Study Identifies Gene Alterations in Lung Cancer

An international team of scientists, supported in part by the National Human Genome Research Institute (NHGRI), one of the National Institutes of Health (NIH), has announced that its systematic effort to map the genomic changes underlying lung cancer has uncovered a critical gene alteration not previously linked to any form of cancer. The research, published in the advance online issue of the journal Nature, also revealed more than 50 genomic regions that are frequently gained or lost in lung adenocarcinoma, the most common type of lung cancer in the United States.

“This view of the lung cancer genome is unprecedented, both in its breadth and depth,” says senior author 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.”

Each year more than 1 million people worldwide die of lung cancer, including more than 150,000 in the United States. The new study focused on lung adenocarcinoma, which, according to the National Cancer Institute (NCI), is the most frequently diagnosed form of lung cancer in the United States, accounting for approximately 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 DNA changes that accrue in cells throughout a person’s life. But the nature of these changes and their biological consequences remain largely unknown, which has inspired the recent formation of multi-disciplinary teams that are using new genomic tools and technologies to study cancer in a more systematic, comprehensive manner.

The latest study was conducted as part of the Tumor Sequencing Project (TSP), an ongoing effort to apply large-scale approaches to the identification of genomic changes in lung adenocarcinoma. NHGRI is a major funder of TSP, which unites scientists and clinicians throughout the cancer research community.

“This outstanding work clearly demonstrates the value of comprehensive approaches for exploring the genomic underpinnings of cancer. The impacts of these findings extend far beyond lung cancer and indicate that many more important cancer-related genes still await our discovery,” NHGRI Director Francis Collins says. “Now, we must forge ahead and apply this strategy as quickly as possible to other common types of cancer.”

Specifically, the TSP researchers uncovered a total of 57 genomic changes that occur frequently in lung cancer patients. Of these changes, more than 40 appear to be associated with genes not previously known to be involved in lung adenocarcinoma. More research is needed to precisely identify and characterize these genes, but researchers are excited by the possibility that their findings may suggest new ways of attacking this deadly cancer.

The most common abnormality identified by the TSP team 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. NKX2.1 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.

“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. More broadly, the study represents a general approach that can and should be used to analyze all types of cancer,” says Eric Lander, one of the study’s co-authors and founding director of the Broad Institute of MIT and Harvard.

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Genetic Study May Help Predict Diseases

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Googling Brain Proteins With 3-D Goggles

The Allen Brain Atlas, a genome-wide map of the mouse brain on the Internet, has been hailed as "Google of the brain." The atlas now has a companion of the brain's working molecules, a sort of pop-up book of the proteins, or proteome map, that those genes express.

The protein map is "the first to apply quantitative proteomics to imaging," says Richard Smith, Battelle fellow at the US Department of Energy's Pacific Northwest National Laboratory, who led the mapping effort with Desmond Smith of UCLA's David Geffen School of Medicine.
"Proteins are the lead actors, the most important part of the picture," PNNL's Smith says. "They are the molecules that do the work of the cells."

Fine-tuning such proteome maps will enable comparisons of healthy brains with others whose protein portraits look different. Contrasts in location and abundance of proteins may display the earliest detectable stages of Alzheimer's, Parkinson's and other neurological diseases. They hope such diseases might be curbed if caught and treated early enough.

The National Institutes of Health-funded study, performed at DOE's Environmental Molecular Sciences Laboratory on PNNL's campus, is published in the advance online edition of Genome Research and featured in current Nature online Neuroscience Gateway.

To produce the map, the team characterized center-brain slices as scores of 1 millimeter cubes, or "voxels," to "show us where proteins appear in the brain and where they vary in abundance," PNNL's Smith says. "We labeled all the proteins so we would have reference points so we know we're looking at the same protein between different parts of the brain and from one mouse to another."

Until now, proteomics, which enlists a specially modified instrument called a mass spectrometer for the task of identifying proteins and tallying them, has been akin to flying blind over a lake of proteins. The abundance and protein type could be discerned from a given sample, but "knowing their location and how the abundances change in different cases is important for understanding what they do," PNNL's Smith says.

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Feds Fund Research on 'Economically Important Plants'

Scientists will find improved ways of studying the structure, function and evolution of the genomes of economically important plants, thanks to $14 million in new awards from the U.S. National Science Foundation (NSF).

Resources to be developed include genomic sequences, genetic markers, maps and expressed sequence collections. These are much-needed tools for researchers working in areas as diverse as genome evolution and plant breeding.

Awardees will address scientific questions including the role of polyploidy in genome evolution, the genomic basis of speciation, and the relationships between cultivated plants and their weedy relatives.

"If the Plant Genome Research Program has been making the bricks that build a conceptual framework for the genomes of economically important crop plants, these projects will provide the mortar," says James Collins, NSF assistant director for biological sciences. "The impact of genomics in evolutionary, ecological and population studies of crop plants will be far-reaching."

Many crop plants have large, complex genomes that in some cases are "polyploid" -- containing multiple genomes. Polyploidy is widespread in plants and animals, and can lead to dramatic changes in gene content and genome organization that are only just beginning to be understood.
A project led by researchers at Iowa State University will develop sequence and map resources to study polyploidy in cotton, while researchers at the University of Missouri will look at the impact of polyploidy on plant form in Brassica species, which includes plants such as canola and Brussels sprouts. Other projects at the University of Georgia and the University of Arizona will develop sequence resources to study genome organization in wheat and rice.

The outcomes from these projects will allow researchers to understand how extra copies of genes function in these plants, and how genomes from different sources can work together in a single plant.

The ever-growing collection of genome sequences is shedding light on the variation between individuals within a species. For example, in a forest of trees or a field of corn, there may be many versions of a particular gene, each with minor sequence differences. These sequence differences can sometimes have dramatic effects on growth and development.

Projects based at the University of California at Davis and Cornell University will catalog variants in pine trees and in maize, respectively, to allow researchers to link genetic variation with changes in gene function. This information could have applications in plant breeding.
More than half of the world's most cultivated crops have relatives that are invasive weeds, competing with the crop for nutrients and water and leading to reduced yields.

One example is red rice, a weedy form of rice that reduces the yields of cultivated rice by as much as 80 percent and contaminating harvests with its small red-coated grains. A project led by researchers at Washington University St. Louis will examine the regions of the red rice genome associated with weediness to find out whether it originated from the domesticated crop or if it was introduced as a weed from Asia.

A related project led by investigators at Michigan State University will investigate differences in gene expression in weedy and cultivated radishes to uncover which genes are associated with invasiveness.The outcomes of these projects could lead to a great understanding of how plants become weedy and invasive, and yield possible avenues for better selective control of weeds, scientists believe.

"The outcomes of this new program will tie together studies of the evolution of gene structure, function and regulation across the whole plant kingdom," says Collins.

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