NUTLEY, N.J., June 29, 2020 /PRNewswire/ -- By sequencing entire genomes for DNA modifications, and analyzing both cancer tissues and healthy ones, Hackensack Meridian Health researchers and doctors have found what could be a key to risks for cancer and other diseases: specific locations in the DNA where those expression changes (methylation) are imbalanced, according to a new publication.
The authors, from the Center for Discovery and Innovation (CDI), Hackensack University Medical Center and its John Theurer Cancer Center (JTCC), and the National Cancer Institute-recognized Georgetown Lombardi Comprehensive Cancer Center Consortium, published their findings in the major journal Genome Biology on June 29.
The most strongly disease-relevant genetic variants can be hard to localize in widespread scanning of the genome – but by zooming in on key genetic locations associated with these DNA methylation imbalances in multiple normal and cancer tissues, the scientists report they have uncovered promising new leads beneath the broader statistical signals.
"Our dense map of allele-specific methylation (i.e., DNA methylation imbalances dictated by genetic variation) will help other scientists prioritize and focus their work on the most relevant genetic variants associated with diseases," said Catherine Do, M.D., Ph.D., assistant member of the CDI, and the first author. "Because we also dug into the mechanisms of this phenomenon to understand how it can result in disease susceptibility, our study will help identify new interesting biological pathways for personalized medicine and drug development."
"Cancer cells are gangsters, but in our approach we make them work for us in a useful way," said Benjamin Tycko, M.D., Ph.D., the CDI lab director who oversaw the study. "These 'footprints' of allele-specific methylation are more abundant in cancers than in normal tissues, but since Catherine's work has shown they are produced by the same biological pathways, we can use our dense maps to understand the beginnings of both cancers and non-cancerous diseases – such as autoimmune, neuropsychiatric, and cardiometabolic disorders."
The current study generated one of the largest high-quality datasets used in this kind of approach. Among the DNA samples studied were various tissue types from 89 healthy controls, plus 16 cancer samples from three types of tumors treated by oncologists and surgeons at the JTCC: B-cell lymphomas, multiple myeloma, and glioblastoma multiforme (a common and difficult-to-treat brain tumor).
The scientists identified a total of 15,112 allele-specific methylation sites including 1,838 sites located near statistical signals of disease susceptibility from genome-wide association studies (GWAS). These data have been made publicly available so that other scientists can test new hypotheses in "post-GWAS" studies.
Also among its novel findings, the paper reports evidence that non-coding mutations (that do not change protein sequences) "might play roles in cancer through long range regulatory effects on gene expression." One specific example cited in the paper is a mutation that causes allele-specific methylation in the TEAD1 gene, which evidence has shown becomes over-expressed in aggressive and treatment-refractory forms of multiple myeloma.
Another discovery is that some disease-relevant genetic variants can reside in "chromatin deserts," places in the DNA which few or no specific biological signals in available tissue types – but which are revealed by the footprints of allele-specific methylation and may have been active at different times of the cell history or development stages.
"This could be a key breakthrough in determining how cancer starts – and give us a better chance to treat it," said David Siegel, M.D., founding director of the Institute for Multiple Myeloma and Lymphoma at the CDI, and also the chief of the Multiple Myeloma Division at John Theurer Cancer Center at Hackensack University Medical Center, and one of the authors. "Finding non-coding mutations that cause epigenetic activation of genes such as TEAD1 in multiple myeloma can potentially help us narrow in on the most promising targets for developing new treatments."
"Advanced epigenetic research like this will drive clinical decisions in the near future," said Andre Goy, M.D., M.S., physician-in-chief for oncology at Hackensack Meridian Health and director of John Theurer Cancer Center, also an author of the paper. "Studies like this, looking at the most detailed changes of DNA methylation and gene expression, could help us solve the riddle of how cancer starts – and perhaps how to conquer it."
"I applaud this important contribution to our understanding of cancer and its underlying biology that can potentially be applied to other disease," said Louis M. Weiner, M.D., director of Georgetown Lombardi Comprehensive Cancer Center and the MedStar Georgetown Cancer Institute. "This research finding is yet more evidence of what can be achieved by bringing together investigators from different institutions and specialties."
Authors of the study from the JTCC and CDI also include David (Kar Fai) Chow, M.D., attending pathologist and medical director of the Hackensack Meridian Health Biorepository; Rena Feinman, Ph.D., an associate member of the CDI; Emmanuel Dumont, Ph.D., a research assistant member of CDI working in Dr. Tycko's epigenetics group; George J. Kaptain, M.D., director of Neuro-Oncology, Skull-Base Surgery and Radiosurgery within the Department of Neurosurgery at Hackensack University Medical Center; Samuel Goldlust, M.D., a neuro-oncologist at John Theurer Cancer Center; Nicholas Illsley, D.Phil, senior scientists in the Department of Obstetrics and Gynecology at Hackensack University Medical Center; Angelica Castano, M.D., a research associate in the Tycko lab; and Martha Salas, also of the Tycko lab. Subha Madhavan, Ph.D., chief data scientist at the Georgetown University Medical Center and director of the Innovation Center for Biomedical Informatics (ICBI) and associate professor of Oncology was another author; and other important collaborators took part from Columbia University, Johns Hopkins, and the Karolinska Institute.
ABOUT HACKENSACK MERIDIAN HEALTH
Hackensack Meridian Health is a leading not-for-profit health care organization that is the largest, most comprehensive and truly integrated health care network in New Jersey, offering a complete range of medical services, innovative research and life-enhancing care.
Hackensack Meridian Health comprises 17 hospitals from Bergen to Ocean counties, which includes three academic medical centers – Hackensack University Medical Center in Hackensack, Jersey Shore University Medical Center in Neptune, JFK Medical Center in Edison; two children's hospitals - Joseph M. Sanzari Children's Hospital in Hackensack, K. Hovnanian Children's Hospital in Neptune; nine community hospitals – Bayshore Medical Center in Holmdel, Mountainside Medical Center in Montclair, Ocean Medical Center in Brick, Palisades Medical Center in North Bergen, Pascack Valley Medical Center in Westwood, Raritan Bay Medical Center in Old Bridge, Raritan Bay Medical Center in Perth Amboy, Riverview Medical Center in Red Bank, and Southern Ocean Medical Center in Manahawkin; a behavioral health hospital – Carrier Clinic in Belle Mead; and two rehabilitation hospitals - JFK Johnson Rehabilitation Institute in Edison and Shore Rehabilitation Institute in Brick.
Additionally, the network has more than 500 patient care locations throughout the state which include ambulatory care centers, surgery centers, home health services, long-term care and assisted living communities, ambulance services, lifesaving air medical transportation, fitness and wellness centers, rehabilitation centers, urgent care centers and physician practice locations. Hackensack Meridian Health has more than 34,100 team members, and 6,500 physicians and is a distinguished leader in health care philanthropy, committed to the health and well-being of the communities it serves.
The network's notable distinctions include having four hospitals among the top 10 in New Jersey by U.S. News and World Report. Other honors include consistently achieving Magnet® recognition for nursing excellence from the American Nurses Credentialing Center and being named to Becker's Healthcare's "150 Top Places to Work in Healthcare/2019" list.
The Hackensack Meridian School of Medicine at Seton Hall University, the first private medical school in New Jersey in more than 50 years, welcomed its first class of students in 2018 to its On3 campus in Nutley and Clifton. Additionally, the network partnered with Memorial Sloan Kettering Cancer Center to find more cures for cancer faster while ensuring that patients have access to the highest quality, most individualized cancer care when and where they need it.
Hackensack Meridian Health is a member of AllSpire Health Partners, an interstate consortium of leading health systems, to focus on the sharing of best practices in clinical care and achieving efficiencies.
For additional information, please visit www.HackensackMeridianHealth.org.
About the Center for Discovery and Innovation
The Center for Discovery and Innovation, a newly established member of Hackensack Meridian Health, seeks to translate current innovations in science to improve clinical outcomes for patients with cancer, infectious diseases and other life-threatening and disabling conditions. The CDI, housed in a fully renovated state-of-the-art facility, offers world-class researchers a support infrastructure and culture of discovery that promotes science innovation and rapid translation to the clinic.
About John Theurer Cancer Center at Hackensack University Medical Center
John Theurer Cancer Center at Hackensack University Medical Center is New Jersey's largest and most comprehensive center dedicated to the diagnosis, treatment, management, research, screenings, and preventive care as well as survivorship of patients with all types of cancers. The 14 specialized divisions covering the complete spectrum of cancer care have developed a close-knit team of medical, research, nursing, and support staff with specialized expertise that translates into more advanced, focused care for all patients. Each year, more people in the New Jersey/New York metropolitan area turn to John Theurer Cancer Center for cancer care than to any other facility in New Jersey. John Theurer Cancer Center is a member of the Georgetown Lombardi Comprehensive Cancer Center Consortium, one of just 16 NCI-approved cancer research consortia based at the nation's most prestigious institutions. Housed within a 775-bed not-for-profit teaching, tertiary care, and research hospital, John Theurer Cancer Center provides state-of-the-art technological advances, compassionate care, research innovations, medical expertise, and a full range of aftercare services that distinguish John Theurer Cancer Center from other facilities. For additional information, please visit www.jtcancercenter.org.
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