The recent focus of the group has been to understand the molecular events that are occurring as HDGC stomach cancers develop and progress. By understanding these events we will be better placed to identify (i) the reasons and triggers that underlie the variable age of onset in HDGC families (ii) which drugs may be effective in treatment and (iii) possible drugs which can be used to prevent cancer development (chemoprevention).
Our research has demonstrated that specific epigenetic changes to the DNA are critical for the initiation of HDGC. Epigenetic changes consist of modifications to the chromosome micro-structure that prevent genes being normally active. Importantly, these changes differ from mutations in that they are potentially reversible. We have shown that the 2nd copy of the E-cadherin gene (CDH1) is knocked out in early HDGC cancers by an epigenetic change called DNA methylation. The combination of the inherited mutation of one copy of the gene and the later methylation (in the stomach) of the second copy results in affected stomach cells having no E-cadherin. We believe this deficit is sufficient to trigger the start of the cancers. We don’t yet know what is causing the methylation; it may be something preventable (eg perhaps triggered by inflammation) or it may simply be a necessary consequence of normal gastric function. Regardless, the clear role of epigenetic changes in cancer initiation suggests that drugs which can reverse or prevent the changes may be useful in the chemoprevention of gastric cancer.
As a result, a major focus of our future HDGC research will be to identify and test drugs which can inhibit or reverse the epigenetic inactivation of CDH1. The long-term goal would be to identify a drug or drugs that can be used in combination with gastroscopic surveillance in the management of HDGC families. The first objectives in this research programme will be to develop the necessary techniques to measure epigenetic changes in gastric biopsy samples and then to systematically characterise the changes induced by selected epigenetic drugs to gain confidence that they will be useful in cancer prevention without causing limiting side effects. If these steps progress well over the next couple of years, we would progress to testing the drug(s) in formal clinical trials.
Parry Guilford, Bostjan Humar and Helen More; Cancer Genetics Laboratory, University of Otago