Hereditary diffuse gastric cancer: Research update May 2009
Parry Guilford, Bostjan Humar, Helen More and Soroush Nasri; Cancer Genetics Laboratory, University of Otago
The lab has two HDGC research projects in progress at the moment. The first which is being carried out by Helen More in collaboration with our colleagues in Munich, Vancouver and New York, and funded by the New Zealand Health Research Council, aims to get a better understanding of the clinical importance of some fairly common variants in the CDH1 gene. These variants are found in the gene’s regulatory regions; that is, they are involved in regulating the amount of E-cadherin produced by a cell and probably the timing of its expression and repression. We, and others, have shown in the past that these variants cause a small increase in the risk of gastric cancer (small, when compared to the inactivating mutations found in HDGC families). That is, people with these variants have an increased risk of apparently sporadic diffuse gastric cancer, but the risk is generally insufficient to cause multiple cases in single families. However, our hypothesis is that these variants have a more severe effect when they occur in someone who has one of the inactivating family mutations. This severity might express itself as an earlier age of cancer onset. Thus, this research project may help us identify individuals from HDGC families with the greatest risk of disease at an early age.
The second project, being carried out by a PhD student in the group, Soroush Nasri, is trying to further our understanding of the early events in HDGC development. Specifically, Soroush is trying to unravel what happens to the chromosomes in a cell that has lost E-cadherin expression. The hypothesis is that the disruption of the normal cell architecture (that is, its shape and internal scaffolding) that occurs following E-cadherin loss leads to parts of the chromosomes being disrupted. This disruption may affect specific genes that then contribute to the progression of the early stage (T1a) cancers into the underlying stomach layers. It is hoped that this understanding will help us pinpoint drugs which may be useful for early intervention.
A third project, on the chemoprevention of HDGC, was described in the last update. Briefly, this project aims to explore whether particular compounds can be used to prevent the good copy of CDH1 being lost in people carrying mutations in the other copy. By keeping this second copy active, we believe initiation of the disease can be prevented. This project is the subject of a major grant application which is still under review. Unfortunately, chemoprevention research is very demanding and can be difficult to fund. This is because it can take years and very large studies to prove that the chosen compound is working, and not causing other problems elsewhere in our complex biology. I have argued that HDGC provides an exceptionally amenable system for this type of study, but we will have to wait to see whether the reviewers have been convinced!
