Molecular and Cellular Oncology Laboratory

Director
Prof Robyn Ward

Team Leader
Dr Luke Hesson

Main Interest Area
The main focus is on the cellular and molecular basis of colorectal cancer and how key changes that predispose to cancer, or occur during cancer formation, influence the clinical treatment of patients.

The research conducted in the Molecular and Cellular Oncology Laboratory is divided into two broad areas:

1. Over the past 12 years the laboratory has worked with the surgical teams and collected specimens from colorectal cancers and corresponding normal tissue, as well as clinical data, from over 1000 individuals who have undergone curative surgery for colorectal cancer at St Vincent's Hospital Sydney. This biological and data resource has formed the mainstay of numerous laboratory-based studies into the cellular and molecular changes that occur during colorectal cancer development. More recently, these studies have focussed on the genetic and epigenetic basis of colorectal cancer and how particular changes are associated with clinical outcomes. For example, it is well known that 'coating' of cancer-protector genes with the chemical methylation causes them to be switched off, and that this occurs frequently in cancer. Methylation of the cancer-prevention gene MLH1 leading to a particular type of bowel cancer that most frequently affects elderly females is a classic example of this. In one project led by Dr Megan Hitchins, we showed that when MLH1 is affected by methylation, other genes in the neighbourhood are simultaneously affected, resulting in an entire 'suburb' of genes being switched off (link to Hitchins et al Cancer Res 2007). We now aim to determine if this process occurs early in cancer development and thus may serve as a risk marker for individuals at risk of cancer, and whether additional gene 'suburbs' are also affected in other types of cancer. This project is funded by the Cancer Council NSW, following a 'start-up' grant from the Cure Cancer Australia Foundation. In another project led by Prof Nicholas Hawkins and funded by the NHMRC, the role and frequency of mutations in the cancer-causing gene B-RAF are under study. Mutation of B-RAF in cancer is associated with the simultaneous methylation of multiple genes at different locations in the genome, but the reason that these seemingly disparate genetic and epigenetic changes occur in the same cancers, and how this affects clinical outcome, require further work.
   
   
2. Study of families with heritable forms of cancer, referred from family cancer clinics, to determine the nature of the genetic change that underlies their disease. Most recently, in work led by Dr Megan Hitchins and directed by Prof Robyn Ward, the group identified the novel mechanism of "germline epimutations" of the cancer-prevention gene MLH1 in individuals with a cancer syndrome that is usually caused by a mutation (spelling mistake) in the same gene. In these cases, the gene sequence was entirely normal, but instead had become paralysed by a chemical 'coat' referred to as CpG methylation. The group have shown that this defect can be transmitted from parent to child but in a currently unpredictable manner. (Suter et al Nat Genet 2004, Hitchins et al Gastroenterology 2005, Hitchins et al., N Engl J med 2007, Hitchins&Ward Nat Genet 2007). For details of further work into this novel area see Epigenetics Laboratory.