Tumor genome analysis unveils new insights into lung cancer
Reported November 04, 2007
HOUSTON — (November 4, 2007) — An international consortium of scientists today in an advanced online publication in the journal Nature revealed a comprehensive view of the altered genetic background of the type of lung cancer that is the most common cause of cancer deaths in humans.
Of particular interest was a specific proto-oncogene called NKX2-1 that appears involved in as many as 12 percent of lung adenocarcinomas the most common cause of cancer deaths worldwide, said the group, whose work was in part financed by the National Human Genome Research Institute. The group noted, however, that analysis indicates that many of the genes that play a role in the disease remain to be discovered.
“This view of the lung cancer genome is unprecedented, both in its breadth and depth,” said senior author Dr. Matthew Meyerson, a senior associate member of the Broad Institute of MIT and Harvard in Cambridge, Mass., and an associate professor at Dana-Farber Cancer Institute and Harvard Medical School in Boston. “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 report is the first to emerge from the Tumor Sequencing Project that involves three genome centers: Baylor College of Medicine Human Genome Sequencing Center in Houston, The Broad Institute of Harvard and MIT in Cambridge, Mass., and Washington University in St. Louis, Mo.; and five cancer centers: Dana-Farber Cancer Institute in Boston, The University of Texas M. D. Anderson Cancer Center in Houston, Memorial Sloan-Kettering Cancer Center in New York, the University of Michigan and Washington University.
Each year, more than 1 million people worldwide die of lung cancer. In the United States, the annual death toll is 150,000. Lung adenocarcinoma, the topic of this study, is the most common cause of lung cancer.
“This study illustrates the value in using high through-put sequencing and microarray analysis to understand the fundamental properties of tumors at the molecular level,” said Dr. Richard Gibbs, director of the BCM Human Genome Sequencing Center, and one of the paper’s co-authors. “The identification of this gene demonstrates the power of copy number analysis using arrays (or gene chips).”
The authors wrote: “This study represents a step toward comprehensive genomic characterization for one of the most common lung cancers, lung adenocarcinoma… Recent advances in massively parallel DNA sequencing technology may soon make it feasible to undertake similar comprehensive studies to identify all translocations, point mutations and epigenomic changes in cancer and thus point the way to an integrated picture of the cancer genome.” Dr. Barbara A. Weir of Dana-Farber and the Broad Institute, Michele S. Woo of Dana-Farber and Gad Getz of the Broad Institute are first authors on the paper and contributed equally to the work.
The team found 57 frequent genomic changes in their analysis of the genetics of tumors taken from lung cancer patients. Of these, 15 are linked to genes known to be involved in lung cancer. The rest remain to be discovered.
The gene NKX2-1 is essential in the development of cells that line the alveoli of the lungs. Mice lacking the gene die at birth because they cannot breathe. However, it is a proto-oncogene, which means that it can mutate into a gene that promotes development of cancer.
Lung adenocarcinoma is the leading cause of cancer death worldwide. Using gene chip or microarrays, researchers compared the genomes of 371 lung adenocarcinomas to 242 normal lung samples using special gene chips to analyze approximately 250,000 genetic markers. Their analyses identified areas of genetic material that has been repeated or deleted in the tumors. Among these were six areas currently associated with known mutations in lung cancers.
The most common event was an increase in genetic information on one arm of chromosome 14, where NKX2-1 is found in that area of the chromosome. Using a variety of techniques, including RNA interference, they determined that NKX2-1 is essential for the survival of lung cancer cell lines that express the gene.
Funding for the research came from the Ruth L. Kirschstein National Research Service Award of the National Institutes of Health, the National Cancer Institute, the Canadian Cancer Society/National Cancer Institute of Canada, the American Lung Association, Joan’s Legacy Foundation, the American Cancer Society, the International Association for the Study of Lung Cancer, the U.S. Department of Defense and the Carmel Hill Fund.
Researchers from The Brigham and Women’s Hospital, Nagoya City University Hospital in Japan and the University Health Network in Toronto, Canada, also contributed samples to this work. Researchers from the University of Ulm in Germany, UT Southwestern Medical Center in Dallas, Max-Planck Institute for Neurological Research in Germany, the University of Cologne in German, Harvard Medical School, and Princess Margaret Hospital in Toronto were also members of the consortium.
