Analysis of chromosome-scale changes and DNA methylation as markers for colorectal cancer recurrence.
This NHMRC funded project will identify biomarkers for recurrence in stage C colorectal cancers. DNA from 80 primary stage C cancers from persons without relapse and from 80 primary stage C cancers from persons who have relapsed as well as the matching 80 metastases will be used. All tumour DNA samples plus matched normal DNA will have whole genome SNP typing / copy number variation and promoter methylation analysis performed. The platforms used will be the Illumina 610 Quad array and the Affymetrix whole genome promoter array. Comparisons will be made between primary and metastasis pairs, and between stage C cancers with and without relapse.

Identification of a gene expression signature for metastasis for colorectal cancer outcome.
This AACR funded project will utilize the same sample set as for the previous project. We will establish an expression signature for stage 3 colorectal cancers predictive of outcome after potentially curative surgery and validate this signature in an independent group of colorectal cancers. It will be possible to compare genome wide expression profile of a set of stage 3 colorectal cancers with patterns of genomic gain and loss and global methylation and to compare expression profiles in primary colorectal cancer and corresponding liver metastases.

Sequencing of oncogenes in 1000 colorectal cancers. Influence of mutation pattern on clinical parameters.
In collaboration with the J Craig Venter Institute we are performing mutation detection on 1000 stage B and C colorectal cancers for the genes known to be mutated in this disease and examining them singly, and in combination, as markers of prognosis. We are also analyzing the corresponding germline DNA from this group of 1000 patients for variants which may be associated with response to known drug therapies. 

Genome wide analysis of 1000 colorectal cancer/normal DNA pairs for SNPs and copy number variation.
This project will utilize the same sample set as the above project and will utilize the Illumina 610 Quad array. We will identify novel germline variants, somatic LOH and DNA copy-number changes associated with CRC presentation, outcome, drug response and toxicity and determine the extent to which the genetic background influences the acquisition of somatic LOH and DNA copy-number changes (both site and type). The study will classify CRCs into molecular subtypes based on their profile of germline and somatic changes and we will then produce a clinical algorithm based on the profile of genetic changes to guide clinical management of CRC patients.

Identification of novel downstream targets of the Wnt signalling pathway that are over-expressed in colorectal cancer
Colorectal cancer development is initiated as a result of mutation of the Wnt signalling pathway members, adenomatous polyposis coli (APC) or beta-catenin (CTNNB1) and is accompanied by specific gene expression changes. Consistent gene expression changes which occur in benign and malignant colorectal tumours as compared to normal colorectal mucosa are candidate downstream targets of Wnt signalling. Our microarray analysis identified 188 genes which were significantly changed in FAP adenomas, sporadic adenomas and carcinomas as compared to normal colorectal epithelium, with 45 and 138 genes showing consistent up- or down-regulation in benign and malignant lesions, respectively. We will identify novel genes consistently over-expressed in benign and malignant colorectal tumours as compared to normal colorectal mucosa and assess the potential role of these over-expressed genes in driving or promoting colorectal cancer development.