Colorectal cancer (CRC) is a heterogeneous disease, developing through a multipathway sequence of events guided by clonal selections. Pathways included in the development of CRC may be broadly categorized into (a) genomic instability, including chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP), (b) genomic mutations including suppression of tumour suppressor genes and activation of tumour oncogenes, (c) microRNA, and (d) epigenetic changes. As cancer becomes more advanced, invasion and metastases are facilitated through the epithelial-mesenchymal transition (EMT), with additional genetic alterations. Despite ongoing identification of genetic and epigenetic markers and the understanding of alternative pathways involved in the development and progression of this disease, CRC remains the second highest cause of malignancy-related mortality in Canada. The molecular events that underlie the tumorigenesis of primary and metastatic colorectal carcinoma are detailed in this manuscript. 1. Introduction Despite increased general awareness, colorectal cancer (CRC) remains the second leading cause of cancer-related death in Canadian men and women combined [1], with a third of CRC patients dying from this disease [2]. These are grim statistics given that this cancer is a well-studied malignancy with defined risk factors, a slow progression, and preneoplastic lesions that can be detected and treated by colonoscopic polypectomy [3]. Though 5-year survival rates for early stage cancers (Dukes A and B) is up to 95% and 60–80% respectively, survival rates drop dramatically to 35% with lymph node involvement (Dukes C), indicating early detection and treatment is imperative for best patient management [4]. Recognition that histologically identical tumours may have drastically different prognosis and/or response to treatment prompted the theory that, rather than a single malignancy, CRC is a heterogenous, multifactorial disease [5, 6]. It is theorized, perhaps, that individual tumours are initiated and progress in a unique manner that is not necessarily identical amongst all tumours [7]. As a result, the focus of CRC research is shifting from a clinical perspective towards developing an understanding of the molecular basis of this malignancy, including individual susceptibility, development, progression, response, and resistance to antitumour treatment and metastatic spread [8]. Cancer develops through multiple and sequential genetic alterations [3, 9], and some patients may have synchronous alterations in two or
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