Colorectal Cancer Development
Pathway from normal colorectal epithelium to cancer
Colorectal cancer develops via an adenoma to carcinoma sequence with the accumulation of a number of genetic and epigenetic mutations (Figure 1‑3) (Morson 1968; Fearon and Vogelstein 1990). The mutations accumulated vary in hereditary cancer depending on the initiating mutation. In their normal state, tumour suppressor genes inhibit cell proliferation. Growth inhibition is lost when both alleles are inactivated by mutation and/or epigenetic changes, such as promoter methylation which stifles expression of the gene. Tumour suppressor genes broadly conform to Knudson’s classic two-hit hypothesis, where inactivation of both alleles is required for tumour suppressor genes to lose their normal function (Knudson 1971). In contrast, proto-oncogenes act by promoting cell proliferation. Mutation of these genes leads to abnormal oncogenic over-expression or increased activity of the protein.
The adenoma-to-carcinoma sequence for colorectal cancer is probably most commonly initiated by bi-allelic mutation of the APC tumour suppressor gene. APC mutations have been found in microadenomas (Otori et al. 1998), the earliest lesion on the pathway (also called aberrant crypt foci (Roncucci et al. 1991)), and in ~60-80% of early sporadic adenomas and carcinomas (Cottrell et al. 1992; Miyoshi et al. 1992; Nakamura et al. 1992). APC is a key member of the canonical Wnt signalling pathway, and the key mechanism by which mutation of this gene contributes to carcinogenesis is by activation of this pathway. However, further accumulated mutations in additional genes are required for progression of the early lesions to cancer.
- The adenoma-to-carcinoma sequence: A: Aberrant crypt foci are seen using chromoendoscopy with x200 magnification (centre and 2 o’clock) surrounded by normal crypts. An early initiating mutation occurs here, usually a tumour suppressor gene such as APC. B: Adenomatous Polyp: Mutations in proto-oncogenes such as KRAS and BRAF lead to adenomatous polyp formation. C: Other genetic and epigenetic alterations such as promoter hypo-/hyper-methylation cause progression. There are hyperchromatic nuclei with prominent nucleoli indicate highly dysplastic crypts on the left side of this image. D; Adenocarcinoma, with invasion through the muscularis layer, and mucin producing glands with abnormal polarity. This is often associated with genomic copy number variation of regions such as 18q and 17p (P53).
Activating mutations of the oncogenes KRAS (Kirsten rat sarcoma viral oncogene homolog) and BRAF (v-raf murine sarcoma viral oncogene homolog B1), both members of the MAPK (mitogen activated protein kinase) signalling pathway, are found in the transition from early to an intermediate lesion in approximately 50% and 10% of cases respectively (Bos et al. 1987; Rajagopalan et al. 2002; Yuen et al. 2002). Mutations of codons 12 and 13 in exon 2 of KRAS tend to occur in 30-60% of colorectal carcinomas (Kressner et al. 1998). The KRASgene product,a 21 kDa protein located at the inner plasma membrane, is involvedin the transduction of mitogenic signals. The Ras protein isactivated transiently as a response to extracellular signalssuch as growth factors, cytokines and hormones that stimulate cell surface receptors (Campbell et al. 1998), and mutations in KRAS constitutively activate the Ras protein.
The substitution mutation of BRAF V600E is present in 4-12% of unselected colorectal tumours, and it is associated with sporadic MSI tumours but not HNPCC tumours (Vandrovcova et al. 2006). MSI tumours outside the context of HNPCC are usually caused by methylation of the MLH1 promoter. Indeed, there is a hypothesis that some tumours might develop through a separate hyperplastic polyp-serrated adenoma pathway (Spring et al. 2006).
Epigenetic changes such as promoter hypo-/hyper-methylation can cause disregulation of expression of many genes important in colorectal cancer (Hitchins et al. 2005; Hitchins et al. 2006). Further progression to late type adenoma is associated with loss of 18q in 50% of large adenomas and 75% of carcinomas (Vogelstein et al. 1988; Fearon et al. 1990). This causes loss of SMAD2 and SMAD4, members of the TGF-ß signalling pathway. Point mutations of these genes have also been identified in colorectal cancer (Eppert et al. 1996; Hahn et al. 1996; Thiagalingam et al. 1996). The adenoma to carcinoma transition appears to be associated with loss of 17p (Fearon et al. 1987; Rodrigues et al. 1990; Akiyama et al. 1998). The 17p locus contains the P53 gene (Baker et al. 1990), the so-called gatekeeper of the cell which has important roles in the regulation of the cell cycle and apoptosis. Loss of heterozygosity of 17p correlates with missense and truncating mutations in P53 (Baker et al. 1989; Baker, Preisinger et al. 1990). Tumour invasion and metastasis are associated with loss of 8p (Hughes et al. 2006), and loss of E-cadherin function, a component of adherens-junctions (Hao et al. 1997; Christofori and Semb 1999).
The progression from adenoma to invasive carcinoma probably takes 10-40 years (Ilyas et al. 1999). However, not all lesions will undergo malignant transformation, the reason for which is unclear. It may be that the necessary mutations do not accumulate because of death, or because of environmental influences such as diet.
Genetic instability and colorectal cancer
Colorectal cancer may be subdivided genetically by the types of mutations which accumulate genome-wide during carcinogenesis. It had been observed nearly a century ago that most cancers were aneuploid, and it has been noted that the degree of aneuploidy in colorectal cancer correlates with the severity of the neoplastic behaviour (Heim and Mitelman 1989). A series of deletions, duplications, and rearrangements occur. Allelic losses appear to be important in the progression from premalignant to malignant neoplasia in the colorectum. This process is called chromosomal instability (CIN) and accounts for approximately 75% of colorectal cancers. Ten to 15% are not CIN but do have smaller mutational events which are caused by loss of DNA mismatch repair (Fishel et al. 1993) and are referred to as MSI tumours. The CpG island mutator phenotype (CIMP) is associated with methylation of promoter regions, CpG rich regions, which causes silencing of genes. Tumours are often both MIN and CIMP, as methylation of mismatch repair gene promoters usually occurs in sporadic MSI tumours (Kane et al. 1997).
The role of genomic instability in causing and promoting tumour growth remains controversial (Lengauer et al. 1998; Tomlinson and Bodmer 1999). Some argue that instability is necessary for tumourigenesis (Loeb 1991), while others take the viewthat Darwinian selection is the driving force. It is becoming clear that many cancers harbour multiple mutations, the great majority of which probably have no significant effect on tumour growth. It may well be that some tumours with an inherited DNA repair defect accumulate more mutations than others.
- Hereditary Colorectal Cancer Syndromes (familyhistorybowelcancer.wordpress.com)
- Colorectal Cancer Aetiology (familyhistorybowelcancer.wordpress.com)
- Hyperplastic Polyposis Syndrome (familyhistorybowelcancer.wordpress.com)
- Lynch Syndrome and other non-polyposis inherited cancer syndromes (familyhistorybowelcancer.wordpress.com)
- Low penetrance risk and colorectal cancer: A review (familyhistorybowelcancer.wordpress.com)
- Polyposis (familyhistorybowelcancer.wordpress.com)
- Hereditary mixed polyposis syndrome (HMPS) (familyhistorybowelcancer.wordpress.com)
- Tumour suppressor genes and ATOH1 in colorectal cancer (pharmastrategyblog.com)