A Singapore-based large-scale genomics study
has identified more than 600 genes that are mutated in stomach cancer, the
second-most lethal cancer worldwide.
Researchers
in Singapore have identified hundreds of novel genes that are mutated in
stomach cancer, paving the way for treatments tailored to the genetic make-up
of individual stomach tumors.
The
study, which appeared online this week in Nature Genetics, was a collaborative
effort involving three research groups affiliated with the Duke-NUS Graduate
Medical School (Duke-NUS) and the National Cancer Center Singapore (NCCS),
headed by Patrick Tan, M.D., Ph.D, Steve Rozen, Ph.D., and Teh Bin Tean, M.D.,
Ph.D..
Stomach
cancer is the second leading cause of cancer death globally with more than
700,000 deaths each year, and is highly prevalent in East Asia. Treatment of
this deadly disease is often difficult and unsuccessful because of late
detection of tumors and a poor understanding of the causes of stomach cancer.
In the United States, less than quarter of patients survive more than five
years after diagnosis, even after treatment.
“Until
now, the genetic abnormalities that cause stomach cancers are still largely
unknown, which partially explain the overall poor treatment outcome,” said Dr.
Tan who is associate professor at Duke-NUS and also leader of the Genomic
Oncology Program at the Cancer Science Institute of Singapore, as well as a
group leader at the Genome Institute of Singapore.
Rather
than sequence the entire three billion letters of the human genomic blueprint
in each tumor and tissue sample, the researchers used a strategy that focused
only on the protein-coding portions of 18,000 genes, known as exons.
Collectively referred to as the exome, this is thought to be the most
functionally important part of the human genome even though it makes up only
about one percent of the genome.
Through
sequencing the exomes of tumor samples and normal tissue taken from 15
patients, the researchers were able to identify over 600 gene mutations that
were previously not known to be mutated in stomach cancer.
Two of
the 600 stomach cancer-associated genes identified, FAT4 and ARID1A, proved to
be particularly interesting because of their roles in mediating cell adhesion
and chromatin remodeling, respectively.
Mutations
in the cell adhesion gene, FAT4, may potentially increase the mobility of
cancer cells into surrounding tissue and to other parts of the body as
metastases.
Chromatin
remodeling genes like ARID1A are responsible for altering the chromatin
structure of the DNA and maintaining the stability of the genome. Mutations in
ARID1A may lead to abnormal chromatin structures, genomic instability, and the
accumulation of further genetic abnormalities.
To find
out if FAT4 and ARID1A are frequently mutated in stomach tumors, the
researchers analyzed a larger sample of about 100 stomach tumors and found
these genes to be mutated in 5 percent and 8 percent of stomach cancers,
respectively. In some patients, portions of the chromosome containing the two
genes were found to be missing, evidence that genetic defects affecting these
genes occur frequently in stomach cancer.
Further
experiments in the lab demonstrated the importance of these two genes in
driving stomach cancer, as manipulation of FAT4 and ARID1A function altered the
growth of stomach cancer cells.
“More
research is required to realize the clinical implications of these findings.
ARID1A and FAT4 are likely also involved in many other cancer types, not just
stomach cancer,” noted Dr. Tan, whose research team is actively working on
translating the results of this study into clinical applications.
With
more than 100,000 new cases of stomach cancer each year likely to be caused by
mutations in FAT4 or ARID1A, it is hoped that drugs against these targets may
someday lead to more effective treatment of stomach tumors and other cancers.
Yuka
Suzuki
AsianScientist
The
article can be found at: Zang ZJ, Cutcutache I et al. (2012) Exome Sequencing Of Gastric
Adenocarcinoma Identifies Recurrent Somatic Mutations In Cell Adhesion And
Chromatin Remodeling Genes.
Source: Duke-NUS Graduate Medical
School
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