Molecular Biology of Dysplasia and Cancer in Inflammatory Bowel Disease

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Causation: Genes Versus Environment

Although CAC accounts for less than 1% of all CRC cases, patients with IBD are among the highest risk groups for developing CRC. It is assumed that the increased risk of CRC in patients with IBD relates to the many years of colonic inflammation. Indeed, recent evidence confirms that patients with more severe degrees of histologic and endoscopic inflammation are at increased risk of CAC [2]. How much of the cancer predisposition is genetic as opposed to environmental is not known, however. A

Molecular Pathways of Sporadic Colon Carcinogenesis

To place the molecular pathogenesis of colitis-associated neoplasia in proper perspective, it is important to appreciate the molecular events involved in the development of sporadic colorectal neoplasia. CRCs arise as a result of genomic instability. There are two main types of genomic instability that contribute to colon carcinogenesis: chromosomal instability (CIN) and MSI. Most (80%–85%) of sporadic CRCs seem to arise via the CIN pathway. This results in abnormal segregation of chromosomes

Genomic Instability and Clonal Expansion in Inflammatory Bowel Disease

Like sporadic CRC, colon carcinogenesis in IBD is a consequence of sequential episodes of somatic genetic mutation and clonal expansion. Unlike sporadic colonic neoplasia, however, where only one or two dysplastic lesions arise in extremely focal areas of the colon, it is not unusual for dysplasia or cancer to be multifocal in colitic mucosa, reflecting a broader “field change.” This is best exemplified by careful mapping studies that used DNA aneuploidy as a molecular marker to gain insights

Role of Chronic Inflammation in Inflammatory Bowel Disease Neoplasia

Because CAC arises in the setting of chronic inflammation, it is logical to assume that factors associated with inflammation, such as oxidative stress, contribute to the molecular alterations seen in IBD tissues [15]. Support for this theory comes from a study showing a high frequency of p53 mutations in inflamed tissues more so than in uninflamed tissues of patients with UC [16]. This study also revealed that reactive oxygen species, which are common byproducts of inflammation, contributed to

Molecular Pathways of Colitis-Associated Colon Carcinogenesis

Many of the molecular alterations responsible for sporadic CRC development also play a role in colitis-associated colon carcinogenesis. In fact, the emerging evidence suggests that the two major pathways of CIN and MSI also apply to colitis-associated CRCs and with roughly the same frequency (85% CIN, 15% MSI) (Table 1) [22], [23]. As discussed in the following sections, however, the timing of these genomic alterations seems to differ between colitis-associated and sporadic neoplasms (Fig. 1).

Chromosomal Instability

Just as with sporadic CRC, CIN represents the major pathway by which cancers seem to arise in patients with IBD. The technique of comparative genomic hybridization demonstrates that a similar number of chromosomal alterations occur in UC-associated and sporadic CRCs, and the frequency of losses and gains of various chromosomal arms is quite similar between the two types of neoplasms [33]. Using probes specific for chromosomes 8, 11, 17, and 18, studies employing fluorescent in situ

Microsatellite Instability

MSI is not found in normal colonic mucosa from healthy controls or from patients with other types of benign inflammatory colitis [66], [67]. MSI is also quite rare in colonic mucosa from patients with Crohn's colitis [68]. As many as 15% to 40% of patients with UC demonstrate MSI in cancer tissues, however (see Table 1). In some studies, UC-associated cancers were more likely to express MSI-L rather than MSI-H [50], [69], [70], but other studies indicate that the two types of instability can

Promoter Methylation

Methylation of CpG islands in several genes seems to precede and be more widespread than dysplasia [77]. In colitis-associated neoplasms, hMLH1 hypermethylation was observed in 6 (46%) of 13 MSI-H, 1 (16%) of 6 MSI-L, and 4 (15%) of 27 MSS specimens, implicating this epigenetic change as a cause of MSI [71]. The cell cycle inhibitor, p16INK4a, loss of which has been implicated in sporadic CRC [78], [79], is commonly hypermethylated in UC neoplasms [80]. Approximately 10% of biopsies without

Markers of Cancer Progression

Histologic evidence of dysplasia on colonic biopsies is the “gold standard” marker for determining cancer risk and deciding on clinical management. There are many limitations of dysplasia, however, such as variations in pathologic interpretation, focality of dysplasia often making random biopsy detection difficult, and the fact that cancers can arise without any apparent preceding detectable dysplasia. This has raised the question of whether newer molecular markers could be complementary to

Problem of Polypoid Dysplasia in Inflammatory Bowel Disease

One dilemma that worries clinicians is the finding of dysplasia in a polypoid lesion of a patient with long-standing IBD. If the lesion is considered a sporadic adenoma, it can be removed endoscopically and the patient continued under surveillance. If it is a more ominous DALM, however, this usually prompts a recommendation for total proctocolectomy because of the high synchronous and metachronous rate of CRC. Recent studies suggest that if the polypoid lesion can be completely removed by

New Molecular Screening Approaches

Most efforts to date have understandably focused on studying tissues from patients with IBD to identify molecular markers that might be helpful for understanding cancer pathogenesis or possibly assigning risk. A more comprehensive technique applied to tissues is molecular profiling using microarrays, which, in a recent study, identified 699 transcripts that differed between benign mucosa and HGD and 242 transcripts that differed between benign mucosa and CAC. Additional studies are needed to

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