Nav: Home

Changes in cancer epigenome implicated in chemotherapy resistance and lymphoma relapse

April 20, 2015

NEW YORK (April 20, 2015) -- Genomic studies have illuminated the ways in which malfunctioning genes can drive cancer growth while stunting the therapeutic effects of chemotherapy and other treatments. But new findings from Weill Cornell Medical College investigators indicate that these genes are only partly to blame for why treatment that was at one point effective ultimately fails for about 40 percent of patients diagnosed with the most common form of non-Hodgkin Lymphoma.

The study, published April 20 in Nature Communications, suggests that global changes in cancer cells' epigenome that turn normal genes on when they should be off, and vice versa, may be a powerful force in determining disease progression. The investigators made this discovery by reviewing biopsies taken from patients with diffuse large B-cell lymphoma (DLBCL) before treatment and again after the treatment failed and cancer resurged. They compared the two samples and found that the epigenome in these patients' cancer cells had substantially changed after treatment.

They also found that the global epigenome of pre-treatment biopsies was substantially different in patients whose disease did not recur compared to patients whose disease came back. The researchers found more cell-to-cell heterogeneity, that is, a greater variety of epigenetic patterns in patients who relapsed.

The epigenome, which surrounds genetic DNA like a bubble, is powerful; it can determine which genes are turned on or off, influencing the production of proteins -- the workhorses of human biology. The epigenome can modify gene expression by adding or removing a chemical compound, known as a methyl group, to a specific place in a gene's DNA. Adding a methyl group to a gene turns the gene off, and removing a methyl group allows a gene to turn on when it shouldn't.

This explains why the findings are so significant, investigators say, because drugs that disrupt the epigenetic machinery in cancer cells might reverse treatment resistance and help chemotherapy and other drugs to do their jobs.

"This is the first study I know of in cancer that looks at changes in the epigenome before and after treatment, and what we found could ultimately make traditional treatments much more effective," said senior author Dr. Olivier Elemento, an associate professor of physiology and biophysics and head of the Laboratory of Cancer Systems Biology in the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine at Weill Cornell.

"The epigenome is flexible and can change faster than the genome can, but changes in the epigenome are lasting -- they are maintained from one cell division to the next," Dr. Elemento said.

Epigenetic modifications can therefore be inherited, or can be influenced by a person's environment, such as diet and pollutants. Yet the cause of global epigenetic changes in cancer, including DLBCL, Dr. Elemento added, is unknown.

To help uncover the role of epigenetic involvement, Dr. Elemento utilized biopsies banked by collaborators Dr. Giorgio Inghirami and Dr. Wayne Tam, who are blood cancer pathology specialists and lymphoma researchers at Weill Cornell.

In each sample set, investigators looked at sites in the epigenome where a methyl group was added or removed after cancer recurred. They found a change in methylation that occurred between 39,808 and 1,035,960 specific methylation sites, depending on the cancer sample. In addition, they identified between 78 and 13,162 differently methylated regions in the epigenome in relapsed cancer.

"These are massive changes -- given that the epigenome has 20 million methylation sites, our study shows that in some cases, up to one-twentieth of the entire epigenome is changed after treatment," Dr. Elemento said. "There are many more epigenetic changes than there are altered genes in DLBCL."

"Once you have changes in methylation, the end result is an imbalanced expression of proteins," added Dr. Inghirami, a professor of pathology and laboratory medicine at Weill Cornell. "The tumor after chemotherapy is not the same as the tumor before treatment. This why it is so critical to have biopsies before any treatment of either primary as well as of relapsed lesions."

Given how important the epigenome seems to be in cancer, the investigators say future success in this new avenue of research and treatment depends on collecting cancer biopsies from patients before and after treatment. They hope that this work will ultimately allow clinicians and researchers to predict treatment resistance in individual patients.

"By studying more samples, it may ultimately be possible to scan the most informative regions of the epigenome of a patient's lymphoma at diagnosis to predict whether treatment will be successful and whether the cancer may recur," said Dr. Tam, an associate professor of clinical pathology and laboratory medicine at Weill Cornell.
Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist. For more information, visit

Office of External Affairs
Weill Cornell Medical College
tel: 646.317.7401
Follow WCMC on: Twitter, Facebook, and Instagram

Weill Cornell Medicine

Related Cancer Articles:

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
More Cancer News and Cancer Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#540 Specialize? Or Generalize?
Ever been called a "jack of all trades, master of none"? The world loves to elevate specialists, people who drill deep into a single topic. Those people are great. But there's a place for generalists too, argues David Epstein. Jacks of all trades are often more successful than specialists. And he's got science to back it up. We talk with Epstein about his latest book, "Range: Why Generalists Triumph in a Specialized World".
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at