Surgical Pathology and Current Molecular Aspects of Dysplasia in the GI Tract
Section 9 -
Molecular Basis of Colitis-associated Neoplasia
Robert D. Odze, M.D.
Jonathan Glickman, M.D., Ph.D.
Mark Redston, M.D.
The molecular genetic basis of colorectal adenoma-to-carcinoma progression has served as
the prototypical model of human neoplastic genetic progression
and the molecular biologic
alterations in general have been extensively studied (reviewed in
. While colitis-associated
neoplasms account for only a small portion of the overall burden of colorectal cancers, the molecular
biologic alterations in this pathway have been well studied (reviewed in
. Compared to
progression in sporadic colorectal neoplasia, there are three interesting aspects to the molecular
pathogenesis of colitis-associated neoplasms: 1) There are significant differences in the overall
frequency of alterations of specific genetic targets. 2) There are significant differences in the timing
of occurrence of alterations during morphologic progression. 3) There are abundant genetic alterations
present in non-dysplastic epithelium of colitis patients with associated neoplasia, or at high risk of
neoplasia (longstanding extensive disease). This latter finding has been the most exciting in terms of
developing molecular markers that may help predict the risk of progression to dysplasia and cancer.
Recently, the role of free radical injury, particularly due to nitrous oxide, has been of interest in the
etiology of this genetic damage . A comparison of conventional and colitis-associated neoplasia is
presented in Table 1. Potential use of biomarkers in diagnosis and patient management is reviewed in
Predicting the Risk of Progression in Colitis-Associated Neoplasia
It has long been recognized that aneuploidy is a frequent feature of colitis-associated
neoplasms . Rubin et al performed seminal studies demonstrating that aneuploidy is also commonly
identified in non-dysplastic mucosa . They found that aneuploidy was absent in biopsies of UC
patients with a low cancer risk, but frequent, and correlated with the severity of histologic
abnormality, in high cancer risk patients. In a propsective study of 25 high risk UC patients without
dysplasia, 5 with aneuploidy all progressed to dysplasia in 1-2.5 years, whereas no dysplasia was found
in 19 patients without aneuploidy followed for 2-9 years. Following this original description, there
have been multiple reports of aneuploidy in mucosa adjacent to dysplasia and cancer . There are
several other reports of aneuploidy preceding the development of dysplasia or cancer
Lindberg et al studied 147 patients surveilled over a 13 year period . Aneuploidy was
found in 20 patients, including 10 without morphologic abnormalities. Of these 10, dysplasia was
subsequently identified in 4, compared to an absence of dysplasia in 127 patients without aneuploidy.
Holzmann et al analyzed 1486 biopsy samples from 769 locations in 83 patients with long standing UC
. Aneuploidy was found in 27/83 (32.5%) patients but in none of 16 patients with irritable bowel
syndrome. There was a significant association between aneuploidy and the subsequent identification of
dysplasia during surveillance (P < 0.001). Aneuploidy was more predictive than p53 mutations. Kras
mutations were not independently predictive of dysplasia.
In a separate publication, Holzmann et al reported analyses of 5404 biopsy specimens from 368 patients
with extensive and localized disease . Aneuploidy was found in 32/368 (8.7%), and was significantly
associated with extent of disease, duration longer than 10 years, presence of primary sclerosing
cholangitis, and the development of dysplasia.
Although most of the studies investigating the use of aneuploidy as a biomarker have utilized fresh
tissue samples, some studies have shown good results from paraffin-embedded tissue . Promising
results have also been obtained using image analysis . Recent technical modifications have included
the use of mechanical dissociation .
2. LOH of 17p and Other Loci
Brentnall et al were among the first to identify genetic alterations other than aneuploidy
in non-dysplastic tissue of patients with colitis-associated neoplasms . By studying multiple tissue
samples of colitis-associated neoplasms that had a known p53 mutation in the primary tumor, they found
p53 mutations in diploid non-dysplastic mucosa. 17p LOH events were less commonly identified.
The presence of aneuploidy in non-dysplastic mucosa of patients with chronic UC suggests that
chromosomal instability may be present in these tissues. Indeed, studies have revealed occasional LOH
events at chromosomes 3, 5, 6, 7, 9, 12, and 17  in chronically inflamed microdissected epithelial
samples from chronic UC patients. Similar findings were obtained by Willenbucher et al . Using CGH,
they identified clonal chromosomal alterations in 36% of non-dysplastic samples from colectomy cases that
had cancer elsewhere.
Further studies by Rabinovitch et al demonstrated widespread chromosomal instability throughout the
colon in UC patients with high grade dysplasia or cancer . Using FISH for centromere and arm probes
for chromosomes 8, 11, 17, and 18, they found abnormalities to be frequent and common, particularly 17p
losses in rectal biopsies that were negative for dysplasia. Chromosomal arm instability was 100%
sensitive and specific for distinguishing control biopsies from histologically negative rectal biopsies
obtained from patients with dysplasia or cancer. These findings suggest that assays of chromosomal
instability may be useful as predictive markers. Unfortunately, these analyses require fresh tissue
samples and sophisticated methodology.
In a recent study, O'Sullivan et al studied the relationship between chromosomal
instability in non-dysplastic mucosa and the presence of associated dysplasia or cancer in the same
patient . They studied biopsy samples from three patient populations: non-UC controls, UC
non-progressors (no dysplasia or cancer in any biopsies), and UC progressors (histologically negative or
indefinite biopsies from patients with dysplasia or cancer elsewhere in the colon). They assayed
chromosomal instability by measuring the loss of chromosomal arms or centromeres for 8q, 11q, 17p, and
18q by FISH. They found that arm and centromere losses were significantly more common in UC progressors
than in UC non-progressors (P = 0.001) and non-UC controls (P < 0.001). All studies were conducted
using fresh tissue specimens and sophisticated FISH analysis that are not used in most diagnostic labs.
3. p53 Inactivation
Deletion of 17p and mutations of p53 have long been recognized as frequent events in
colitis-associated neoplasms. In comparison to sporadic neoplasia, where p53 mutations are most commonly
acquired during the transition from high grade dysplasia to cancer, most studies have shown that p53
mutations are present prior to invasion in colitis-associated neoplasms
immunohistochemical detection of p53 stabilization/overexpression has served to be a useful surrogate for
p53 mutation in the setting of colitis-associated neoplasia , and that it may represent a better
marker than 17p LOH as a predictor of risk of progression .
It is also well established that p53 mutations are often present in non-dysplastic mucosa
adjacent to dysplasia and cancer
and in non-dysplastic tissue in patients without
dysplasia or cancer . Some of these studies have suggested that p53 alterations in dysplasia may be
an independent predictor of progression to invasive carcinoma. Some authors have also suggested that p53
alterations could be used as supportive evidence of definite dysplasia in borderline histology cases,
although this is not at present an accepted form of clinical practice.
Several studies have investigated the utility of p53 alterations as a marker for progression to
dysplasia or carcinoma. Lashner et al studied 95 patients with long standing pan-UC enrolled in a
surveillance program . Using p53 immunohistochemistry, the 37 patients with positive p53 were
significantly more likely to develop dysplasia or cancer (relative risk = 4.53, 95% CI 2.16-9.48).
Holzmann et al analyzed 1486 biopsy samples from 769 locations in 83 patients with long standing UC .
Mutations in p53 were detected by SSCP analysis, and were found in 18/83 UC patients (21.7%) but in none
of 16 irritable bowel control patients. Dysplasia was identified during endoscopic surveillance in 7/18
patients with p53 mutation, and in 3/64 patients with wild type p53 (P = 0.05). Aneuploidy was more
predictive than p53 mutations.
4. Telomere Shortening
Telomeres are important in maintaining genome stability during cellular replication . Telomere
loss is associated with cellular senescence, or with increased genome instability when there is a
concomitant abnormality in cell cycle checkpoints
Rapid cell turnover and oxidative injury,
such as that which occurs in chronic IBD are associated with accelerated telomere shortening .
Increased genome instability is known to be present in non-dysplastic mucosa of patients with
colitis-associated neoplasia . As a possible link between these observations, it has recently been
shown that telomere erosion occurs in colorectal epithelium of UC patients . It is associated with
an increased risk of neoplastic progression, and is highly correlated with loss of chromosomal arms and
In a series of elegant experiments, O'Sullivan et al utilized quantitative fluorescence in situ
hybridization (QFISH) with a telomeric probe to study telomere length in colonic epithelial cells .
They studied biopsy samples from three patient populations: non-UC controls, UC non-progressors (no
dysplasia or cancer in any biopsies), and UC progressors (histologically negative or indefinite biopsies
from patients with dysplasia or cancer elsewhere in the colon). They found that the average telomere
length in UC progressors was 47% shorter compared to non-UC controls (P = 0.001), and 30% shorter than UC
non-progressors (P = 0.02). They also examined specific chromosomal abnormalities at 8q, 11q, 17p, and
18q by FISH, and found that arm and centromere losses were significantly more frequent in UC progressors.
Furthermore, they found a strong correlation between telomere shortening and loss of chromosomal arms and
centromeres (P < 0.001), suggesting a direct role for telomere shortening in the genesis of
In addition to telomere length, O'Sullivan et al also exmained anaphase bridges . These are
chromatin bridges that are not resolved after anaphase. They are a hallmark of telomere dysfunction, and
may lead to chromosomal losses, gains, or rearrangements
Utilizing DAPI staining of flow
sorted cells with 4N DNA content, they found that the frequency of anaphase bridges in UC progressors was
67% higher than in non-UC controls (P = 0.0002) and UC non-progressors (P = 0.011).
Unfortunately, while these elegant experiments provide dramatic evidence for the possible clinical
utility of measurement of telomere length and chromosomal instability, all of these analyses require
analysis of fresh tissue, and other sophisticated methodologies (including flow sorting and QFISH).
5. Microsatellite Instability
Occasional colitis-associated colorectal cancers have high frequency microsatellite
instability and DNA mismatch repair deficeincy , although this genetic alteration seems to be less
frequent than in sporadic colorectal cancer
Microsatellite instability has also been described
in non-dysplastic mucosa of UC patients
although it is not clear if this represents a true
mismatch repair deficiency, or a form of genomic instability related to chronic inflammation and
6. Proliferation Index
Studies that have investigated labelling indices have found that Ki67 (MiB-1) staining is
always confined to the basal third of the crypt in non-dysplastic tissue, and always extends above the
basal third in dysplastic biopsies .
7. Other Markers
A number of other molecular biologic alterations have been described in colitis-associated
neoplasms, and have been proposed as possible biomarkers
Among these other possible markers,
there have been studies to assess the expression of laminin-5 gamma2 chain ,
cyclin A ,
sialosyl-Tn antigen ,
metallothionein , and cystein rich fibroblast growth
factor receptor-1 (CFR-1/PAM-1) . In one recent study, methylation of the CDH1 (E-cadherin) gene
promoter and loss of immunoreactivity were more common in biopsy samples from patients with dysplasia
Methylation silencing of p14ARF and HPP1 have also been described in early colitis neoplasia
Loss of a portion of chromosome 6 has also been specifically associated with colitis-associated
cancers, but has not yet been characterized in non-invasive lesions . Recent comparative genomic
hybridization studies have also identified novel genetic alterations in colitis-associated cancers,
including widespread amplifications . However, the results are too preliminary to determine the
possible utility of these markers.
Differentiating DALMs and sporadic adenomas in ulcerative colitis
Several studies have investigated the molecular genetic differences of polypoid dysplasia
(dysplasia associated lesion or mass, DALM) and sporadic adenomas (which may occur in colitis patients).
Whereas polypoid dysplasia-like DALMs have some distinct molecular genetic features, such as more
frequent p53 mutations, adenoma-like DALMs resemble their sporadic counterparts
are other useful clinical and pathologic guidelines for the separation and management of these lesions
the need for molecular biomarkers has been less pressing.
Molecular screening for rare mutations in UC patients
In addition to evaluating molecular markers on tissue biopsy samples, other molecular
genetic approaches to screening have also been considered. One methodology is to test for mutations in
fecal DNA that are present from shed neoplastic cells. The identification of Kras mutations in the stool
of colonic adenoma and carcinoma patients as well as pancreatic carcinoma patients has been shown to be
One of the limitations of this technology has been the difficulty in
screening for mutations versus detecting a known mutation. Thus it is easier to search for Kras codon 12
mutations than to screen for p53 mutations. This has hampered its application to UC patients because of
the unique molecular alterations present in this pathway. Recently, there have been a number of
refinements to the technique, and there are commercial tests available
with a number of ongoing
clinical trials in colorectal cancer. These tests may become feasible for UC patients in the future.
Other refinements have included the use of colonic lavage specimens for molecular analyses
There are also reports attempting to centrifuge lavage specimens for cytologic examination and
image cytometry .
Table 1: Molecular alterations in conventional and colitis-associated
|Conventional Colorectal Neoplasia ||Colitis-Associated Neoplasia|
| ||Kras mutation|
| ||17 pLOH/p53 mutation|
| ||9p LOH/p16 down-regulation|
| ||other allelic deletions (18q, others)|
| ||telomere erosion/instability|
|Hyperplastic polyp/Epithelial serration|
| Kras mutation ||Kras mutation|
| CpG island methylation |
| allelic deletions (uncommon) ||allelic deletions (uncommon)|
| abnormal proliferation index ||abnormal proliferation index|
| p27 down-regulation ||P27 down-regulation|
| Kras mutation ||Kras mutation (less frequent)|
| 5q LOH/APC mutation; beta-catenin mutation; nuclear stabilization of beta-catenin ||5q LOH/APC mutation; beta-catenin mutation; nuclear stabilization of beta-catenin (less frequent)|
| allelic deletion ||allelic deletion|
| ||17 pLOH/p53 mutation|
| 17p LOH/p53 mutation |
| 18q LOH |
| Aneuploidy |
| 9p LOH/p16 down-regulation (less frequent) |
| p27 down-regulation (less frequent) ||p27 down-regulation|
| other chromosomal deletions (including 1q, 4p, 6p, 6q, 8p, 9p, 9q, 18p, 22q) ||other chromosomal deletions (not as well characterized)|
- Vogelstein, B., et al., Genetic alterations during colorectal-tumor development. N Engl J Med, 1988. 319(9): p. 525-32.
- Fearon, E.R. and B. Vogelstein, A genetic model for colorectal tumorigenesis. Cell, 1990. 61(5): p. 759-67.
- Kinzler, K.W. and B. Vogelstein, Lessons from hereditary colorectal cancer. Cell, 1996. 87(2): p. 159-70.
- Kinzler, K.W., Vogelstein, B., Colorectal Tumors, in The Genetic Basis of Human Cancer, B. Vogelstein, Kinzler, K. W., Editor. 1998, McGraw-Hill. p. 565-590.
- Fearon, E.R., Gruber, S. B., Molecular Abnormalities in Colon and Rectal Cancer, in The Molecular Basis of Cancer, J. Mendelsohn, Howley, P. M., Israel, M. A., Liotta, L. A., Editor. 2001, W. B. Saunders Company. p. 289-312.
- Lynch, J.P. and T.C. Hoops, The genetic pathogenesis of colorectal cancer. Hematol Oncol Clin North Am, 2002. 16(4): p. 775-810.
- Houlston, R.S., What we could do now: molecular pathology of colorectal cancer. Mol Pathol, 2001. 54(4): p. 206-14.
- Leslie, A., et al., The colorectal adenoma-carcinoma sequence. Br J Surg, 2002. 89(7): p. 845-60.
- Grady, W.M. and S.D. Markowitz, Genetic and epigenetic alterations in colon cancer. Annu Rev Genomics Hum Genet, 2002. 3: p. 101-28.
- Calvert, P.M. and H. Frucht, The genetics of colorectal cancer. Ann Intern Med, 2002. 137(7): p. 603-12.
- Liefers, G.J. and R.A. Tollenaar, Cancer genetics and their application to individualised medicine. Eur J Cancer, 2002. 38(7): p. 872-9.
- Gryfe, R., et al., Molecular biology of colorectal cancer. Curr Probl Cancer, 1997. 21(5): p. 233-300.
- Benhattar, J. and E. Saraga, Molecular genetics of dysplasia in ulcerative colitis. Eur J Cancer, 1995. 31A(7-8): p. 1171-3.
- Harpaz, N. and I.C. Talbot, Colorectal cancer in idiopathic inflammatory bowel disease. Semin Diagn Pathol, 1996. 13(4): p. 339-57.
- Wong, N.A. and D.J. Harrison, Colorectal neoplasia in ulcerative colitis-recent advances. Histopathology, 2001. 39(3): p. 221-34.
- Pohl, C., A. Hombach, and W. Kruis, Chronic inflammatory bowel disease and cancer. Hepatogastroenterology, 2000. 47(31): p. 57-70.
- Tomlinson, I., et al., A comparison of the genetic pathways involved in the pathogenesis of three types of colorectal cancer. J Pathol, 1998. 184(2): p. 148-52.
- Hofseth, L.J., et al., Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc Natl Acad Sci U S A, 2003. 100(1): p. 143-8.
- Itzkowitz, S., Colon carcinogenesis in inflammatory bowel disease: applying molecular genetics to clinical practice. J Clin Gastroenterol, 2003. 36(5 Suppl): p. S70-4; discussion S94-6.
- Malcomson, R.D. and A.H. McGregor, Molecular screening for colon cancer in inflammatory bowel disease. Eur J Gastroenterol Hepatol, 2002. 14(10): p. 1045-7.
- Levine, D.S., et al., Distribution of aneuploid cell populations in ulcerative colitis with dysplasia or cancer. Gastroenterology, 1991. 101(5): p. 1198-210.
- Rubin, C.E., et al., DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gastroenterology, 1992. 103(5): p. 1611-20.
- Holzmann, K., et al., Comparative analysis of histology, DNA content, p53 and Ki-ras mutations in colectomy specimens with long-standing ulcerative colitis. Int J Cancer, 1998. 76(1): p. 1-6.
- Befrits, R., et al., DNA aneuploidy and histologic dysplasia in long-standing ulcerative colitis. A 10-year follow-up study. Dis Colon Rectum, 1994. 37(4): p. 313-9; discussion 319-20.
- Markowitz, J., et al., Endoscopic screening for dysplasia and mucosal aneuploidy in adolescents and young adults with childhood onset colitis. Am J Gastroenterol, 1997. 92(11): p. 2001-6.
- Lindberg, J.O., R.B. Stenling, and J.N. Rutegard, DNA aneuploidy as a marker of premalignancy in surveillance of patients with ulcerative colitis. Br J Surg, 1999. 86(7): p. 947-50.
- Holzmann, K., et al., Comparison of flow cytometry and histology with mutational screening for p53 and Ki-ras mutations in surveillance of patients with long-standing ulcerative colitis. Scand J Gastroenterol, 2001. 36(12): p. 1320-6.
- Holzmann, K., et al., Flow cytometric and histologic evaluation in a large cohort of patients with ulcerative colitis: correlation with clinical characteristics and impact on surveillance. Dis Colon Rectum, 2001. 44(10): p. 1446-55.
- Hartmann, D.P., et al., Flow cytometric DNA analysis of ulcerative colitis using paraffin-embedded biopsy specimens: comparison with morphology and DNA analysis of fresh samples. Am J Gastroenterol, 1995. 90(4): p. 590-6.
- Keller, R., et al., Diagnostic value of DNA image cytometry in ulcerative colitis. Dig Dis Sci, 2001. 46(4): p. 870-8.
- Molnar, B., et al., Immediate DNA ploidy analysis of gastrointestinal biopsies taken by endoscopy using a mechanical dissociation device. Anticancer Res, 2003. 23(1B): p. 655-60.
- Brentnall, T.A., et al., Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology, 1994. 107(2): p. 369-78.
- Park, W.S., et al., Loss of heterozygosity and microsatellite instability in non-neoplastic mucosa from patients with chronic ulcerative colitis. Int J Mol Med, 1998. 2(2): p. 221-224.
- Willenbucher, R.F., et al., Genomic instability is an early event during the progression pathway of ulcerative-colitis-related neoplasia. Am J Pathol, 1999. 154(6): p. 1825-30.
- Rabinovitch, P.S., et al., Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis. Cancer Res, 1999. 59(20): p. 5148-53.
- O'Sullivan, J.N., et al., Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet, 2002. 32(2): p. 280-4.
- Burmer, G.C., et al., Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. Gastroenterology, 1992. 103(5): p. 1602-10.
- Greenwald, B.D., et al., Loss of heterozygosity affecting the p53, Rb, and mcc/apc tumor suppressor gene loci in dysplastic and cancerous ulcerative colitis. Cancer Res, 1992. 52(3): p. 741-5.
- Yin, J., et al., p53 point mutations in dysplastic and cancerous ulcerative colitis lesions. Gastroenterology, 1993. 104(6): p. 1633-9.
- Kern, S.E., et al., Molecular genetic profiles of colitis-associated neoplasms. Gastroenterology, 1994. 107(2): p. 420-8.
- Thomas, H.J., The timing of p53 inactivation in chronic ulcerative colitis. Gastroenterology, 1993. 104(6): p. 1889-91.
- Fogt, F., et al., Comparison of genetic alterations in colonic adenoma and ulcerative colitis-associated dysplasia and carcinoma. Hum Pathol, 1998. 29(2): p. 131-6.
- Harpaz, N., et al., p53 protein expression in ulcerative colitis-associated colorectal dysplasia and carcinoma. Hum Pathol, 1994. 25(10): p. 1069-74.
- Yoshida, T., et al., Diverse p53 alterations in ulcerative colitis-associated low-grade dysplasia: full-length gene sequencing in microdissected single crypts. J Pathol, 2003. 199(2): p. 166-75.
- Chaubert, P., et al., K-ras mutations and p53 alterations in neoplastic and nonneoplastic lesions associated with longstanding ulcerative colitis. Am J Pathol, 1994. 144(4): p. 767-75.
- Klump, B., et al., Distribution of cell populations with DNA aneuploidy and p53 protein expression in ulcerative colitis. Eur J Gastroenterol Hepatol, 1997. 9(8): p. 789-94.
- Hussain, S.P., et al., Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res, 2000. 60(13): p. 3333-7.
- Lashner, B.A., et al., Evaluation of the usefulness of testing for p53 mutations in colorectal cancer surveillance for ulcerative colitis. Am J Gastroenterol, 1999. 94(2): p. 456-62.
- Maser, R.S. and R.A. DePinho, Connecting Chromosomes, Crisis, and Cancer. Science, 2002. 297(5581): p. 565-569.
- Rudolph, K.L., et al., Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet, 2001. 28(2): p. 155-9.
- Hande, M.P., et al., Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J Cell Biol, 1999. 144(4): p. 589-601.
- von Zglinicki, T., Role of oxidative stress in telomere length regulation and replicative senescence. Ann N Y Acad Sci, 2000. 908: p. 99-110.
- Loeb, K.R. and L.A. Loeb, Genetic instability and the mutator phenotype. Studies in ulcerative colitis. Am J Pathol, 1999. 154(6): p. 1621-6.
- Kinouchi, Y., et al., Telomere shortening in the colonic mucosa of patients with ulcerative colitis. J Gastroenterol, 1998. 33(3): p. 343-8.
- Gisselsson, D., et al., Abnormal nuclear shape in solid tumors reflects mitotic instability. Am J Pathol, 2001. 158(1): p. 199-206.
- Gisselsson, D., et al., Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc Natl Acad Sci U S A, 2001. 98(22): p. 12683-8.
- Brentnall, T.A., et al., Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis. Cancer Res, 1996. 56(6): p. 1237-40.
- Cravo, M.L., et al., Microsatellite instability in non-neoplastic mucosa of patients with ulcerative colitis: effect of folate supplementation. Am J Gastroenterol, 1998. 93(11): p. 2060-4.
- Wong, N.A., et al., Immunohistochemical assessment of Ki67 and p53 expression assists the diagnosis and grading of ulcerative colitis-related dysplasia. Histopathology, 2000. 37(2): p. 108-14.
- Habermann, J., et al., Ulcerative colitis and colorectal carcinoma: DNA-profile, laminin-5 gamma2 chain and cyclin A expression as early markers for risk assessment. Scand J Gastroenterol, 2001. 36(7): p. 751-8.
- Azarschab, P., et al., Epigenetic control of the E-cadherin gene (CDH1) by CpG methylation in colectomy samples of patients with ulcerative colitis. Genes Chromosomes Cancer, 2002. 35(2): p. 121-6.
- Itzkowitz, S.H., et al., Sialosyl-Tn antigen: initial report of a new marker of malignant progression in long-standing ulcerative colitis. Gastroenterology, 1995. 109(2): p. 490-7.
- Bruewer, M., et al., Metallothionein: early marker in the carcinogenesis of ulcerative colitis-associated colorectal carcinoma. World J Surg, 2002. 26(6): p. 726-31.
- Brandlein, S., et al., Cysteine-rich fibroblast growth factor receptor 1, a new marker for precancerous epithelial lesions defined by the human monoclonal antibody PAM-1. Cancer Res, 2003. 63(9): p. 2052-61.
- Sato, F., et al., Hypermethylation of the p14(ARF) gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res, 2002. 62(4): p. 1148-51.
- Sato, F., et al., Aberrant methylation of the HPP1 gene in ulcerative colitis-associated colorectal carcinoma. Cancer Res, 2002. 62(23): p. 6820-2.
- Ezaki, T., et al., A specific genetic alteration on chromosome 6 in ulcerative colitis-associated colorectal cancers. Cancer Res, 2003. 63(13): p. 3747-9.
- Habermann, J.K., et al., Pronounced chromosomal instability and multiple gene amplifications characterize ulcerative colitis-associated colorectal carcinomas. Cancer Genet Cytogenet, 2003. 147(1): p. 9-17.
- Mueller, E., et al., The differentiation of true adenomas from colitis-associated dysplasia in ulcerative colitis: a comparative immunohistochemical study. Hum Pathol, 1999. 30(8): p. 898-905.
- Fogt, F. and N. Alsaigh, Polypoid dysplasias in ulcerative colitis and sporadic adenomas: genetic approach to the differential diagnosis (review). Oncol Rep, 1999. 6(4): p. 721-5.
- Fogt, F., et al., Distinction between dysplasia-associated lesion or mass (DALM) and adenoma in patients with ulcerative colitis. Hum Pathol, 2000. 31(3): p. 288-91.
- Walsh, S.V., et al., P53 and beta catenin expression in chronic ulcerative colitis--associated polypoid dysplasia and sporadic adenomas: an immunohistochemical study. Am J Surg Pathol, 1999. 23(8): p. 963-9.
- Odze, R.D., et al., Genetic alterations in chronic ulcerative colitis-associated adenoma-like DALMs are similar to non-colitic sporadic adenomas. Am J Surg Pathol, 2000. 24(9): p. 1209-16.
- Torres, C., D. Antonioli, and R.D. Odze, Polypoid dysplasia and adenomas in inflammatory bowel disease: a clinical, pathologic, and follow-up study of 89 polyps from 59 patients. Am J Surg Pathol, 1998. 22(3): p. 275-84.
- Odze, R.D., Adenomas and adenoma-like DALMs in chronic ulcerative colitis: a clinical, pathological, and molecular review. Am J Gastroenterol, 1999. 94(7): p. 1746-50.
- Engelsgjerd, M., F.A. Farraye, and R.D. Odze, Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis. Gastroenterology, 1999. 117(6): p. 1288-94; discussion 1488-91.
- Sidransky, D., et al., Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors. Science, 1992. 256(5053): p. 102-5.
- Caldas, C., et al., Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res, 1994. 54(13): p. 3568-73.
- Traverso, G., et al., Detection of APC mutations in fecal DNA from patients with colorectal tumors. N Engl J Med, 2002. 346(5): p. 311-20.
- Traverso, G., et al., Detection of proximal colorectal cancers through analysis of faecal DNA. Lancet, 2002. 359(9304): p. 403-4.
- Keller, R., et al., Cytology and image cytometry after colonic lavage: a complementary diagnostic tool in patients with ulcerative colitis. Dig Liver Dis, 2003. 35(1): p. 24-31.
- Lang, S.M., et al., Molecular screening of patients with long standing extensive ulcerative colitis: detection of p53 and Ki-ras mutations by single strand conformation polymorphism analysis and differential hybridisation in colonic lavage fluid. Gut, 1999. 44(6): p. 822-5.
- Heinzlmann, M., et al., Screening for p53 and K-ras mutations in whole-gut lavage in chronic inflammatory bowel disease. Eur J Gastroenterol Hepatol, 2002. 14(10): p. 1061-6.
- Keller, R., et al., Density gradient centrifugation of colonic fluid after segmental lavage: a method of purification of exfoliative epithelial colonic cells for cytological interpretation and image cytometry in patients with long-standing ulcerative colitis. Am J Gastroenterol, 1999. 94(2): p. 404-9.