Genetics Research

Genetics Research Across Medical Specialties Now Yielding Secrets and Improving the Practice of Medicine

The decoding of the human genome and subsequent concerted efforts by physician scientists to decipher the relationships between specific genes and the diseases they influence have already yielded tremendous advancements in medicine. This work is fostering important strides in understanding and caring for people with diseases affecting all health systems, and much of the laboratory and translational studies, as well as clinical research, are being done at Columbia University College of Physicians and Surgeons, Weill Cornell Medical College, and NewYork-Presbyterian Hospital.

Research abounds in every field. The field of geriatrics, for instance, was intrigued by a study led by Columbia University researcher Lawrence S. Honig, MD, PhD, Professor of Clinical Neurology in the Taub Institute, an Alzheimer's disease research center funded by the National Institute on Aging.¹

Dr. Honig's research found that telomere length relates both to the likelihood of the patient developing dementia and his or her overall remaining life span. This research could lead to the use of telomere length as an accurate biomarker of aging in people, as well as an early warning sign for future dementia.

The researchers examined telomere lengths from DNA samples of white blood cells obtained from 1,983 individuals aged 66 to 101 years. These patients were followed for an average of 8 years. After adjusting for age and education, among other factors, researchers found that those individuals with shorter telomeres had higher rates of both dementia and mortality. The researchers must now examine whether shorter telomeres directly increase the risk for dementia and death, or if the telomeres are being influenced by some other factor that is both shortening telomere length while at the same time increasing dementia and mortality risk.

Significant research on the genetics behind psychological illness is being undertaken at Weill Cornell Medical College. As just one example, Francis S.Y. Lee, MD, PhD, Professor and Vice Chair for Research in the Department of Psychiatry and Professor in the Department of Pharmacology, who is also an Attending Psychiatrist at the Hospital, directs efforts focused on using genetic models to define the role of growth factors, such as brain-derived neurotrophic factor, and their affect on the pathophysiology and treatment of affective disorders.²

Nephrologists and psychiatrists, meanwhile, were interested in the results of a large multinational study in which Columbia University played an important role.³ The study, led by Ali Gharavi, MD, Associate Director of the Division of Nephrology at NewYork-Presbyterian/Columbia, is the first to link congenital kidney disease, which together with urinary tract defects accounts for about one fourth of all birth defects in the United States, with neurodevelopmental disorders. The study found that 10% of children born with kidney defects have genomic alterations that have been linked with neurodevelopmental delay and mental illness. The finding is important because it paves the way for identifying subgroups of patients with kidney defects whose treatment will be guided by specific genetic information.

The finding also alerts physicians who care for children with congenital kidney disorders that there may be a genetic basis for a neurodevelopmental delay or a mental illness that will occur later in life.

Perhaps no area of medicine has been as affected by research into the genetic foundations of disease as much as oncology. Examples of genetic discoveries in oncology are plentiful. An important recent discovery is the revelation that certain cases of glioblastoma are caused by the fusion of 2 genes.⁴ Researchers, led by Antonio Iavarone, MD, Professor of Pathology and Neurology at Columbia's Institute for Cancer Genetics at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian/Columbia, conducted genetic analyses of patients with glioblastomas, searching for evidence of gene fusions. They found them, with the most common being fusions involving the fibroblast growth factor receptor (FGFR1 or FGFR3) and transforming acidic coiled coil (TACC1 or TACC3) genes. The protein produced by the fusion of FGFR-TACC disrupts the mitotic spindle, causing aneuploidy, and from there tumorigenesis. The finding is important because it provides researchers with a protein target for pharmaceutical research for a cancer that is especially difficult to treat.

Gastroenterologists have been interested in recent work performed by Manish Shah, MD, Director of Gastrointestinal Oncology at Weill Cornell Medical College, who with his colleagues elucidated the heterogeneity of gastric cancer, dividing it into 3 types.⁵ The first type, non-cardia gastric cancer, is linked to environmental factors such as high dietary salt, tobacco use, and increasing age; clinical factors such as Helicobacter pylori infection and use of nonsteroidal anti-inflammatory drugs; and genetic factors including immune regulatory single-nucleotide polymorphisms. A second type, diffuse gastric cancer, is associated with CDH1 mutation and family history and has no known environmental or clinical factors. The third type, proximal gastric cancer, is caused by tobacco and alcohol use; has no known genetic link; and is associated with obesity, high body mass index, and gastroesophageal reflux disease. Dr. Shah's work has alerted those performing drug clinical trials that testing should be based on these subtypes and not on gastric cancer as a whole. Because of the genetic differences in subtypes, the effects of drug therapy may vary significantly between groups.

The field of clinical genetics is rapidly changing and improving the practice of medicine. As the field of genetics continues to grow so too the physician-scientists at Columbia University College of Physicians and Surgeons, Weill Cornell Medical College, and NewYork-Presbyterian Hospital will continue to be at the forefront of integrating genetics into all specialties.

References

1. Honig LS, Kang MS, Schupf N, et al. Association of shorter leukocyte telomere repeat length with dementia and mortality. Arch Neurol. 2012;69(10):1332-1339.

2. Soliman F, Glatt CE, Bath KG, et al. A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science. 2010;327(5967):863-866.

3. Sanna-Cherchi S, Kiryluk K, Burgess KE, et al. Copy-number disorders are a common cause of congenital kidney malformations. Am J Hum Genetics. 2012;91(6):987-997.

4. Singh D, Chan JM, Zoppoli P, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science. 2012;337(6099):1231-1235.

5. Shah MA, Kelsen DP. Gastric cancer: a primer on the epidemiology and biology of the disease and an overview of the medical management of advanced disease. J Natl Compr Canc Netw. 2010;8(4):437-447.