Surgery (RMH) - Theses
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ItemMolecular prognostic and predictive biomarkers in colorectal cancer( 2012)Increasing knowledge of the underlying signalling pathways and molecular defects involved in colorectal cancer (CRC) growth/progression has led to the development of several novel target-based therapeutics along with the discovery of various prognostic and predictive biomarkers. The mitogen-activated protein kinase (MAPK) signalling pathway plays a critical role in colorectal cancer progression. Mutations in BRAF, a principal effector of Ras in this signaling cascade, are found in 10% of CRC. The low frequency of this mutation makes it a challenging target for drug development, unless subsets of patients with higher rates of BRAFV600E can be defined. This thesis first investigates the potential of enriching a CRC patient population for BRAFV600E mutations based on clinical features and KRAS status. The mutational concordance between primary-metastasis pairs, and the impact of BRAFV600E and other molecular changes on patient outcome were also evaluated. This was achieved by analyzing primary CRC from 525 patients evenly matched for age, gender and tumour location, and 81 primary-metastasis pairs. BRAFV600E, KRAS, PIK3CA, NRAS mutations, microsatellite instability (MSI) and loss of heterozygosity (LOH) were determined and correlated with clinical features and patient outcomes. The prevalence of BRAFV600E was found to be considerably higher in older females with KRAS wild-type right-sided colon cancers (50%) compared to the unselected cohort (10%). BRAFV600E was associated with inferior overall survival in metastatic CRC and is independent of MSI status. The previous study suggested that BRAF mutant cancers represent a discrete subset of metastatic CRC defined by poorer survival, right-side tumour location and association with MSI. Whether BRAF mutant CRC is further defined by a distinct pattern of metastatic spread was investigated by using prospective clinical data and molecular analyses from 2 major centers (Royal Melbourne Hospital and The University of Texas MD Anderson Cancer Center). Patients with known BRAF mutation status were analysed for clinical characteristics, survival, and metastatic sites. A distinct pattern of metastatic spread was observed in BRAF mutant tumours, namely higher rates of peritoneal metastases (46% vs 24%, P=0.001), distant lymph node metastases (53% vs 38%, P=0.008), and lower rates of lung metastases (35% vs 49%, P=0.049). To further develop the concept of cancer gene mutations as predictors of site of relapse, CRC metastases from different sites were then examined for oncogene mutation profiles. One-hundred CRC metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analysed for genes with identified mutations. Mutation prevalence was compared between metastases from liver, lung and brain. Differential mutations between metastasis sites were evaluated as predictors for site of relapse in patients from the VICTOR trial. KRAS mutation prevalence differed between metastasis sites, being more common in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P=0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. KRAS mutation was found to be predictive of lung relapse but not liver relapse in patients from the VICTOR trial.