Work draws upon several large-scale methods, reveals key molecular defects shared with other cancers

Matthew Meyerson, MD, PhD, co-senior author of the lung cancer study

Scientists today announced the results of the largest genomic study to date of lung adenocarcinoma, the most common form of lung cancer.

Led by researchers from Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and other research institutions nationwide, the collaborative study unearthed a variety of genetic alterations in patient tumors and pinpointed 26 frequently altered genes — more than doubling the number already linked to the disease.

The work, which appears in the October 23 advance online edition of the journal Nature, draws upon multiple large-scale approaches to highlight key molecular defects in lung tumors that are often found in other forms of cancer, a convergence that could open important avenues for treatment.

"In recent years, there's been some important successes for targeted therapies for some types of lung cancer," said co-senior author Matthew Meyerson, MD, PhD, an associate professor at Dana-Farber Cancer Institute and Harvard Medical School and a senior associate member of the Broad Institute of MIT and Harvard. "This work helps identify new targets that might show promise for treating broader groups of lung cancer patients."

Lung cancer exacts an overwhelming human toll. With over one million deaths worldwide each year, it ranks as the primary cause of cancer-related mortalities. As in the majority of cancers, lung adenocarcinoma stems from abnormalities that accumulate in cells' DNA over a person's lifetime, causing uncontrolled cell growth. However, the nature and precise genomic locations of those changes, and how they work to promote cancer, are largely unknown.

Harnessing the latest tools and technologies, a consortium of researchers came together to characterize the complete sets of DNA, or genomes, derived from tumors of nearly 200 patients with lung adenocarcinoma. The effort, known as the Tumor Sequencing Project (TSP), involved decoding or sequencing the DNA of several hundred genes with known or suspected ties to cancer.

In addition, the scientists scanned tumor genomes to reveal chunks of DNA that are either missing or present in excess copies. Scanning the tumor genomes also allowed them to identify abnormally active as well as silent genes.

These techniques, known as DNA copy number analysis and gene expression analysis respectively, together with advanced computational methods, helped provide a detailed view of the genomic landscape of lung cancer.

"Integrative approaches like these allow us to more clearly pinpoint important genes than a single method alone would," said Meyerson.

As a result of this work, the researchers identified more than 1,000 genetic alterations, the majority of which had not been previously described. While some of these mutations reflect genes already linked to lung adenocarcinoma, a substantial number signify new discoveries.

For example, the NF1, ATM, RB1 and APC genes, which have not before been associated with lung cancer, were mutated in a significant portion of the lung tumors analyzed. Interestingly, these genes have been implicated in other tumor types, suggesting roles in multiple forms of cancer.

The consortium also unearthed genetic ties to a critical class of genes known as tyrosine kinases. Kinases act as molecular switches — when flipped on, they can promote cell growth — and are considered important candidates in the search for new cancer drugs. In lung tumors, the researchers uncovered mutations that cluster in several groups of related tyrosine kinase genes, including the EGF, EPH, FGF, NTRK, and VEGF receptor gene families.

Beyond revealing abnormalities within individual genes, the researchers uncovered extraordinary connections among them. By integrating DNA sequencing, gene expression, and DNA copy number data, they discovered that genetic aberrations are often localized to groups of genes that function together, relaying information from one part of the cell to another. All told, there are about 200 of these molecular circuits or "signaling pathways" that operate in human cells — far fewer than the roughly 20,000 genes.

"One of the key findings from our study is that some of the newly discovered genes and pathways that are mutated in lung cancer are also known to be defective in other cancers," said Meyerson. "That gives us hope that targeted therapies could be used across multiple cancer types."

Among the broken pathways identified are the MAPK, Wnt, p53, and mTOR pathways. Strikingly, the MAPK pathway was altered in roughly 70 percent of the tumors analyzed, suggesting a broad role in the disease. In addition, the p53 and mTOR pathways were affected in roughly one-half and one third of the tumors, respectively.

The TSP was first launched as a pilot project to investigate how various genomic technologies could be effectively applied and integrated to reveal the molecular underpinnings of lung adenocarcinoma. Together with related efforts, including The Cancer Genome Atlas (TCGA), the results of the Nature paper provide a critical foundation to enhance future genomic work in lung adenocarcinoma and initiate comprehensive genomic mapping for other common cancers.

The research was funded in part by National Human Genome Research Institute. The study's first authors were Li Ding, PhD, Washington University, St. Louis; Gad Getz, PhD, the Broad Institute; and David Wheeler, PhD, Baylor College of Medicine. Other authors were based at Dana-Farber and Brigham and Women's Hospital, in Boston; the Broad Institute; Memorial Sloan-Kettering Cancer Center, New York; the University of Cologne, Germany; the University of Michigan, Ann Arbor; and M.D. Anderson Cancer Center, Houston.

About Dana-Farber Cancer Institute

Dana-Farber Cancer Institute (www.dana-farber.org) 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.

About the Broad Institute of MIT and Harvard

The Broad Institute of MIT and Harvard was founded in 2003 to bring the power of genomics to biomedicine. It pursues this mission by empowering creative scientists to construct new and robust tools for genomic medicine, to make them accessible to the global scientific community, and to apply them to the understanding and treatment of disease.

The Institute is a research collaboration that involves faculty, professional staff and students from throughout the MIT and Harvard academic and medical communities. It is jointly governed by the two universities.

Organized around Scientific Programs and Scientific Platforms, the unique structure of the Broad Institute enables scientists to collaborate on transformative projects across many scientific and medical disciplines.