Molecular Events Associated With Colon Carcinogenesis
The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.[23,24,25] This tumor progression model was deduced from comparison of genetic alterations seen in normal colon epithelium, adenomas of progressively larger size, and malignancies.[26,27] At least five to seven major deleterious molecular alterations may occur when a normal epithelial cell progresses in a clonal fashion to carcinoma. There are at least two major pathways by which these molecular events can lead to CRC. While the majority of CRCs are due to events that result in chromosomal instability (CIN), 20% to 30% of CRCs display characteristic patterns of gene hypermethylation, termed CIMP (CpG island methylator phenotype), of which a portion display microsatellite instability (15% of CRCs).[25,28,29,30,31,32]
The spectrum of somatic mutations contributing to the pathogenesis of CRC is likely to be far more extensive than previously appreciated. A comprehensive study that sequenced more than 13,000 genes in a series of CRCs found that tumors accumulate an average of approximately 90 mutant genes. Sixty-nine genes were highlighted as relevant to the pathogenesis of CRC, and individual CRCs harbored an average of nine mutant genes per tumor. In addition, each tumor studied had a distinct mutational gene signature.
Key changes in CIN cancers include widespread alterations in chromosome number (aneuploidy) and detectable losses at the molecular level of portions of chromosome 5q, chromosome 18q, and chromosome 17p; and mutation of the KRAS oncogene. The important genes involved in these chromosome losses are APC (5q), DCC/MADH2/MADH4 (18q), and TP53 (17p),[24,34] and chromosome losses are associated with instability at the molecular and chromosomal level. Among the earliest events in the colorectal tumor progression pathway is loss of the APC gene, which appears to be consistent with its important role in predisposing persons with germlineAPC mutations to colorectal tumors. Acquired or inherited mutations of DNA damage-repair genes also play a role in predisposing colorectal epithelial cells to mutations. Furthermore, the specific genes that undergo somatic mutations and the specific type of mutations the tumor acquires may influence the rate of tumor growth or type of pathologic change in the tumors. For example, the rate of adenoma-to-carcinoma progression appears to be faster in microsatellite-unstable tumors compared with microsatellite-stable tumors. Characteristic histologic changes such as increased mucin production can be seen in tumors that demonstrate microsatellite instability (MSI), suggesting that at least some molecular events contribute to the histologic features of the tumors.
The key characteristics of MSI cancers are that they are tumors with a largely intact chromosome complement and that, as a result of defects in the DNA mismatch repair (MMR) system, they more readily acquire mutations in important cancer-associated genes compared with cells that have an effective DNA MMR system. These types of cancers are detectable at the molecular level by alterations in repeating units of DNA that occur normally throughout the genome, known as DNA microsatellites.