Epigenome Map of Cell May Help Show Cancer Evolution & Drug Resistance

Man Touching DNA

Due to its widespread impact across various developed countries and cultures, cancer has been the focus of an ever-increasing number of studies worldwide. What makes these studies difficult, however, is the complicated nature of how cells become cancerous and/or malignant, and further is the overwhelming amount of diversity of the kinds of diseases that all fall under the umbrella of “cancer.”

Scientists have made headway in studying the various genetic mutations that occur in cancer cells which make them behave so differently and adversely to healthy cells. These observed changes have provided the medical community with new signs and signals that are giving insight into how far along cancer development has progressed in patients.

It seems, though, that the puzzle of cancer is increasingly more complex when we look at the problem through the epigenetic lens. Although relatively fewer studies have been performed in this area, researchers at Weill Cornell Medicine and New York Genome Center (NYGC) set out to help shed additional light here, by developing a new approach to track the evolution of cancers at a molecular level.

In a pair of studies published in Nature and Nature Communications, Dr. Dan Landau of Weill Cornell Medicine & NYGC and colleagues mapped out the epigenomes in thousands of cancerous cells from patients with chronic lymphocytic leukemia (CLL). CLL, as both studies explain, is a prime example for illustrating cancer evolution thanks to the considerable genetic variation and evolution that occurs after therapy.

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However, these studies differed from many performed in the past by measuring the epimutation rate [the rate at which changes occur in the chemical structure of DNA that don’t change the DNA coding sequence] at single-cell resolution. This was done to help determine whether they affected CLL populations as a whole or if the changes were heterogeneous throughout the population.

The idea was to analyze the vast set of epigenomic data to show how the cancerous cells had evolved and how the cells responded to the drug ibrutinib; a kinase inhibitor that works by slowing or stopping the growth of cancer cells.

The technique used in the studies strayed from the bulk sequencing methods in favor of applying multiplexed single-cell reduced-representation bisulfite sequencing (RRBS). A similar approach of using RRBS was performed in a study by researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences who used it to measure DNA methylation levels in brain tissue from patients who had glioblastoma to determine a link between epigenetic modifications and disease progression.

DNA Methylation is the major epigenetic modification in which a methyl group (written as CH3) is added to the position 5 of cytosine, resulting in 5-methylcytosine (5-mc). This mechanism effectively determines which genes are expressed as well as which are repressed and can be inherited through cell division.

All of these studies focused on viewing DNA methylation at single-cell resolution, although the CeMM Research Center study combined findings of DNA methylation in the brain tissue with brain imaging and digital pathology while the current studies observed methylation in the DNA of cells of areas affected by CLL (the white blood cells from the blood and bone marrow called B Cells).

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In the study published in Nature, Dr. Landau and colleagues used their developed technique to map DNA methylations of more than 800 normal B cells from six healthy people and on over 1,800 cancerous B cells from 12 CLL patients.

The researchers analyzed the CLL cells back to their cancerous origin to show how they evolved through the course of the disease. Afterward, the researchers classified the CLL cells into different clades (groups) based on how closely related their epigenomic patterns were.

They found that not only were some cancerous cells more diversified than others but also that these diversifications affected how sensitive the cells were to the ibrutinib treatment. Dr. Landau noted, “This enormous diversity within each cancerous cell population means that in each patient, we’re dealing with thousands of variants of the cancer rather than just one entity, and all this variation increases the cancer’s potential to adapt to challenges such as drug therapy… here we’re extending that concept to show that there is epigenetic diversity as well.”

The Nature Communications study took this concept one step further by not only analyzing the methylations but also the histone modifications on the DNA of patients’ CLL cells. Histones are proteins which chromosomes are spooled around that, with specific chemical changes, can be tightened or loosened so that genes are either expressed or repressed. The unique combination of the methylation of DNA plus the histone modifications (and perhaps a score of other epigenetic alterations) is how genes are essentially “turned on or off” in the cells throughout the wide spectrum of species on earth.

The study, which was a collaboration between Dr. Landau and Dr. Omar Abdel-Wahab of Memorial Sloan Kettering Cancer Center, concluded that the CLL cells do indeed diversify their sets of histone modifications as well as the epigenetic marks (like the methylations from the first study). Dr. Landau talked about this change and the dramatic impact it had in regards to the cells function: “Normal human cells are programmed to function in a precisely defined way within a multicellular organism… cancerous cells devolve into something more like a one-celled life form, like bacteria—in which you also see this diversifying tendency that makes the cell population more resilient.”

Additional research is needed understand how different cancers affect both the genetic and epigenetic structure of cells and their DNA to become such a serious threat to the body and the technique developed here can be reutilized to aid in this analysis. Studies such as these opens new doors of understanding how cancerous cells can develop resistance to the drugs meant specifically to treat them.

Sources:

Pastore S et. al. (2019) Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL Nature Communications 10:1874

Gaiti S et. al. (2019) Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia Nature 2019

Reference:

Weill Cornell Medicine Tracking the Epigenetic Evolution of a Cancer, Cell by Cell Weill Cornell Medicine News. May 2019

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