Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Study finds molecular 'signature' for rapidly increasing form of esophageal cancer

During the past 30 years, the number of patients with cancers that originate near the junction of the esophagus and stomach has increased approximately 600 percent in the United States.

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.

Although A-to-C changes are not commonly observed in cancer, there is some evidence that oxidative damage can produce these changes. (Oxidative damage occurs when cells cannot neutralize the potentially harmful products of oxygen's reactions with other molecules.) "Gastric reflux can produce this type of damage, suggesting that reflux may underlie this pattern of mutations," Bass commented.

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

Anne Doerr
Rob Levy
(617) 632-4090

Anne Doerr | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht ‘Farming’ bacteria to boost growth in the oceans
24.10.2016 | Max-Planck-Institut für marine Mikrobiologie

nachricht Calcium Induces Chronic Lung Infections
24.10.2016 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Oasis of life in the ice-covered central Arctic

24.10.2016 | Earth Sciences

‘Farming’ bacteria to boost growth in the oceans

24.10.2016 | Life Sciences

Light-driven atomic rotations excite magnetic waves

24.10.2016 | Physics and Astronomy

More VideoLinks >>>