Molecular genetics

The development of most colorectal carcinomas is believed to begin in a col-

orectal epithelial cell with a mutational inactivation of the APC (adenomatous polyposis coli) suppressor gene {922, 636, 186}. This inactivation has multiple consequences, including interference with E-cadherin homeostasis and dys-regulation of transcription of genes. Clonal accumulation of additional genetic alterations then occurs, including activation of proto-oncogenes such as c-myc {680} and ras, and inactivation of additional suppressor genes. The genes commonly inactivated during progression include genes on chromosome 18 {1583, 614} and the TP53 gene on the short arm of chromosome 17 {1056, 415}. The mutated TP53gene product, in turn, fails to regulate normally a variety of genes regulated by wild-type p53, including p21WAF1/CIP1 cyclin-depend-ent kinase inhibitor which complexes with proliferating cell nuclear antigen {349}, and genes leading to apoptosis, including BAX {278}. For many suppressor genes, inactivation of one allele is often caused by loss of all or part of the chromosome where the gene resides. Various other chromosomal loci have high frequencies of loss in colorectal cancer due to chromosomal instability {1044}, but the target genes are not yet known.

Microsatellite instability (MSI)

Some colorectal cancers are distinguished by extensive nucleotide insertions or deletions in numerous, intrinsically unstable repeated sequences in tumour DNA, termed microsatellite instability (MSI), also termed ubiquitous somatic mutations, DNA replication errors (RER), or nucleotide instability {1540, 860}.

MSI is defined as a change of any length due to either insertion or deletion of repeating units, in a microsatellite within a

Fig. 6.42 Low-grade intraepithelial neoplasia in ulcerative colitis. A Patchy hyperbasophilic regular glands, with dysplasia extending to the luminal surface. B Haphazardly arranged dysplastic glands.

Fig. 6.41 Reactive epithelial changes in ulcerative colitis.

Fig. 6.42 Low-grade intraepithelial neoplasia in ulcerative colitis. A Patchy hyperbasophilic regular glands, with dysplasia extending to the luminal surface. B Haphazardly arranged dysplastic glands.

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Fig. 6.43 A - C High-grade intraepithelial neoplasia in ulcerative collitis with multilayered hyperchromatic elongated nuclei extending to the luminal surface.

tumour when compared to normal tissue. It has been recommended that a panel of five microsatellites should be used as a reference standard (BAT25, BAT26, D5S346, D2S123, D17S250) for carcinomas of the large intestine {164}. If two or more of these markers show MSI, the lesion is classified as high-frequency microsatellite instability (MSI-H); if only one marker shows MSI, it is classified as low-frequency microsatellite instability (MSI-L); if no markers show MSI it is classified as microsatellite stable (MSS). If more than five markers are used, the criteria should be modified to reflect the percentage of markers demonstrating MSI. Thus, MSI-H lesions would exhibit MSI in more than 30-40% of markers tested. MSI-H carcinomas are characteristic of hereditary nonpolyposis colorectal cancer syndrome (HNPCC) due to germline mutation of one of a group of DNA mismatch repair genes followed by somatic inactivation of the other allele. Sporadic MSI-H tumours comprise about 15% of colorectal carcinomas. They usually follow transcriptional silencing of both alleles of the hMLHl mismatch repair gene due to aberrant methylation of cytosine residues in the cytosine and guanine-rich promoter region {886, 696}. The alterations that accumulate during progression of both hereditary and sporadic neoplasms characterized by MSI-H include mutations in microsatellites within the coding region of some genes, such as the type II receptor for TGF-beta1 and BAX {548}. In contrast to microsatellite-stable cancers, MSI-H cancers display nucleotide rather than chromosomal instability; allelic deletions are rare {1044}.

Recent studies indicate a functional link between defective DNA mismatch repair and the Wnt-signalling pathway. Approximately 25% of sporadic colorectal carcinomas with defective mismatch repair (MSI-H) were shown to contain frameshift mutations in the AXIN2 gene, which leads to a stabilization of p-catenin and activation of p-catenin/T-cell factor (TCF). This was associated with an accumulation in tumour cell nuclei which was absent in colorectal cancer without mis match repair deficiency and In the absence of APC mutations. AXIN2 mutant protein appears to be more stable than the wild-type gene product, suggesting a dominant-negative effect {1079A}.

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