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HKU researchers found new gene mutations that cause stomach cancer

19 Dec 2011

 

In Hong Kong, stomach cancer is the 6^th most common cancer and 4^th most common cause of cancer death, with over 1000 new cases and over 600 deaths recorded yearly.  Cancer developed due to mutation accumulating in the DNA of stomach cells that turn it into a malignant cell.  However, it is not previously known how many mutations are needed to turn a normal stomach cell into cancer.  Researchers at the Department of Pathology of The University of Hong Kong Li Ka Shing Faculty of Medicine conducted a research recently, which utilized the most advanced genomic technology to unveil all gene mutations in stomach cancers and discovered a frequently mutated cancer causing gene.  The research team discovered 20 stomach cancer driver genes including one, known as ARID1A, which is found mutated in 70 to 80% of specific stomach cancer subtypes.  The discovery of these mutated cancer causing genes give rise to the development of new targeted drugs or testing of pre-existing drugs that can be used for treating stomach cancer.  This ground-breaking research was just published in the leading scientific journal Nature Genetics.

About stomach cancer
Stomach cancer accounts for 8% of the total incidence and 10% of total deaths worldwide. It is estimated that nearly one million new cases have occurred in 2008, and around 740,000 deaths are caused by it.  As early gastric cancer is usually asymptomatic, majority of patients presented at advanced stage with no effective cure. Cancer developed due to mutation accumulating in the DNA of stomach cells that turn it into a malignant cell.  These mutations are induced by environmental risk factors such as infection by the bacteria Helicobacter Pylori, carcinogens derived from ingesting lots of smoked or salted meat or pickled vegetables, smoking, or simply due to advancing age or obesity.

Research background
It is not previously known how many mutations are needed to turn a normal stomach cell into cancer.  Knowing all the cancer causing gene mutations can lead to development of targeted drugs that can selectively kill cancer cells carrying the specific mutation, thus with less toxic side effects.  

To identify cancer causing gene mutation has been difficult and slow, through DNA sequencing in a gene-by-gene basis in the vast genome containing over 30,000 genes and 3 gigabases of DNA sequence.  As a result, after several decades of research, only around a dozen cancer causing genes have been known in stomach cancer.  Majority of the cancer causing mutations reside in region of the genome know as "exon" (constituting 2% of the human genome) that is responsible to make protein, the building block of our body.  Recently, progress in next-generation sequencing has revolutionized the research.  The technology, known as exome-sequencing, involved selective capture and sequencing of all exons of all known human genes.  The test can be completed in two weeks for each cancer sample and it can reveal all cancer causing mutations in the cancer genome.

Research methods and findings
In an attempt to find new ways to treat stomach cancer, HKU researchers team up with the pharmaceutical company Pfizer inc. to pin down all cancer causing mutations in stomach cancer samples.  The team proceeded to sequence over 160,000 exons in 22 stomach cancer samples and its corresponding normal counterparts from Hong Kong patients to derive all the cancer causing mutations.  In total, the team found an average stomach cancer can harbor 62 mutations that changed the protein sequence whereas the highest can exceed a thousand.  Some of the mutations, though infrequent, occur in genes that has pre-existing drugs that can be used for treatment, and hence raise the possibility of personalized genomic medicine.

Genes that are commonly mutated in many stomach cancer samples are likely to be critical for cancer development, and thus known as cancer driver genes.  The team discovered 20 stomach cancer driver genes, including many that are not previously known.  Specifically, one stomach cancer driver gene, known as ARID1A, is found mutated in 70 to 80% of specific stomach cancer subtypes.  Moreover, this gene belongs to the group of chromatin modification genes that functions by changing the chromatin architecture of a cell.  Our DNA, being a delicate strand, has to be supported by the chromatin, the conformation or architecture of which would decide whether specific gene could function or not.  Chromatin modification genes constitute an emerging group of cancer driver genes with lots of interest by pharmaceutical industry to pursue as drug targets.  New drugs have been or are being developed that change the chromatin architectures, previously intended for treatment of other diseases.  With our findings of frequent chromatin modification gene mutation in stomach cancer, these drugs may now be explored to treat stomach cancer.

Impact of the study
The study by deciphering all mutations that can happen in a stomach cancer improved our understanding of how cancer develop and may provide ways for early detection and personalized treatment.  Moreover, the discovery of stomach cancer driver genes provides a rich resource for development of new drugs to treat stomach cancer.  The frequent mutation of chromatin modification genes including ARID1A provides opportunities to treat stomach cancer by using drugs to modulate chromatin architecture.

About the research team
The research is led by Professor LEUNG Suet-yi from the Department of Pathology, The University of Hong Kong Li Ka Shing Faculty of Medicine and Dr. XU Jiangchun from Pfizer inc..  Other key researchers included Dr. KAN Junsuo, Professor YUEN Siu-tsan, Professor CHU Kent-man and Professor Simon LAW from HKU, Dr. WANG Kai and Dr. MAO Mao from Pfizer inc. 

(From left) Professor LEUNG Suet-yi, Clinical Professor, Dr. KAN Junsuo, Post-doctoral Fellow and Professor YUEN Siu-tsan, Honorary Clinical Professor, of Department of Pathology, The University of Hong Kong Li Ka Shing Faculty of Medicine	Professor LEUNG Suet-yi and her research team discovered a new gene that causes stomach cancer
Professor YUEN Siu-tsan says that the discovery of cancer gene mutation facilitates the development of new drug in treating stomach cancer.	Dr. KAN Junsuo is extracting stomach cancer genes from the sample