Genome study charts genetic landscape of lung cancer

November 04, 2007

An international team of scientists today announced the results of a systematic effort to map the genetic changes underlying lung cancer, the world's leading cause of cancer deaths. Appearing in the November 4 advance online issue of the journal Nature, the research provides a comprehensive view of the abnormal genetic landscape in lung cancer cells, revealing more than 50 genomic regions that are frequently gained or lost in human lung tumors. While one-third of these regions contain genes already known to play important roles in lung cancer, the majority harbor new genes yet to be discovered. Flowing from this work, the scientists uncovered a critical gene alteration -- not previously linked to any form of cancer -- that is implicated in a significant fraction of lung cancer cases, shedding light on the biological basis of the disease and a potential new target for therapy.

"This view of the lung cancer genome is unprecedented, both in its breadth and depth," said senior author Matthew Meyerson, a senior associate member of the Broad Institute of MIT and Harvard and an associate professor at Dana-Farber Cancer Institute and Harvard Medical School. "It lays an essential foundation, and has already pinpointed an important gene that controls the growth of lung cells. This information offers crucial inroads to the biology of lung cancer and will help shape new strategies for cancer diagnosis and therapy."

"The genomic landscape of lung cancer gives us a systematic picture of this terrible disease, confirming things we know, but also pointing us to many missing pieces of the puzzle," said Eric Lander, one of the study's co-authors and the founding director of the Broad Institute of MIT and Harvard. "More broadly, the study represents a general approach that can and should be used to analyze all types of cancer. Indeed, the study was designed as a pilot project for an even more comprehensive effort to unearth the genetic causes of cancer."

Lung cancer is the leading cause of cancer deaths worldwide -- each year more than 1 million people die of the disease, including more than 150,000 in the United States. New approaches to treatment rely on a deeper understanding of what goes wrong in cells to spur cancer growth. Through decades of research, it has become clear that lung cancer -- like most human cancers -- stems mainly from DNA changes that accrue in cells throughout a person's life. But the nature of these changes and their biological consequences remain largely unknown.

To assemble a genome-wide catalog of genetic differences in lung cancer cells, a large-scale project was recently launched in lung adenocarcinoma. The effort, known as the Tumor Sequencing Project (TSP), unites scientists and clinicians throughout the cancer research community.

The TSP researchers studied more than 500 tumor specimens from lung cancer patients. Access to this large collection of high-quality samples made it possible to determine the genetic changes shared among different patients -- such recurring changes can highlight important genes involved in cancer growth. "This project was made possible through the foresight of a dedicated group of oncologists, pathologists, and surgeons, who carefully and diligently preserved tissues from lung cancer patients over many years," said Meyerson.

To analyze DNA from each lung tumor, the scientists relied on recent genomic technologies to scan the human genome for hundreds of thousands of genetic markers, called single nucleotide polymorphisms or SNPs. This high-resolution view helped pinpoint which parts of the tumor genome were present in excess copies or missing altogether. The regions of genomic aberration were then identified with new analytical tools, including a computational method called GISTIC and methods for visualizing SNP data developed by co-first authors Gaddy Getz and Barbara Weir and co-authors Rameen Beroukhim and Jim Robinson.

From this work, the researchers uncovered a total of 57 genomic changes that occur frequently in lung cancer patients. Of these, only about 15 are linked to genes previously known to be involved in lung adenocarcinoma. The rest, though, remain to be discovered.

Strikingly, the most common abnormality identified in the Nature study involves a region on chromosome 14 that encompasses two known genes, neither of which had been previously associated with cancer. Through additional studies in cancer cells, co-first author Sue-Ann Woo and other researchers at Dana-Farber Cancer Institute revealed that one of the genes, NKX2.1, influences cancer cell growth. The NKX2.1 gene normally acts as a sort of "master regulator" -- controlling the activity of other key genes -- in a special group of cells lining the lungs' tiny air sacs, called alveoli. This discovery, that a gene functioning in a select group of cells rather than all cells can promote cancer growth, may have broad implications for the design of novel, molecularly targeted cancer drugs.

The second phase of the TSP, now underway, will examine the same lung tumor samples analyzed in the first phase, but at an even greater level of genetic detail. Using high-throughput DNA sequencing methods, the scientists will characterize small changes in the genetic code of several hundred human genes, which are already implicated in other cancers or more generally in cell growth.
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Participating institutions in the TSP include three large-scale DNA sequencing centers -- Baylor College of Medicine, Broad Institute of MIT and Harvard, and Washington University -- and six medical institutions-- Brigham and Women's Hospital, Dana-Farber Cancer Institute, M.D. Anderson Cancer Center, Memorial Sloan-Kettering Cancer Center, the University of Michigan, and Washington University. Investigators from Nagoya City University, the Ontario Cancer Institute/Princess Margaret Hospital, and the University of Texas-Southwestern Medical School also participated in the SNP study.

In addition to Matthew Meyerson and Eric Lander, the scientific leaders of the TSP include Harold Varmus of the Memorial Sloan-Kettering Cancer Center, Richard Gibbs of the Baylor College of Medicine, and Richard Wilson of Washington University in Saint Louis.

The TSP is helping to lay the foundation for future large-scale cancer genome projects, including The Cancer Genome Atlas (TCGA) pilot project. In December 2005, the National Human Genome Research Institute and the National Cancer Institute launched the TCGA pilot to test the feasibility of a comprehensive, systematic approach to exploring the genomics of a wide range of common human cancers. In its pilot phase, TCGA is focusing on glioblastoma multiforme, the most common form of brain cancer; ovarian cancer; and squamous cell lung cancer.

Data access

All data generated by the TSP are being made available to the scientific community in public databases, including: http://caintegrator-info.nci.nih.gov/csp. Data can also be accessed through the Broad Institute website, at: http://www.broad.mit.edu/tsp.

Weir B et al. Characterizing the cancer genome in lung adenocarcinoma. Nature DOI: DOI: 10.1038/nature06358.

A complete list of the study's authors and their affiliations:

Barbara A. Weir1,2*, Michele S. Woo1*, Gad Getz2*, Sven Perner3,4, Li Ding5, Rameen Beroukhim1,2, William M. Lin1,2, Michael A. Province6, Aldi Kraja6, Laura A. Johnson3, Kinjal Shah1,2, Mitsuo Sato8, Roman K. Thomas1,2,9,10, Justine A. Barletta3, Ingrid B. Borecki6, Stephen Broderick11,12, Andrew C. Chang14, Derek Y. Chiang1,2, Lucian R. Chirieac3,16, Jeonghee Cho1, Yoshitaka Fujii18, Adi F. Gazdar8, Thomas Giordano15, Heidi Greulich1,2, Megan Hanna1,2, Bruce E. Johnson1, Mark G. Kris11, Alex Lash11, Ling Lin5, Neal Lindeman3,16, Elaine R. Mardis5, John D. McPherson19, John D. Minna8, Margaret B. Morgan19, Mark Nadel1,2, Mark B. Orringer14, John R. Osborne5, Brad Ozenberger20, Alex H. Ramos1,2, James Robinson2, Jack A. Roth21, Valerie Rusch11, Hidefumi Sasaki18, Frances Shepherd25, Carrie Sougnez2, Margaret R. Spitz22, Ming-Sound Tsao25, David Twomey2, Roel G. W. Verhaak2, George M. Weinstock19, David A. Wheeler19, Wendy Winckler1,2, Akihiko Yoshizawa11, Soyoung Yu1, Maureen F. Zakowski11, Qunyuan Zhang6, David G. Beer14, Ignacio I. Wistuba23,24, Mark A. Watson7, Levi A. Garraway1,2, Marc Ladanyi11,12, William D. Travis11, William Pao11,12, Mark A. Rubin2,3, Stacey B. Gabriel2, Richard A. Gibbs19, Harold E. Varmus13, Richard K. Wilson5, Eric S. Lander2,17,26 & Matthew Meyerson1,2,16

*These authors contributed equally to this work.

1Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA 02115.
2Cancer Program, Genetic Analysis Platform, and Genome Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA 02142.
3Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA 02115.
4Institute of Pathology, University of Ulm, Ulm, Germany 89081.
5Genome Sequencing Center
6Division of Statistical Genomics and
7Department of Pathology and Immunology, Washington University in Saint Louis, Saint Louis, Missouri, USA 63130.
8University of Texas Southwestern Medical Center, Dallas, Texas, USA 75390.
9Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max-Planck Society and the Medical Faculty of the University of Cologne, Cologne, Germany 50931.
10Center for Integrated Oncology and Department I for Internal Medicine, University of Cologne, Cologne, Germany 50931.
11Departments of Medicine, Surgery, Pathology, and Computational Biology,
12Human Oncology and Pathogenesis Program,
13Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA 10065.
14Section of Thoracic Surgery, Department of Surgery and
15Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA 48109.
16Department of Pathology and
17Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA 02115.
18Department of Surgery, Nagoya City University Medical School, Nagoya, Japan 467-8602.
19Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA 77030.
20National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA 20892.
21Department of Thoracic and Cardiovascular Surgery,
22Department of Epidemiology,
23Department of Pathology and
24Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA 77030.
25University Health Network and Princess Margaret Hospital, Toronto, Canada M5G 2C4.
26Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA 02142.

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.

For further information about the Broad Institute, go to http://www.broad.mit.edu.

About the 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.

Broad Institute of MIT and Harvard

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