Treatment- Different-3type Gastric Cancer
Three Subtypes of Gastric Cancer
Suggest Different Treatment Approaches
Aug. 27, 2013 — Stomach cancer, one of the leading causes of
cancer death worldwide,
actually falls into three
broad subtypes that respond differently to currently available
therapies, according to researchers at Duke-NUS Graduate Medical School
Singapore.
The finding could greatly improve patient care with the
development of a genetic test to classify tumors and match them to the therapies
that offer the best outcomes."One of the features that makes gastric
cancer so lethal is that it arises from many genetic alterations, creating
differences in how the tumors respond to therapies," said Steve Rozen,
Ph.D., director of the Centre for Computational Biology at Duke-NUS. Rozen is
senior author of the study published in the September issue of the journal
Gastroenterology. "What our study has shown is that
there are actually three distinct molecular classifications that appear to be
biologically and therapeutically meaningful."
Worldwide, only lung cancer is more lethal than stomach cancer. Rates in
all countries have been dropping for decades, and are much lower in the United
States than in Asia, but the malignancy still afflicts more than 21,000 people
in the U.S. a year, according to the National Cancer Institute.
Despite differences in the way their tumors respond to
treatments, patients often receive a "one-size-fits-all" treatment
approach, resulting in a five-year survival rate of about 27 percent in the
United States.
"There has been an urgent need for improved
classification of gastric cancer that provides insight into the biology of the
tumors that might help predict treatment response," said co-senior author
Patrick Tan, M.D., PhD., professor in the Cancer and Stem Cell Biology Program
at Duke-NUS.
Using a technology called microarray-based gene expression
profiling, Rozen and colleagues analyzed 248 gastric tumors, then further grouped
them according to the genes that were expressed in the tumors.
The gene expression analysis broadly sorts the tumors into
three subtypes: proliferative, metabolic and mesenchymal. These subtypes also
differ in their genomic and epigenomic properties.
Tumors of the proliferative subtype have high levels of genomic instability
and a mutation in the TP53 tumor suppressor gene that occurs in many types of
cancers. Cancer cells of the metabolic
subtype are more sensitive to the chemotherapy agent 5-FU. Cancer cells
of the mesenchymal
subtype have some features of cancer stem cells, and are particularly sensitive
to a class of therapies called PI3K−AKT−mTOR inhibitors.
"In terms of clinical treatment, there are two
promising findings from our research," Rozen said. "One is that 5-FU has been
particularly effective against metabolic- subtype tumors, and the second is that drugs
targeting the PI3K−AKT−mTOR
pathway may be particularly effective against mesenchymal-subtype cancers."
"If confirmed in future studies, the classification of
gastric cancers reported here could guide development of therapies tailored to
the molecular subtypes," said lead author Zhengdeng Lei, PhD.
In addition to Rozen, Tan and Lei, study authors include
Iain Beehuat Tan, Kakoli Das, Niantao Deng, Hermioni Zouridis, Sharon Pattison,
Clarinda Chua, Zhu Feng, Yeoh Khay Guan, Chia Huey Ooi, Tatiana Ivanova, Shenli
Zhang, Minghui Lee, Jeanie Wu, Anna Ngo, Sravanthy Manesh, Elisabeth Tan, Bin
Tean Teh, Jimmy Bok Yan So, Liang Kee Goh, Alex Boussiouta, Tony Kiat Hon Lim
and Horst Flotow.
The study was supported by the Duke-NUS Signature Research
Programs, with funding from the Singapore Agency for Science, Technology, and
Research and the Singapore Ministry of Health; the Singapore National Medical
Research Council; the Singapore National Research Foundation and Ministry of
Education; and the Singapore Biomedical Research Council.
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