|Large-Scale Genetic Study Sheds New Light
on Lung Cancer, Opens Door to Individualized Treatment Strategies
A multi-institution team, funded by the National Human Genome
Research Institute (NHGRI) of the National Institutes of Health
(NIH), today reported results of the largest effort to date to
chart the genetic changes involved in the most common form of lung
cancer, lung adenocarcinoma. The findings should help pave the
way for more individualized approaches for detecting and treating
the nation’s leading cause of cancer deaths.
In a paper published in the Oct. 23 issue of the journal Nature,
the Tumor Sequencing Project (TSP) consortium identified 26 genes
that are frequently mutated in lung adenocarcinoma — an achievement
that more than doubles the number of genes known to be associated
with the deadly disease. But the pioneering effort involved far
more than just tallying up genes. Using a systematic, multi-disciplinary
approach, the TSP team also detailed key pathways involved in the
disease, and described patterns of genetic mutations among different
subgroups of lung cancer patients, including smokers and never-smokers.
More than 1 million people worldwide die of lung cancer each year,
including more than 150,000 in the United States. Lung adenocarcinoma
is the most frequently diagnosed form of lung cancer. The average
5-year survival rate currently is about 15 percent, with survival
being longest among people whose cancer has been detected early.
"By harnessing the power of genomic research, this pioneering
work has painted the clearest and most complete portrait yet of
lung cancer’s molecular complexities. This big picture perspective
will help to focus our research vision and speed our efforts to
develop new strategies for disarming this common and devastating
disease," said NHGRI Acting Director Alan E. Guttmacher, M.D.
Like most cancers, lung adenocarcinoma arises from changes that
accumulate in people’s DNA over the course of their lives. However,
little is known about the precise nature of these DNA changes,
how they occur and how they disrupt biological pathways to cause
cancer’s uncontrolled cell growth. To gain a more complete picture,
researchers have joined together to form TSP and other large, collaborative
projects that are using new tools and technologies to examine the
complete set of DNA, or genome, found in various types of cancer.
"We found lung adenocarcinoma to be very diverse from a genetic
standpoint. Our work uncovered many new targets for therapy of
this deadly disease — oncogenes that drive particular forms of
lung adenocarcinoma and tumor suppressor genes that would ordinarily
prevent cancer cell growth," said Matthew Meyerson, M.D., Ph.D.,
a senior author of the paper. Dr. Meyerson is a senior associate
member of the Broad Institute of MIT and Harvard and an associate
professor at the Dana-Farber Cancer Institute and Harvard Medical
In the new study, the TSP team purified DNA from tumor samples
and matching non-cancerous tissue donated by 188 patients with
lung adenocarcinoma. Next, they sequenced the DNA to look for mutations
in 623 genes with known or potential relationships to cancer. Prior
to the study, fewer than a dozen genes had been implicated in lung
adenocarcinoma. The latest research identified 26 new genes that
are mutated in a significant number of samples. Most of these genes
had not previously been associated with lung adenocarcinoma.
Among the genes newly implicated in lung adenocarcinoma are:
- Neurofibromatosis 1 (NF1). Mutations in this gene have previously
been shown to cause neurofibromatosis 1, a rare inherited disorder
characterized by unchecked growth of tissue of the nervous system.
- Ataxia Telengiectasia Mutated (ATM). ATM mutations have previously
been shown to play a role in ataxia telangiectasia, which is
a rare inherited neurological disorder of childhood, and in various
types of leukemia and lymphoma.
- Retinoblastoma 1 (RB1). Past research has tied RB1 mutations
to retinoblastoma, a relatively uncommon type of childhood cancer
that originates in the eye’s retina.
- Adenomatosis polyposis coli (APC). Mutations of this gene are
common in colon cancer.
- Ephrin receptors A3 and A5 (EPHA3 and EPHA5), neurotrophin
receptors (NTRK1 and NTRK3) and other receptor-coupled tyrosine
kinases (ERBB4, KDR and FGFR4). These genes code for cell receptors
coupled to members of the tyrosine kinase family of enzymes,
which are considered prime targets for new cancer therapies.
After identifying the genetic mutations, the team went on to examine
their impacts on biological pathways and determine which of those
pathways were most crucial in lung adenocarcinoma. Such research
is essential to efforts to develop new and better treatments for
For example, TSP researchers found more than two-thirds of the
188 tumors studied had at least one gene mutation affecting the
mitogen-activated protein kinase (MAPK) pathway, indicating it
plays a pivotal role in lung cancer. Based on those findings, the
researchers suggested new treatment strategies for some subtypes
of lung adenocarcinoma might include compounds that affect the
MAPK pathway. One such group of compounds, called MEK inhibitors,
has produced promising results in mouse models of colon cancer.
Likewise, the TSP’s finding that more than 30 percent of tumors
had mutations affecting the mammalian target of rapamycin (mTOR)
pathway raises the possibility that the drug rapamycin might be
tested in lung adenocarcinoma. Rapamycin is an mTOR-inhibiting
compound approved for use in organ transplants and renal cancer.
In addition, the genetic findings suggest that certain lung cancer
patients might benefit from chemotherapy drugs currently used to
treat other types of cancer. For example, chemotherapy drugs known
to inhibit the kinase insert domain receptor (KDR), such as sorafenib
and sunitinib, might be tested in the relatively small percentage
of lung adenocarcinoma patients whose tumors have mutations that
activate the KDR gene.
In their Nature paper, TSP researchers also analyzed the patterns
of genetic changes seen among different subgroups of lung adenocarcinoma
patients, including smokers.
About 90 percent of lung cancer patients have significant histories
of cigarette smoking, but 10 percent report no use of tobacco.
In the TSP study, the number of genetic mutations detected in tumor
samples from smokers was significantly higher than in tumors from
never-smokers. Smokers’ tumors contained as many as 49 mutations,
while none of the never-smokers’ tumors had more than five mutations.
More work is needed to determine what these differences may mean
for the management of lung cancer. However, doctors do know that
in some other types of cancer, high mutation levels may cause a
tumor to spread rapidly and/or be resistant to treatment.
"Our findings underscore the value of systematic, large-scale
studies for exploring cancer. We now must move forward to apply
this approach to even larger groups of samples and a wider range
of cancers," said Richard K. Wilson, Ph.D., a senior author of
the paper and director of the Genome Sequencing Center at Washington
University School of Medicine, St. Louis.
The TSP team also included researchers from Baylor College of
Medicine, Houston; Brigham and Women’s Hospital, Boston; Memorial
Sloan-Kettering Cancer Center, New York; the University of Cologne,
Germany; the University of Michigan, Ann Arbor; and the University
of Texas M.D. Anderson Cancer Center, Houston.
"Clearly, much still remains to be discovered. We have just begun
to realize the tremendous potential of large-scale, genomic studies
to unravel the many mysteries of cancer," said Richard Gibbs, Ph.D.,
a co-author of the lung adenocarcinoma paper and director of the
Human Genome Sequencing Center at Baylor College of Medicine.
The TSP data are complementary to those from other large-scale
cancer genome studies, such as The Cancer Genome Atlas (TCGA) project
funded by NHGRI and the National Cancer Institute (NCI). In its
pilot phase, TCGA is focusing on the most common form of brain
tumor, called glioblastoma; a type of lung cancer called squamous
cell lung cancer; and ovarian cancer. The first results from TCGA’s
glioblastoma study were published in the advance online edition
of Nature on Sept. 4 and published in Nature’s print edition on
The co-publication of these comprehensive cancer genome studies
should provide hope to millions of people and families living with
cancer. By applying advanced genomic tools to the complexities
of cancer, these studies have helped to untangle the biological
roots of these diseases, which will accelerate efforts by the worldwide
scientific community to improve outcomes for cancer patients.
NHGRI is one of 27 institutes and centers at the NIH, an agency
of the Department of Health and Human Services. The NHGRI Division
of Extramural Research supports grants for research and for training
and career development at sites nationwide. Additional information
about NHGRI can be found at its Web site, www.genome.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.