Genomic Medicine Institute News: 2013

Kylie Drake Wins Two Awards to Advance PAH Research

Dr. Drake receiving Gilead Science Research AwardDecember 16, 2013 — Kylie Drake, PhD, Research Associate in the Aldred Lab of the Genomic Medicine Institute, recently won two prestigious awards for her work to cure pulmonary arterial hypertension (PAH). Dr. Drake received a competitive award from Gilead Sciences Research Scholars Program that supports junior faculty researchers. She was chosen by a Scientific Review Committee comprised of leaders in the field of PAH and will receive up to two years of research funding. In addition, Dr. Drake received a Proof-of-Concept award from the Pulmonary Hypertension Association.

PAH is a serious, life-threatening disease characterized by sustained hypertension in lung arteries. In PAH, cells that line artery walls grow excessively and cause restriction. The goal of Dr. Drake’s research is to understand why this cell growth goes haywire, specifically, the extent and mechanisms by which microRNAs become dysregulated. MicroRNAs are small non-coding RNA molecules that regulate gene expression. Their dysregulation disrupts gene functioning in potentially broad and devastating ways, including allowing endothelial cells to proliferate excessively.

Under the mentorship of Micheala Aldred, PhD, Associate Staff of the Genomic Medicine Institute, Dr. Drake has studied the effect of experimental drugs on cultured lung or blood cells isolated from PAH patients. Their work has shown that Ataluren, an investigational drug already in clinical trials for other genetic diseases, can — in some cases, slow or even reverse the excess proliferation of endothelial cells in diseased lung arteries. By monitoring microRNA regulation, they can tell how well ataluren is working to treat PAH. The Gilead grant will continue their work to better understand the genetic factors and signaling pathways involved. The Proof-of-Concept grant will bring her team’s research on ataluren closer to clinical trials.


Whole Genomic Sequencing of the Plasmodium vivax Malaria Parasite

Mosquito & ChloroquineNovember 20, 2013 — The Genomic Medicine Institute is collaborating with Case Western Reserve University, the Institut Pasteur du Cambodge and other geographically dispersed institutions to combat the spread of malaria. Genetic sequencing of the Plasmodium vivax malaria parasite, conducted by David Serre’s lab, sheds light on its mechanism of infecting humans. This research may prove critical for heading off the rapid spread of an adapted form of malaria throughout Africa.

Plasmodium vivax (P. vivax) is the most prevalent human malaria parasite, causing serious public health problems endemic countries. Until recently the Duffy-negative blood group prevalent in most African individuals was thought to confer immunity to vivax malaria. However, several studies have reported P. vivax strains in African countries including Madagascar and Mauitania that cause clinical vivax malaria in Duffy-negative people.

Malaria results from infection of human red blood cells (RBC) by the plasmodium parasite. For
P. vivax
, the process of RBC invasion has been hypothesized to depend on interactions between the parasite’s Duffy binding protein and the human Duffy blood group antigen. This hypothesis has been challenged since Duffy-negative people have been shown vulnerable to RBC infection and disease.

Research from David Serre’s laboratory, recently published in PLoS Neglected Tropical Diseases, identifies DNA sequence rearrangements in the P. vivax genome and announces a new discovery: duplication of the P. vivax Duffy binding protein (PvDBP) gene. The highest prevalence of PvDBP duplication was observed in west-central Madagascar—the same geographic location reporting the highest incidence of Duffy-negative people infected with P. vivax.

The highly conserved nature of the sequence involved in PvDBP duplication suggests that it is a recent evolutionary mutation.  Gaining additional insight into this vivax malaria infection mechanism may prove critical to heading off the rapid spread of an adapted form of malaria throughout Africa.

Read these related press stories:

Science Now

Agence France Presse (English)

Cleveland Plain Dealer

Dawn Caraballo Leads Heart Walk

GMI Heart Walk TeamSeptember 28, 2013 — Many thanks to Dawn Caraballo, captain of GMI’s team that participated in the American Heart Association 2013 Cleveland Heart Walk. That’s her, fourth from the left.

As captain of the GMI team, Dawn encouraged colleagues to participate in the Heart Walk and planned several related fundraising projects. Over $1 million was raised, including a $500 contribution from GMI.


GMI Hosts a Genetics Education Symposium

GMI Education Symposium Audience
A sell-out crowd fills the InterContinental ballroom for the Genomic Medicine Institute’s Genetic Education Symposium.

September 5, 2013 — The Genomic Medicine Institute hosted a genetics education symposium, “Genetics and Genomics: Roadmap for Clinical Practice,” at the InterContinental Hotel in Cleveland.The learning objectives of this continuing medical education (CME)-accredited event included discussing practical approaches for diagnosing, evaluating and managing patients with common genetic disorders, exploring the role of clinical genetic counselors as members of the healthcare team, and analyzing unique genetic cases from various specialties. Dr. Rocio Moran, Medical Geneticist in GMI’s Center for Personalized Genetic Healthcare, delivered a genetics primer and facilitated the day-long symposium, which was attended by over 100 people that included physicians, nurses, advance practice nurses, genetic counselors, researchers, social workers, trainees and students. Attendees from Ohio, West Virginia, Minnesota and Florida benefited from the knowledge shared in 23 case-based lectures. Dr. David Longworth, Chair of the Medicine Institute, delivered the keynote address: “Genetics and Genomics in the Era of Value-based Healthcare.” Email us at to be notified of upcoming physician-education events from GMI.

GMI appreciates the generous sponsorship provided by Genezyme, GeneDX and Myriad.

Angela Ting, PhD Awarded Grant to Study Epigenetic Mechanisms in Colon Cancer

Ting Lab

Ting Laboratory, from left: Angela Ting, PhD, Nagarajavel Vivekananthan, PhD, and Thomas Sweet, PhD

September 4, 2013 Angela Ting, PhD, Assistant Staff in the Genomic Medicine Institute, has been awarded a grant from the Case Comprehensive Cancer Center. Her research, entitled “Functional Delineation of Abnormal 3’ DNA Methylation in Colon Cancer,” will improve our mechanistic understanding of colon cancer development and progression.

Methylation is a powerful means of affecting gene activity. Methyl groups, clusters of carbon and hydrogen atoms, attach to genes and make it easier or harder for genes to receive and respond to messages from the body.  Abnormal DNA methylation is a hallmark of cancer. The Ting laboratory has developed high-throughput sequencing technologies and genome-wide analyses to characterize DNA methylation. These state-of-the-art tools are used to investigate how methylation patterns contribute to the development and progression of prostate and colon cancers.

Specialized Program on Research Excellence (SPORE) grants are awarded to research likely to “further our understanding and ability to impact problems associated with GI [gastro-intestinal] cancers.” Grant funding will be administered by Cleveland Clinic’s Taussig Cancer Institute.

Dr. Ting joined the Genomic Medicine Institute in 2007. She is also a member of the Case Comprehensive Cancer Center and holds academic appointments in the Cleveland Clinic Lerner College of Medicine and in the Department of Genetics and Genome Sciences at Case Western Reserve University.

Dr. Charis Eng Featured in New York Times Article

August 11, 2013 Research connecting autism with the PTEN genetic mutation was recently featured in the New York Times Health section. “Autism’s Unexpected Link to Cancer Gene,” highlighted recent research conducted by Charis Eng, MD, PhD, Chair of the Genomic Medicine Institute, in collaboration with Thomas Frazier, MD, Director of the Cleveland Clinic’s Center for Autism. Read the full story. (NYTimes subscription required.)


Developing Comprehensive Guidelines for Identifying and Managing Patients with PTEN Mutations

Charis Eng, MD, PhD

Charis Eng, MD, PhD, Chair of the Genomic Medicine Institute of the Cleveland Clinic Lerner Research Institute

Photo taken by Stephen Travarca
Cleveland Clinic Center for Medical Art & Photography

June 2013 — PTEN is one of the body’s many tumor suppressor genes. Mutations in the PTEN gene prevent the proper regulation of cell proliferation. Cells grow out of control and turn into either benign (hamartomas) or malignant tumors. Many people with Cowden Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, and a few other genetic conditions have been found to have PTEN gene mutations as the cause of their medical concerns. These conditions as a group are referred to as PTEN Hamartoma Tumor Syndrome (PHTS). Dr. Charis Eng, Chair of the Genomic Medicine Institute at the Cleveland Clinic Lerner Research Institute, led the research team, which in 1997, discovered the causative relationship between PTEN germline mutations and Cowden Syndrome.

PHTS is inherited in an autosomal dominant pattern. That is, a single altered copy of the gene, inherited from one parent, is enough to increase a person’s chance of developing the disorder. People with PHTS have a high lifetime risk of developing many types of cancer, including breast, endometrium, thyroid, colon and kidney.

With funding from the National Institutes of Health, Dr. Eng undertook an ambitious clinical research study to determine for who should be tested for PTEN mutations, and what cancer surveillance strategies should be used for affected individuals. Her work has been instrumental for detecting this rare disease early and improving the clinical care for patients with PHTS.

For adults, the Eng team developed a semi-quantitative score—the Cleveland Clinic (CC) score—that relates the prevalence of clinically observed symptoms (phenotypic data) to the probability of harboring a PTEN mutation (genotypic data). [“A Clinical Scoring system for Selection of Patients for PTEN Mutation Testing Is Proposed on the Basis of a Prospective Study of 3042 Probands,”Tan M, Mester J, Peterson C, Yang Y, Chen J, Rybicki L, Milas K, Pederson H, Remzi B, Orloff M, and Eng C; Am J Hum Genet 2011 Jan 7; 88: 1-15.] PTEN genetic testing is recommended for CC scores of ten and above. Relative to the PTEN testing criteria currently endorsed by the National Comprehensive Cancer Network (NCCN), the CC score is less complex to use, more accurate and can provide individualized estimates of one’s probability of harboring a PTEN gene mutation. For pediatric patients, the Eng team identified highly sensitive criteria to guide PTEN mutation testing, with phenotypic features distinct from adults.

The Eng team also conducted the first prospective clinical study to assess the lifetime cancer risk of PHTS patients. Over 3,300 adult and pediatric patients with PTEN mutations from North America, Europe, and Asia were enrolled in a comprehensive clinical study. Age-related cancer risks and genotype-phenotype correlations were investigated and analyzed. Three additional cancers (colorectal, kidney and melanoma) were shown to be among the cancer spectra arising from PTEN germline mutations. Based on this study, recommendations were published for the medical management and cancer surveillance in patients with PTEN mutations. [“Lifetime Cancer Risks in Individuals with Germline PTEN Mutations,” Tan M, Mester J, Ngeow J, Rybicki L, Orloff M, and Eng C; Clin Cancer Res 2012 Jan 15; 18(2): 400-407.] This evidence-based surveillance strategy is used to identify and treat cancer in its earliest stages.

Byron Lee Wins Lower Memorial Award for PublicationByron Lee, MD, receiving the Lower Memorial Award

June 2013 — Byron Lee, MD, PhD, who completed his research year as part of the Urology residency program in the Genomic Medicine Institute under the mentorship of Angela Ting, PhD, won a second place  Lower Memorial Award in basic science for a paper published in Cancer Research.

The Lower Memorial Awards are named for William E. Lower, one of the founders of the Cleveland Clinic Foundation. Given annually to post-doctoral fellows who demonstrate original investigation and professional excellence in preparing scientific papers, Dr. Lee won second place in basic science for this publication:
"Dysregulation of Cholesterol Homeostasis in Human Prostate Cancer through Loss of ABCA1"
Lee BH, Taylor MG, Robinet P, Smith JD, Schweitzer J, Sehayek E, Falzarano SM, Magi-Galluzzi C, Klein EA, and Ting AH
Cancer Res 2013 Feb 1;73(3):1211-8
PMID: 23233737

David Serre’s Team Wins NIH Award for Genomic Study of Malaria in Cambodia

Schematic of Malaria Lifecycle

Schematic representation of the Plasmodium vivax life cycle in humans.

June 21, 2013 — Overall, the number of malaria infections reported globally has decreased since 1997. However, in many places, the relative proportion of cases due to Plasmodium vivax (P. vivax) has increased, for example from 8% (in 2000) to 25% (in 2009) in Cambodia. Although chloroquine is the treatment of choice, drug resistant strains are emerging. Consequently, the entire malaria control strategy in South East Asia is threatened.

The goals of this five-year grant are to better understand how drug resistance spreads in a population and to identify the genetic basis of drug resistance. Modern fieldwork, conducted by Didier Menard of the Pasteur Institute in Cambodia, will be used in conjunction with state-of-the-art genomic analysis conducted by David Serre and his team at the Genomic Medicine Institute of the Cleveland Clinic Lerner Research Institute. Blood samples will be collected from infected individuals and analyzed with next-generation genome sequencing. These data will be used to perform genetic and evolutionary studies to learn where parasites originate, how they spread and how different strains are distributed geographically. In addition, the researchers will attempt to identify the genetic polymorphisms responsible for drug resistance. By providing the first global perspective on the mechanisms of drug resistance in P. vivax, including choloroquine resistance, these studies have the potential to significantly improve current treatment and elimination of vivax malaria.


Dr. Charis Eng Responds to Questions Raised by Angela Jolie’s Prophylactic Mastectomy

Wayne Dawson, Anchor of WJW-TV8 News in Cleveland, and Dr. Charis EngMay 15, 2013 — Angela Jolie made headlines on Tuesday, when she published an Op-Ed piece in the New York Times about her decision to have a double mastectomy to lower her risk of developing breast cancer. Ms. Jolie tested positive for a mutation in the BRCA1 gene—a genetic condition presumably inherited from her mother, who died of breast cancer at the age of 56. Ms. Jolie followed the medical advice she was given and had a mastectomy to lower her risk of developing breast cancer “from 87 percent to 5 percent”.

Dr. Charis Eng responded to questions about the prevalence of BRCA gene mutations, the associated risks of developing breast, ovarian and other, cancers, as well as the gene testing and treatment options available. Dr. Eng stressed that BRCA mutations affect few people when considering the general population; between 5 and 10 percent of breast cancer is due to mutations in the BRCA1 and BRCA2 genes. If you are concerned about your risk of genetic mutation, here are the highlights of Dr. Eng’s advice:

  • Taking a Cancer Family History is the first step to evaluate one’s risk of genetic mutation. [Visit Dr. Eng’s Health Hub blog “8 Tips for a Better Family Health History.”]
  • Talk to your doctor about your family history. She or he can help you determine whether you should see a genetics professional.  If you are concerned, even if your doctor does not think it necessary, it may be helpful to set up an appointment with a genetic counselor. [Visit Dr. Eng’s Health Hub blog “What a Genetic Counselor Can Do for You.”]
  • For those whose family histories suggest a heritable risk, the next step is to see a genetic counselor or medical geneticist.
  • A genetic counselor will help you weigh the pros and cons of being tested and explain what the test can and can’t tell you, and help you interpret the results afterwards.
  • The biggest misconception about BRCA gene testing is that test results are definitive and easy to interpret. They are not.
  • There are more than 10 different genes, including BRCA1/2, which when altered increase one’s lifetime breast cancer risk—all to a different degree.  Importantly, different genes are also associated with different other cancers; for example, BRCA1 mutation is associated with ovarian cancer while BRCA2 mutations add male breast cancer and pancreatic cancer to the mix. A geneticist is the best person to help decide what gene(s) to test for and to interpret the results.
  • If you do test positive for BRCA gene mutations, prophylactic mastectomy is not the only option. Patients often choose increased surveillance instead: more frequent mammograms and breast MRIs, starting as early as 25 years of age.
  • Typically, having prophylactic surgery is a highly personal choice—one made by the patient.  Based on years of rigorous human genetics research, geneticists inform the patient of the risks and options available to help them make a reasonable and informed choice.  However, rarely the radiologist may not be able to clearly see and safely surveillance the breasts; this situation represents a medical reason for prophylactic surgery.
  • Currently, surveillance for ovarian cancer is not helpful.  Women with mutations in BRCA1 or BRCA2 should have prophylactic removal of the ovaries, fallopian tubes and uterus, in their mid-late 30’s.

Here are links to some of the interviews Dr. Eng provided in response to Ms. Jolie’s announcement.

Dr. Eng’s Health Hub blog “Jolie’s Choice: Why Have a Preventative Mastectomy”

Yahoo! Health

Parade Magazine


Watch Dr. Eng’s interview on WJW-TV8 News