Using a widely known mathematical field designed primarily to study how digital and other information is measured, stored, and shared, scientists at Johns Hopkins Medicine and Johns Hopkins Kimmel Cancer Center claim to have discovered a likely key genetic cause in leukemia. lymphoblastic (ALL).
ALL is the most common form of childhood leukemia, affecting approximately 3,000 children and adolescents each year in the United States alone.
Specifically, the Johns Hopkins team used “information theory,” applying an analysis that relies on strings of zeros and ones – the binary system of symbols common to computer languages and codes – to identify variables. or the results of a particular process. In the case of human cancer biology, scientists have focused on a chemical process in cells called DNA methylation, in which certain chemical groups attach themselves to areas of genes that guide gene on / off switches. .
“This study demonstrates how a mathematical language of cancer can help us understand how cells are supposed to behave and how changes in that behavior affect our health,” says Andrew Feinberg, MD, MPH, Bloomberg Emeritus Professor at Johns Hopkins University School of Medicine. , Whiting School of Engineering and Bloomberg School of Public Health. A founder of the field of cancer epigenetics, Feinberg discovered altered DNA methylation in cancer in the 1980s.
Feinberg and his team say that using information theory to find genes that cause cancer may be applicable to a wide variety of cancers and other diseases.
Methylation is now recognized as a way in which DNA can be modified without changing the genetic code of a cell. When methylation goes awry in such epigenetic phenomena, certain genes are abnormally turned on or off, triggering uncontrolled cell growth or cancer.
“Most people are familiar with genetic changes in DNA, namely mutations that alter the sequence of DNA. These mutations are like the words that make up a sentence, and methylation is like punctuation in a sentence. , providing breaks and stops as we read, ”says Feinberg. In search of a new and more efficient way to read and understand the epigenetic code altered by DNA methylation, he worked with John Goutsias, Ph.D., professor in the Department of Electrical and Computer Engineering at the ‘Johns Hopkins University and Michael Koldobskiy, MD, Ph.D., pediatric oncologist and assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center.
“We wanted to use this information to identify the genes that cause cancer to develop even if their genetic code is not mutated,” says Koldobskiy.
The findings of the study, led by Feinberg, Koldobskiy and Goutsias, were published on April 15 in Biomedical engineering of nature.
Koldobskiy explains that methylation at a particular gene location is binary – methylation or no methylation – and a system of zeros and ones can represent these differences just as they are used to represent computer codes and instructions.
For the study, the Johns Hopkins team analyzed DNA extracted from bone marrow samples from 31 children newly diagnosed with ALL at Johns Hopkins Hospital and Texas Children’s Hospital. They sequenced DNA to determine which genes across the genome were methylated and which were not.
Newly diagnosed leukemia patients have billions of leukemia cells in their bodies, Koldobskiy says.
By assigning zeros and ones to methylated or unmethylated pieces of genetic code and using information theory concepts and computer programs to recognize methylation patterns, scientists were able to find regions of the genome that were consistently methylated in patients with leukemia and those without cancer.
They also saw regions of the genome in leukemia cells that were more randomly methylated, compared to the normal genome, a signal to scientists that these spots may be specifically related to leukemia cells compared to normal cells.
One gene, called UHRF1, was distinguished from other genetic regions of leukemia cells that showed differences in DNA methylation from the normal genome.
“It was a big surprise to find this gene, as its link to prostate and other cancers has been suggested but never identified as a factor in leukemia,” says Feinberg.
In normal cells, protein products of the UHRF1 gene create a biochemical bridge between DNA methylation and DNA packaging, but scientists have not deciphered precisely how the alteration in the gene contributes to cancer.
Experiments by the Johns Hopkins team show that leukemia cells grown in the lab without UHRF1 gene activity cannot self-renew and perpetuate additional leukemia cells.
“Leukemia cells aim to survive, and the best way to ensure survival is to vary the epigenetics in many regions of the genome so that no matter what tries to kill cancer, at least some will survive,” says Koldobskiy.
ALL is the most common pediatric cancer, and Koldobskiy says decades of research into various treatments and the sequence of these treatments has helped clinicians cure most of these leukemias, but recurrence of the disease remains one of the leading causes of cancer death in children.
“This new approach may lead to more rational ways of targeting the alterations that lead to this and possibly many other forms of cancer,” says Koldobskiy.
The Johns Hopkins team plans to use information theory to analyze methylation patterns in other cancers. They also plan to determine whether epigenetic alterations in URFH1 are linked to treatment resistance and disease progression in patients with childhood leukemia.
The new research was funded by the National Institutes of Health’s National Cancer Institute (R01CA65438), the National Institute of Diabetes and Digestive and Kidney Diseases (DP1 DK119129), the National Human Genome Research Institute (R01 HG006282), the National Science Foundation ( 1656201), St. Baldrick Foundation Fellowship, Unravel Pediatric Cancer, and the Damon Runyon Cancer Research Foundation.
In addition to Feinberg, Koldobskiy and Goutsias, research contributors include Garrett Jenkinson, Jordi Abante, Varenka Rodriguez DiBlasi, Weiqiang Zhou, Elisabet Pujadas, Adrian Idrizi, Rakel Tryggvadottir, Colin Callahan, Challice Bonifant, Patrick Brown and Hongkins Ji. and Karen R. Rabin of Baylor College of Medicine.