Breakthrough in gastric cancer research

31 January 2015

In January we caught up with a Hong Kong-based research team led by a Croucher award recipient making significant advances in gastric cancer research.

Professor Leung Suet-yi, a 2007 Croucher senior research fellow, uses whole-genome sequencing and comprehensive molecular profiling to identify new driver mutations in gastric cancer. Her team has completed the world’s largest comprehensive genomic study of gastric cancer, encompassing 100 patients.

Gastric cancer is the third leading cause of cancer death worldwide. Its symptoms are often extremely subtle until it develops into an advanced stage tumour, for which an effective cure has yet to be discovered. There is keen regional interest to further research this cancer due to its specific geographical variation in Asia, China in particular.

The Leung paper reviews all the possibly DNA damage in gastric cancer mutations, and reveals the specific activity of gastric cancer driver genes. It also identifies different environmental factors that contribute to DNA damage and helps uncover the cause of gastric cancer, thus developing a strategy for its prevention. It was published in the May 2014 issue of Nature Genetics.

Leung, together with her team, has succeeded in identifying the complete set of gastric cancer driver genes that could potentially act as good drug target candidates in future clinical therapy. Cancer driver genes are genes with deregulated activity resulting from DNA damage and they are known to drive cancer development. Each cancer has its own unique collection of driver genes.

The team used whole genome sequencing to reveal any misspellings in every nucleotide of the cancer genome. The team also used microarray technology to uncover and assess the gene expression resulting from different types of DNA damage in a cancer cell, namely chromosomal break and mutations, and changes in methylation.

New driver genes that were not previously known to be mutated in gastric cancer but were uncovered by this study include the gene RNF43, which is mutated in around 5% of the cancer instances. According to Leung, there is already a Wynn inhibitor drug that is in phase 1 of clinical trials for treatment of other cancer types that could possibly be used to treat this specific mutation in gastric cancer as well.

The knowledge of the entire group of driver genes for a specific cancer type builds a roadmap for the development of personalized medicine. Drugs that modulate certain driver gene activity can be used to kill cancer cells while sparing normal cells, thus improving treatment response and providing a more targeted therapy to patients in two ways. First, by making use of existing drugs in targeting small groups of various cancers. Second, by developing novel drugs to target newly discovered driver genes.

The success of this study is another merit to add to Leung and her team’s extensive list of accomplishments. They have been pioneers in gastric cancer through the discovery of novel gastric cancer driver genes. In 2011, they published a paper in Nature Genetics that provided the basis for this recent study, in which they identified 20 gastric cancer driver genes that could be linked to cancer development.

Leung is the Y.W. Kan Professor of Natural Sciences and an Associate Dean of the Li Ka Shing Faculty of Medicine, University of Hong Kong. Her laboratory provides a population-wide genetic diagnosis service to perform research into the genetic basis of hereditary colorectal cancer and also, to educate the public and form a strong link between them and medical professionals through a charitable patient referral system.

The beauty of genomics is that you want to put all your data into the public domain so that researchers can make use of it to generate better drugs.

The laboratory has performed tests for over 1000 at-risk families and has identified over 600 gene carriers, which they then refer to hospitals to undergo further screening and treatment. Regular screening and precancerous solutions can be enforced to prevent the development of cancer. In the past seven years, the screening service provided by the laboratory has led to the removal of more than 200 adenomas.

Leung was awarded the Croucher Senior Medical Research Fellowship in 2007, during which she made another key medical discovery that had a significant global impact. She had previously discovered the existence of mosaic methylation in Lynch Syndrome and the inheritance of this trait across families, which she further explored during her fellowship to identify a key mechanism that caused this specific occurrence of methylation. Her findings were incorporated in the standard testing protocol worldwide for Lynch Syndrome.

Regarding the fellowship, she says, “the Croucher award gives us time, protected time after the routine clinical duty to concentrate on research, which is extremely important.”

As a clinical academic, Leung juggles multiple tasks including clinical duties, teaching, research and administration. But, as a key leader in cutting-edge research, she must be fast so as to push her research to the next level. According to her, having protected time endowed by the fellowship helps substantially.

Looking to the future, she hopes to further analyse the data generated by the study in an integrative manner in order to gradually predict drug response in gastric cancer based on genomic features. “The beauty of genomics is that you want to put all your data into the public domain so that researchers can make use of it to generate better drugs.”

To view Leung Suet-yi’s personal Croucher profile, please click here