Study paints genetic portrait of lung cancer

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.

An essential foundation

“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.”

Leading cause of death worldwide

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.

Large-scale collaboration

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.