Study Identifies Novel Gene Alterations in Lung
Cancer;
Comprehensive Analysis Provides New View of Genomic Landscape
of Leading Cause of Cancer Deaths
An international team of scientists, supported in part by the
National Human Genome Research Institute (NHGRI), one of the National
Institutes of Health (NIH), today 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," said senior author Matthew Meyerson,
M.D., Ph.D., 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 S. Collins,
M.D., Ph.D. "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," said Eric Lander, Ph.D.,
one of the study’s co-authors and founding director of the Broad
Institute of MIT and Harvard.
The TSP is helping to establish the groundwork for future large-scale
cancer genome projects, including The Cancer Genome Atlas (TCGA).
In December 2005, NHGRI and NCI 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,
which, according to NCI, accounts for about 20 percent of lung
cancer cases in the United States.
In addition to Drs. Meyerson and Lander, the scientific leaders
of the TSP include Harold Varmus, M.D., Memorial Sloan-Kettering
Cancer Center, New York; Richard Gibbs, Ph.D., Baylor College of
Medicine, Houston; and Richard Wilson, Ph.D., Washington University
School of Medicine, Saint Louis.
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, which is important because shared changes
can highlight important genes involved in cancer growth.
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 helped researchers detect parts
of the genome that were present in excess copies or missing altogether
in the tumor samples. These regions of genomic aberration were
then more finely delineated using new analytical tools, including
a computational method called GISTIC and methods for visualizing
SNP data.
In its second phase, TSP is examining 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 that function in cancer and more generally
in cell growth.
"We look forward to applying the power of large-scale sequencing
to this complex challenge," said Dr. Wilson, head of the Washington
University Genome Sequencing Center. "By zeroing in on the
genetic changes involved in lung adenocarcinoma, we hope to learn
much more about this deadly cancer. This research should also lead
to better strategies for identifying vulnerabilities within all
types of cancerous cells."
Dr. Gibbs, head of the Human Genome Sequencing Center at Baylor,
said, "This project has pulled together an amazing collection
of scientific talent to tackle a most formidable opponent: lung
cancer. By working together, we hope to generate data that will
serve as an effective tool for developing new ways to detect, treat
and, ultimately, prevent this disease."
The TSP team includes NHGRI’s three large-scale sequencing centers
at Baylor College of Medicine, Broad Institute of MIT and Harvard,
and Washington University School of Medicine. Other members of
TSP are cancer researchers at Brigham and Women’s Hospital, Boston;
Dana-Farber Cancer Institute; M.D. Anderson Cancer Center, Houston;
Memorial Sloan-Kettering Cancer Center; the University of Michigan,
Ann Arbor; and Washington University School of Medicine. Investigators
from Nagoya City University, Japan; the Ontario Cancer Institute/Princess
Margaret Hospital, Toronto; and the University of Texas-Southwestern
Medical School, Dallas, also participated in the SNP portion of
the study.
All data generated by the TSP are being made available to the
scientific community in public databases. For information on how
to access the databases, go to: http://www.genome.gov/cancersequencing.
NHGRI and NCI are among the 27 institutes and centers at the NIH,
an agency of the Department of Health and Human Services. Additional
information about NHGRI can be found at its Web site, www.genome.gov and
additional information about NCI can be found at www.cancer.gov.
To learn more about The Cancer Genome Atlas, go to http://cancergenome.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
|