The first extensive probe of the DNA of these esophageal adenocarcinomas (EACs) has revealed that many share a distinctive mix-up of letters of the genetic code, and found more than 20 mutated genes that had not previously been linked to the disease.
The research, led by scientists at Dana-Farber Cancer Institute, the Broad Institute, and other research centers, may offer clues to why EAC rates have risen so sharply. The findings, which are being released as an advanced online publication by Nature Genetics, point to an array of abnormal genes and proteins that may be lynchpins of EAC cell growth and therefore serve as targets for new therapies, according to the study's authors.
"Adenocarcinomas of the esophagus, particularly those that arise at the gastroesophageal junction, were extremely uncommon 40 years ago and now account for approximately 15,000 new cases in the United States each year," said Adam Bass, MD, of Dana-Farber and the Broad Institute, who is co-senior author of the paper with Gad Getz, PhD, of the Broad Institute and Massachusetts General Hospital.
"Unfortunately, it's also a disease with a generally poor prognosis: five years after diagnosis, only about 15 percent of patients are still alive. Bass added that despite the increased incidence of EAC, there have been few new approaches to treatment. "The goal of our study was to identify abnormalities within the genome of EAC cells to develop a foundation to better understand these tumors, diagnose them earlier, and develop better treatments," explained Bass.
EAC is thought to be associated with chronic gastroesophageal reflux, which sends stomach acid gurgling into the esophagus. This produces a condition known as Barrett's esophagus, in which cells at the lower end of the esophagus change to resemble cells in the intestine. Patients with Barrett's esophagus often go on to develop EAC.
Researchers don't know why EAC rates are increasing, but they speculate that it may be due to a rise in obesity, particularly in men: A heavier abdomen puts increased pressure on the stomach, causing acid to back up into the esophagus.
In the new study, researchers "sequenced" specific sections of DNA in cells from 149 EAC tissue samples, reading the individual letters of the genetic code within those areas. They focused on the one percent of the genome that holds the codes for making cell proteins. They also sequenced the entire genome – all the DNA within the cell nucleus – of cells from 15 of these EAC samples. Prior to this study, the largest sequencing study of EAC involved only a dozen tumor samples.
"We discovered a pattern of DNA changes that had not been seen before in any other cancer type," Getz remarked. The pattern involved a subtle swap in one of the four "nucleobases" that form the rungs of the DNA double helix, often designated by the letters C, T, G, and A. The investigators found that in many places where an A nucleobase was followed by another A nucleobase, the second "A" was replaced by a "C," a process known as transversion."We found this type of transversion throughout the genomes of the EAC cells we analyzed," Bass stated. "Overall, about one-third of all the mutations we discovered within these cells involved this type of transversion. In some tumor samples, these transversions accounted for nearly half of all mutations," Getz added.
In addition to the mutational "signature" of AA becoming AC, the research team identified 26 genes that were frequently mutated in the tumor samples.
Five of these were "classic cancer genes" that had previously been implicated in EAC, Bass said, and the others were involved in a variety of cell processes.
Among the genes not previously linked to EAC were ELMO1 and DOCK2, mutations that can switch on a gene called RAC1, which can cause cancer cells to invade surrounding tissue. "The discovery of mutated ELMO1 and DOCK2 in many of these tumors may indicate that this invasive process is particularly active in EAC, promoting metastasis," Bass related. "We know that EAC tumors tend to spread at an earlier stage than many other cancers, which may help explain why survival rates for EAC patients tend to be low."
The RAC1 pathway – the network of genes that control RAC1 activity – is being pursued for pharmaceutical development. The discovery of ELMO1 and DOCK2 mutations in EAC samples may spur testing of new agents targeting this pathway in EAC, said Bass.
"Identifying the mutated genes within these tumors will help us understand the underlying biology of the disease," said Bass. "It also presents us with a slate of known genetic abnormalities that can someday be used to diagnose the disease at an early stage, classify tumors by the particular mutations within EAC cells, and ultimately develop treatment geared to precisely those mutations."
The lead authors of the study are Austin Dulak, PhD, and Petar Stojanov of Dana-Farber and the Broad Institute. Co-authors are: Shouyong Peng, PhD, Cameron Fox and Yu Imamura, MD, PhD, of Dana-Farber; Michael Lawrence, PhD, Chip Stewart, Erica Shefler, Aaron McKenna, Scott Carter, PhD, Kristian Cibulskis, Andrey Sivachenko, Gordon Saksena, Douglas Voet, Alex Ramos, PhD, Daniel Auclair, PhD, Kristin Thompson, PhD, Carrie Sougnez, Robert Onofrio, Stacey Gabriel, PhD, and Candace Guiducci, of the Broad Institute; Steven Schumacher, of Dana-Farber and the Broad; Rameen Beroukhim, MD, PhD, of Dana-Farber, the Broad Institute, and Brigham and Women's Hospital; Shuji Ogino, MD, PhD, of Dana-Farber, Brigham and Women's, and the Harvard School of Public Health; Todd Golub, MD, of Dana-Farber, the Broad Institute, and the Howard Hughes Medical Institute; Santhoshi Bandla, PhD, Tony Godfrey, PhD, and Zhongren Zhou, PhD, of the University of Rochester; Lin Lin, MD, PhD, Jules Lin, MD, Rishindra Reddy, MD, David Beer, PhD, and Andrew Chang, MD, of the University of Michigan; James Luketich, MD, Rodney Landrenau, MD, and Arjun Pennathur, MD, of the University of Pittsburgh Medical Center; and Eric Lander, DPhil, of the Broad Institute, and MIT.
The work was supported in part by grants from the U.S. National Human Genome Research Institute (U54 HG003067), the National Cancer Institute (K08 CA134931), the DeGregorio Family Foundation, the Karin Grunebaum Cancer Research Foundation, Target Cancer, and Connecticut Conquers Cancer.
About Dana-Farber Cancer Institute
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center, and it provides pediatric care with Boston Children's Hospital as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top-ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter or Facebook.
About the Broad Institute of MIT and Harvard
The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.
Anne Doerr | EurekAlert!
Closing the carbon loop
08.12.2016 | University of Pittsburgh
Newly discovered bacteria-binding protein in the intestine
08.12.2016 | University of Gothenburg
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
08.12.2016 | Life Sciences
08.12.2016 | Physics and Astronomy
08.12.2016 | Materials Sciences