LICR Colon Cancer Initiative (LCCI) Workshop
Around 70 clinicians and scientists attended the inaugural LICR Colon Cancer Initiative (LCCI) Workshop, which was held at the Melbourne Museum in Melbourne, Australia, on May 5-7. This multidisciplinary meeting brought together scientists and clinical specialists from a range of fields to share current research and clinical experience about colon and rectal cancer. LICR staff from five Branches (Melbourne, New York, San Diego, São Paulo, and Stockholm) and the Melbourne Center participated along with LICR Affiliates and collaborators from Adelaide, Brisbane, Melbourne, and Sydney (Australia), as well as Nashville and New York (USA).
Drs. Richard Kolodner (LICR San Diego Branch), Edouard Nice (LICR Melbourne Branch) and Ulf Hellman (LICR Uppsala Branch)
Dr. Ian Jones (Royal Melbourne Hospital, Melbourne) discussed the advances in colorectal surgery that have transformed colorectal cancer from an untreatable, fatal disease to one with improved outcomes, particularly if detected early enough. Other clinicians including Dr. Andrew Scott (LICR Melbourne Center) discussed both recently developed and promising developmental therapies that target proteins such as the epidermal growth factor receptor (EGFR), the A33 antigen and the BRAF V600E mutant gene. One important idea from these talks is that targeted therapies are only likely to be effective on subsets of patients. Thus, in order to gain maximum benefit from these therapies, methods must be developed to identify the patients whose disease is most likely to respond to these therapies.
Early detection of colorectal cancer using protein biomarkers can result in more efficacious treatment. Different approaches were mentioned including the proteomics-based detection of soluble proteins (Dr. Richard Simpson, LICR Melbourne Branch), the development of assays to measure concentrations of a selected panel of proteins in blood (Dr. Leah Cosgrove, the Commonwealth Scientific and Industrial Research Organization of Australia), and the detection of peptide fragments from proteins from fecal matter (Dr. Edouard Nice, Melbourne Branch). In addition, the role of existing (CEA and CA19.9) and new (albumin) biomarkers was discussed with respect to patient prognosis (Dr. Susan Shedda, LICR Melbourne Branch and the Royal Melbourne Hospital).
An essential component of the LCCI is a pedigreed tumor bank of tumor and other biological samples from patients, plus their corresponding clinical, epidemiological and pathological data. Dr. Peter Gibbs (Melbourne Branch) discussed how data from several hospitals in Victoria have allowed the integrated study of behavioral and physiological factors associated with increased risk and poorer outcomes for colorectal cancer. Dr. Anamaria Camargo (LICR São Paulo Branch) described the establishment of a new tissue bank by the São Paulo Branch and its host institution, the Hospital Alemão Oswaldo Cruz. These data are being used for several projects, one of which aims to predict the response of rectal cancer to chemoradiation. Collections of tissue and clinical data also facilitated the development of predictive gene signatures for microsatellite instability (MSI) and colorectal cancer outcome, and are finding use in ongoing single nucleotide polymorphism (SNP) studies to search for novel colorectal cancer susceptibility genes.
A greater understanding of key signaling pathways in colon cells should help researchers to better understand the implications of molecular aberrations in colorectal cancers and also further define potential therapeutic targets. Dr. Robert Coffey (Vanderbilt University, Nashville) described the biochemistry of the Naked 2 gene, which was shown to link the Wnt and EGFR pathways and to be down-regulated in some colorectal adenocarcinomas but not in adenomas. Data presented by Dr. Tony Burgess (Director, Melbourne Branch) indicated that the Wnt pathway protein Axin recruits the protein APC to cytoplasmic puncta. Dr. Robert Ramsay (Peter MacCallum Cancer Center, Melbourne) described the transcription factor Myb and its role in the expansion of the colonic crypt. The loss of this factor in the context of APC alteration distorts cell division, favoring differentiation over proliferation. At a more general level, Dr. Richard Kolodner (LICR San Diego Branch) described research in yeast, which has identified a number of genes and pathways that appear to be required to maintain chromosomal integrity. Dr. Francis Barany (LICR Affiliate at Weill Medical College of Cornell University, New York) described the use of identity-by-descent to pinpoint positions of new potential cancer genes.
Drs. Huilin Zhou(LICR San Diego Branch) and Jayesh Desai (LICR Melbourne Branch)
Dr. John Hopper (University of Melbourne) presented an epidemiological study in young colorectal cancer patients whose tumors exhibit MSI or lack any of the DNA repair genes MLH1, MSH2, MSH6 or PMS2. The results show that these patients have a much higher than average chance of having an inherited mutation in one of these genes. Dr. Lara Lipton (Melbourne Branch) discussed the different methods of determining the pathogenicity of difficult-to-assess MLH1 and MSH2 mutations including immunohistochemistry, co-segregation and computational prediction. Dr. Robyn Ward (University of New South Wales and Prince of Wales Hospital, Sydney) described surprising observations of the transmission of MLH1 methylation, which reduces expression of these genes, from mother to offspring in a non-Mendelian manner. Promoter methylation of another DNA repair gene, MGMT, and concordant loss of MGMT expression was observed in 30% of a cohort of colorectal cancer cases (Dr. Nick Hawkins, University of New South Wales). A methylation profiling analysis of more than 400 genes presented by Dr. Oliver Sieber (Melbourne Branch) demonstrated the diversity and complexity of methylation in colorectal cancer cell lines and primary tumors, although most colorectal tumors exhibited hypermethylation in CpG islands.
The LCCI Workshop provided an opportunity for specialists to exchange their ideas and to form research collaborations. The participants in the Initiative now have a deep understanding of the opportunities for productive collaborations. The co-directors of the LCCI, Drs. Andy Simpson (LICR Scientific Director) and Tony Burgess, will facilitate these collaborations and provide more opportunities such as workshops for clinicians and scientists to work together.
Contributed by Drs. Robert Jorissen and Tony Burgess