuals, both children and adults, with macrocephaly (a key phenotype in CS/CSL persons) and autism spectrum disorder (ASD). We were surprised to find 3 of the 17 eligible research participants carrying germline PTEN mutations. This observation has been independently replicated multiple times since our first report in 2005. Since then, we have made the first mouse model of inappropriate PTEN intracellular localization with high-functioning autism as phenotype. The cytoplasm-predominant PTEN protein caused cellular hypertrophy limited to the soma and led to increased NG2 cell proliferation and accumulation of glia. The animals also exhibit significant astrogliosis and microglial activation, indicating a neuroinflammatory phenotype. At the signaling level, PTEN(m3m4) mice show brain region-specific differences in Akt activation. The homozygotes have massive megencephaly in parallel with human patients with PTEN mutations, irrespective of autism status: 94% of those with PTEN mutations have macrocephaly. We subsequently compared PTEN-ASD patients (n=17) to idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and warranting referral to genetics evaluation. Because of our observations in both patients and mouse model, the current thrust of our PTEN-ASD research involves using cell, including stem cell, and mouse models to interrogate the mechanism of neuroinflammation and of white matter abnormalities as well as the role of oligodendroglia versus astrocytes in PTEN-ASD.
Microbiome in Cancer Risk: The microbiome comprises microbial organisms, such as bacteria and fungi, that are found in and on human bodies. Emerging data have shown the microbiome affecting obesity, diabetes and inflammatory bowel disease as well as responses to immune modulation in cancer treatment. We continue to address our hypothesis that the microbiome transduces signals from the environment to our genes. We are therefore studying the microbiome from gut, urine and oral wash as a modifier of cancer and ASD risk in individuals with PHTS, and in those with and without PHTS. In parallel, we are analyzing the microbiome from tumor and non-tumor tissue as well as gut in sporadic solid tumors that are component to PHTS, namely, breast and thyroid cancers. We have already found dysbiosis in the breast tissues and tumors of those with breast cancer compared to those without cancer. We are currently exploring loaded nanoparticles targeting breast cancer dysbiosis in murine models, to be followed by first in human clinical trials should the former be successful.
We are using oropharyngeal/head and neck squamous cell carcinomas (HNSCC) as our high biomass cancer model. Together with collaborator Dr. Mahmoud Ghannoum, we analyzed the bacteriome, mycobiome and metabolome of HNSCC at a time when metagenomic analysis of cancers were non-existent. In a small pilot followed by a large independent validation series of HNSCC, we found that microbiomes of HNSCC tumors were different from their matched non-malignant oral epithelial tissues, and that the diversity of the former was lower than the latter. We found microbiomic differences in the primary tumors belonging to stage I-II compared to those at stage III-IV, and somatic hypermethylation of such genes as MDR1 and RASSF1A. In parallel, we have found clear metabolomic and mycobiomic differences in HNSCC compared to matched normal oral epithelium. We are now poised to analyze the mechanism by which the microbiome, especially of mixed organisms (bacteria and fungi), and its dysbiosis leads to HNSCC genesis.