Molecular Pathogenesis of Gastrointestinal Neoplasia
Moderators: Dr. Wataru Yasui and Dr. Jeremy Jass
Section 6 -
The Pathogenesis of Colorectal Carcinoma in Inflammatory Bowel Disease
Thomas C Smyrk
Department of Pathology, Mayo Clinic
Inflammatory bowel disease confers increased risk for colorectal carcinoma. The risk is best
documented for ulcerative colitis (UC), but Crohn's disease is unequivocally a cancer-associated
condition as well. A meta-analysis covering 116 published studies put the overall prevalence of
colorectal cancer in patients with UC at 3.7%, and documented increasing risk with increased duration of
pancolitic disease: the cumulative incidence was 2% at 10 years, 9% at 20 years and 18% after 30 years
of disease.  One recent single-institution study found lower risk and deserves mention here:
prospectively collected data from the surveillance program operating at over a 30-year period St Mark's
Hospital showed a cumulative cancer incidence of 2.5% at 20 years, 7.6% at 30 years and 10.8% after 40
years of disease.  The cancer incidence was constant over the duration of disease and there was a
significant reduction in cancer incidence after 1975, perhaps reflecting better control of inflammation
by disease-modifying drugs. A similar temporal trend has been observed in Scandinavia  and Olmsted
County, Minnesota .  In fact, no Olmsted County resident diagnosed with UC after 1980 has developed
carcinoma (201 patients).
In addition to duration of disease, putative risk factors for colorectal cancer in UC are
anatomic extent of disease, disease activity, presence of primary sclerosing cholangitis and a family
history of colorectal cancer. Ekbom et al found a relative risk for carcinoma of 1.7 in patients with
proctitis only, 2.8 in patients with disease extending to the hepatic flexure, and 14.8 in patients with
disease beyond the hepatic flexure.  A case-control study from St Mark's Hospital found a
correlation between inflammation scores (both endoscopic and histologic) and the risk for colorectal
neoplasia.  On multivariate analysis, only the histologic inflammation score had a significant
relationship to cancer occurrence; a 1-unit change in the semiquantitiative score (0-4) increased the
odds of colorectal neoplasia by a factor of 4.69. Backwash ileitis, which can be considered another
marker of disease severity, has also been implicated as a risk factor for carcinoma.  Patients with
both UC and primary sclerosing cholangitis are approximately four times as likely to develop carcinoma as
those without PSC, according to a recent meta-analysis of 11 studies.  In our own unpublished study
of 111 patients with UC-carcinoma, 27% also had primary sclerosing cholangitis, compared to 2% of
controls matched for age, sex and extent of disease. Family history of colorectal cancer was associated
with a relative risk for carcinoma of 2.5 in a population-based cohort study of nearly 20,000 patients
with UC or Crohn's disease.  In our own unpublished study, UC patients with carcinoma were more
likely to have a sibling with any type of malignancy than control patients (16% vs 8%).
All of the above highlights two contributors to carcinoma in UC: chronic inflammation
and, as suggested by the association with family history, innate patient characteristics.
Many common cancers develop in the setting of chronic inflammation: hepatocellular
carcinoma (in chronic viral hepatitis), gastric cancer (in chronic gastritis) and colorectal cancer
(inflammatory bowel disease) are examples. Persistent inflammation drives increased cellular turnover,
particularly in the epithelium. Free radicals generated by inflammatory responses can injure cells by
gene mutation or by post-translational modification, leading to disruption of protective functions such
as DNA repair, cell-cycle checkpoints and apoptosis. p53 appears to be a critical mediator of response
to stress; nearly every study of carcinogenesis in UC makes disruption of p53 function an important early
step. In fact, it has been convincingly established that there are extensive clonal abnormalities of p53
(among other genes) even in the non-dysplastic mucosa of colitic patients with dysplasia or carcinoma.
 The critical role of the p53 network as a response to inflammatory stress was beautifully outlined
by Staib et al.  The authors compiled the gene expression profiles associated with four different
components of the inflammatory response: nitric oxide, hydrogen peroxide, DNA replication arrest and
hypoxia. Overall, 1396 genes changed in a p53-dependent manner. There appeared to be unique profiles
associated with each type of injury, with ony 14 genes altered in response to all four conditions. It
seems clear that interference with p53-mediated response to inflammatory stress can have complex and
significant downstream effects.
How do dysplasia and carcinoma develop in this "initiated" background? As in sporadic
colorectal cancer, three overlapping pathways may be in play: the tumor suppressor pathway, the mutator
pathway and the methylator pathway. All have been implicated in UC-related carcinogenesis. Maia et al
 argue that the suppressor pathway is the main contributor to colitis-associated cancers. The
authors studied samples from inactive chronic colitis without dysplasia, with dysplasia and with
carcinoma using a broad array of techniques: microsatellite instability, loss of heterozygosity (LOH)
and allelic imbalance (AI), methylation analysis of MLH1 and CSPG2, and mutation analyses of p53 and
APC. No microsatellite instability was detected in any sample. There was no hypermethylation of MLH1,
and only a single example of CSPG2 methylation. LOH and AI were frequently observed, particularly at
loci on chromosomes 5, 9 and 18, close to the genes for APC, p16 and DCC. This emphasis on mutational
changes is consistent with the work of Chen et al, who used DNA fingerprinting to demonstrate mutational
changes in 10-20% of sites examined, even in non-dysplastic mucosa; half of those changes were clonally
The contribution of the mutator pathway to UC carcinogenesis is under debate, with
estimates on the prevalence of microsatellite instability high (MSI-H) carcinoma in UC ranging from 1% to
45%. A recent large, multi-institutional series found a prevalence of 19/124 (15%), similar to the rate
in sporadic carcinoma.  The specific mutational profile, however, was different in UC-carcinoma,
with TGFbetaR2 and ACVR2 mutations being less common than in sporadic MSI-H, and ICA1 mutations being
more common. Tahara et al  argue for a more important role for microsatellite instability. The
authors used five microsatellite markers and defined MSI-H as alterations in 2 or more loci. They found
MSI-H phenotype in 8 of 12 UC-cancers, 4/6 UC-high grade dysplasias, 2/6 low grade dysplasias and 15/59
samples of inflamed UC mucosa without dysplasia. Four patients with MIS-H carcinoma were shown to have
microsatellite instability in non-dysplastic biopsies obtained 2-12 years before the cancer diagnosis.
The contribution of hypermethylation to UC carcinogenesis also has its advocates. Issa
et al proposed the concept of accelerated age-related CpG island methylation, perhaps resulting from
chronic inflammation in the setting of increased cell turnover, and suggested that UC can be viewed as
causing premature aging of colorectal epithelial cells.  Since then, preferential hypermethylation
of numerous genes has been documented in dysplastic UC epithelium, or even in non-dysplastic epithelium.
The Issa paper specifically mentioned estrogen receptor, CSPG2, MYOD and p16. Others have confirmed
methylation of estrogen receptor in non-neoplastic epithelium as a marker of neoplasia risk. 
Hypermethylation of HPP1 has also been described as an early event in UC neoplasia.
of CDH1 (the E-cadherin gene)
may also be an early event,  and may be a way to affect the wnt pathway
without mutations in APC. 
Hyperphosphorylation is another post-translational modification that could play a role
in carcinogenesis. Ying et al demonstrated hyperphosphorylation of the retinoblastoma protein in both
mouse and human colitis, with subsequent release of E2F1 and downstream genes associated with
proliferation (PCNA and cyclin D1) and apoptosis inhibition (phosphor-Akt).
The chronic inflammation of UC inflicts cellular damage via free radical injury and
generates abnormal cell populations well before the appearance of dysplasia. Interference with normal
functioning of the p53 tumor suppressor network is a critical early event. Mutations and
post-translational modifications probably both play a role in promoting the development of dysplasia and
carcinoma, but the nature and timing of the specific abnormalities remains under investigation.
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