Genome Researchers Uncover Novel Genetic Alterations in Lung Cancer

Contact:
Caroline Arbanas
314-286-0109
arbanasc@msnotes.wustl.edu

Nov. 4, 2007 – Scientists at Washington University School of Medicine in St. Louis, working as part of an international team of researchers, have completed a massive effort to map the genetic changes underlying the most commonly diagnosed form of lung cancer. Their results are published in the Nov. 4 advance online issue of the journal Nature.

The research provides an unprecedented view of the abnormal genetic landscape in lung cancer cells from patients with adenocarcinoma. The investigators found more than 50 genomic regions that are frequently gained or lost in these tumors. Although one-third of these regions contain genes already known to play roles in lung cancer, the remaining ones harbor genes that had not yet been linked to the disease.

The team also uncovered a key genetic alteration not previously linked to any form of cancer that is associated with many cases of lung cancer. This discovery sheds light on the biological basis of the disease and points to a potential new target for therapy.

"We have assembled a very intriguing initial picture of the lung cancer genome," says Siteman Cancer Center member Richard Wilson, PhD, director of the Washington University's Genome Sequencing Center, which contributed to the research. "This is a direct pay-off of the Human Genome Project and a critical step toward understanding the biology of lung cancer. Our hope is that this work will help shape new strategies for the early diagnosis of the disease and novel therapies."

The study was conducted as part of the Tumor Sequencing Project (TSP), an effort to assemble a genomewide catalog of genetic alterations in lung adenocarcinoma, and funded by the National Human Genome Research Institute (NHGRI). The TSP includes NHGRI's large-scale sequencing centers at Washington University School of Medicine, Massachusetts Institute of Technology and Baylor College of Medicine.

"The Nature study is also significant in terms of the sheer number of tumors from which DNA was analyzed," says Elaine Mardis, PhD, co-director of the Genome Sequencing Center. The TSP researchers studied more than 500 tumor specimens from lung cancer patients. Many of those samples were provided by the Siteman's Tissue Procurement Core Facility, directed by Mark Watson, MD, PhD, associate professor of pathology and immunology.

The scientists compared DNA from the tumors to the patient's normal DNA. This analysis allowed researchers to look for variations in the tumor DNA that are specific to lung cancer. Access to the large collection of high-quality samples also made it possible to determine the genetic changes shared among different patients. Such recurring changes can highlight important genes involved in cancer.

More than 1 million people worldwide die of lung cancer each year, including more than 150,000 in the United States. Lung adenocarcinoma, the most common type of lung cancer in the United States, accounts for about 30 percent of cases.

New approaches to cancer treatment rely on a deeper understanding of what goes wrong in tumor cells to spur uncontrolled growth. Through decades of research, it has become clear that lung cancer – like most human cancers – stems mainly from changes that accumulate in cells during a patient's lifetime. But the nature of these changes and their biological consequences remain largely unknown.

In the new research, the TSP team uncovered a total of 57 genomic changes that occur frequently in lung cancer patients. Of these, only 15 contained genes previously known to be involved in lung adenocarcinoma.

To analyze the 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, coupled with advanced statistical methods, 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.

"We took the genomic analysis to a new level," Mardis says. "By looking at SNPs and copy number variation, we identified regions of the genome altered in tumor samples that contained genes that weren't on our list of usual suspect genes. This analysis gives us genomewide clues to what's going on in lung cancer."

Strikingly, the most common abnormality 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, the researchers discovered that one of the genes, NKX2.1, influences cancer cell growth. The gene normally acts as a master regulator that controls the activity of other key genes in cells lining the lungs' tiny air sacs, called alveoli. The discovery that a gene functioning in a select group of cells – rather than in all cells – can promote cancer growth may have broad implications for the design of drugs for a wide range of cancers.

"By pinpointing the genetic changes involved in lung adenocarcinoma, we hope to learn much more about this deadly cancer," Wilson says. "This research should also lead to better strategies for identifying vulnerabilities within all types of cancer cells."

The TSP is helping to lay the foundation for future large-scale cancer genome projects, including the Cancer Genome Atlas. Last year, Washington University received a grant to initiate a pilot project, as part of the Cancer Genome Atlas, to test the feasibility of a comprehensive, systematic approach to exploring the genomics of a range of common human cancers. In the pilot phase, the focus is on glioblastoma, the most common form of brain cancer, ovarian cancer and squamous cell lung cancer.

Other members of the TSP are cancer researchers at Brigham and Women's Hospital and Dana-Farber Cancer Institute, both in Boston; M.D. Anderson Cancer Center in Houston; Memorial Sloan-Kettering Cancer Center in New York; and the University of Michigan in Ann Arbor. Investigators from Nagoya City University in Japan; the Ontario Cancer Institute/Princess Margaret Hospital in Canada; and the University of Texas-Southwestern Medical School in Dallas also participated in the study.

All data generated by the TSP are available to the scientific community in public databases. For information on how to access the databases, go to: http://www.genome.gov/cancersequencing.