Neoplastic progression in ulcerative colitis: Histology, DNA content, and loss of a p53 allele

Burmer, Glenna C.; Rabinovitch, Peter S.; Haggitt, Rodger C.; Crispin, David A.; Brentnall, Teresa A.; Kolli, Venkateswara R.; Stevens, Alexander R.; Rubin, Cyrus E.

doi:10.1016/0016-5085(92)91184-6

Cited by 267 publications

(148 citation statements)

References 20 publications

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“…The colectomy specimens were mapped histologically in a gridlike manner as previously described. 22 The biopsies were classified independently by two gastrointestinal pathologists (MPB and RCH) as negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, or invasive carcinoma. Histological criteria used were those defined by the Inflammatory Bowel Disease Dysplasia Morphology Study Group, with the exception that the indefinite category was not subdivided.…”

Section: Patients and Histologymentioning

confidence: 99%

The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

Agoff

Brentnall

Crispin

et al. 2000

The American Journal of Pathology

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Cyclooxygenase 2 (COX-2) overexpression has been described in sporadic colonic neoplasia, but its role in ulcerative colitis (UC) neoplastic progression remains unexplored. Although the specific role of cyclooxygenase in colonic neoplasia is uncertain, its inhibition by nonsteroidal anti-inflammatory drugs decreases the risk of sporadic colonic adenocarcinoma and causes regression of adenomas in familial adenomatous polyposis. To investigate the role of COX-2 in UC-associated neoplasia, we assessed COX-2 protein and mRNA expression throughout the spectrum of UC-associated neoplastic lesions in four total colectomy specimens, using immunocytochemistry and a novel TaqMan reverse transcriptase-polymerase chain reaction assay. The findings were correlated with DNA ploidy and inflammatory activity. We found COX-2 overexpression throughout the neoplastic spectrum in UC (P < 0.0001, R 2 ‫,)35.0؍‬ even in diploid samples that were negative for dysplasia. Overall, neoplastic change explained 53% of the variation in COX-2 expression, whereas inflammatory activity explained only 11%. COX-2 was overexpressed in all aneuploid samples and in 38% of diploid samples (P ‫؍‬ 0.0074). cDNA representational difference analysis was also performed and revealed that COX-2 mRNA was an up-regulated cDNA representational difference analysis difference product. COX-2 overexpression occurs early in UC-associated neoplasia, and the increase cannot be explained by inflammatory activity alone. The data suggest that COX-2-specific inhibitors may have a chemopreventative role in UC but the possibility that they could exacerbate UC inflammatory activity needs to be tested. Cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) are cyclooxygenase enzymes that convert arachidonic acid to inflammatory and other physiological mediators, including prostaglandins, prostacyclin, and thromboxane. 1,2 COX-1 is constitutively expressed in most tissues, including the gastrointestinal tract, at a relatively stable level and is thought to help protect the gastrointestinal tract from injury. 1,2 COX-2 is an inducible cyclooxygenase whose production is stimulated by interleukin-1, tumor necrosis factor, and many other mediators. 1,2 COX-2 is thought to play a role in the reparative process after mucosal injury in the gastrointestinal tract. 1,2 Multiple studies suggest that COX-2 plays a role in sporadic colorectal neoplasia, based on its overexpression in colonic adenomas and carcinomas, as shown by both immunohistochemistry and reverse transcriptasepolymerase chain reaction (RT-PCR). [3][4][5] Cyclooxygenase inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) substantially decrease the risk of colorectal cancer, as well as the number and size of adenomas in familial adenomatous polyposis patients. 6 -8 Experimentally, NSAIDs prevent colonic adenocarcinoma in rodents with an familial adenomatous polyposis phenotype (the APC min mouse model). 9,10 Understanding the role of COX-2 in colonic neoplasia is thus particularly important because of these t...

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Section: Patients and Histologymentioning

confidence: 99%

The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

Agoff

Brentnall

Crispin

et al. 2000

The American Journal of Pathology

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“…© 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from common methodology to observe ACF. Regarding the genetic abnormality of ACF, we found a highly frequent K-ras mutation and GSTP1-1 overexpression and also showed that GSTP1-1 endows ACF with resistance to bile salt -induced apoptosis (11 -13).With regard to the genetic abnormality of colitis-associated cancer and dysplasia, mutations of K-ras and APC are relatively rare (14 -17), and in contrast, p53 mutation is frequently positive (16,18,19). Moreover, hypermethylation of genes such as the p16 gene has recently been detected (20,21).…”

mentioning

confidence: 85%

“…With regard to the genetic abnormality of colitis-associated cancer and dysplasia, mutations of K-ras and APC are relatively rare (14 -17), and in contrast, p53 mutation is frequently positive (16,18,19). Moreover, hypermethylation of genes such as the p16 gene has recently been detected (20,21).…”

Section: Human Cancer Biologymentioning

confidence: 99%

Aberrant Crypt Foci as Precursors of the Dysplasia-Carcinoma Sequence in Patients with Ulcerative Colitis

Kukitsu¹,

Takayama²,

Miyanishi³

et al. 2008

Clinical Cancer Research

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Purpose: Long-standing ulcerative colitis (UC) predisposes patients to the development of colorectal cancer, but surveillance of colitis-associated cancer by detecting the precancerous lesion dysplasia is often difficult because of its rare occurrence and normal-looking appearance. In sporadic colorectal cancer, aberrant crypt foci (ACF) have been reported by many investigators to be precursor lesions of the adenoma-carcinoma sequence. In the present study, we analyzed the genetic background of ACF to determine whether they could be precursors for dysplasia, and we examined the usefulness of endoscopic examination of ACF as a surrogate marker for surveillance of colitis-associated cancer. Experimental Design: ACF were examined in 28 UC patients (19 patients with UC alone and 9 patients with UC and dysplasia; 2 of those patients with dysplasia also had cancer) using magnifying endoscopy. K-ras, APC, and p53 mutations were analyzed by two-step PCR RFLP, in vitro^synthesized protein assay, and single-strand conformation polymorphism, respectively. Methylation of p16 was analyzed by methylation-specific PCR. Results: ACF that appeared distinct endoscopically and histologically were identified in 27 out of 28 UC patients. They were negative for K-ras, APC, and p53 mutations but were frequently positive for p16 methylation (8 of 11; 73%). In dysplasia, K-ras and APC mutations were negative but p53 mutation (3 of 5; 60%) and p16 methylation (3 of 5; 60%) were positive. There was a significant stepwise increase in the number of ACF from patients with UC alone to patients with dysplasia and to patients with cancer. Univariate and multivariate analyses showed significant correlations between ACF and dysplasia. Conclusions: We have disclosed an ACF-dysplasia-cancer sequence in colitis-associated carcinogenesis similar to the ACF-adenoma-carcinoma sequence in sporadic colon carcinogenesis. This study suggests the use of ACF instead of dysplasia for the surveillance of colitis cancer and warrants further evaluation of ACF as a surveillance marker in large-scale studies.It is commonly recognized that long-standing ulcerative colitis (UC) predisposes patients to the development of colorectal cancer (1). However, the detection of early colorectal cancer is often difficult in patients with UC because there is inflammation in the background mucosa and it predominantly represents flat-type ill-delineated lesions (2, 3). Therefore, colitis-associated cancer is often detected at an advanced stage and is characterized by a very poor prognosis. One approach to overcome this difficulty is to use dysplasia, which is considered to be a precancerous lesion in colitis-associated cancer, as a surrogate marker for early detection of colitis-associated cancer (4, 5). However, identification of dysplasia by endoscopy requires greater skill than detection of cancer itself because of its rare occurrence and apparently normal-looking appearance (6).We previously succeeded in identifying aberrant crypt foci (ACF) in non-UC subjects using ...

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“…There is a relatively good correlation of aneuploidy with dysplasia since the percentage of DNA aneuploidy in non-dysplastic mucosa occurred in only 2.5-14.6% in other studies [23,24,37,35]. Detection of isolated aneuploidy reflects an increased risk for the development of dysplasia or the progression of dysplastic lesions [23,35,63,77]. Mutation in the APC gene occurs less frequently in CC than SCRC but since UC follows the process of clonal expansion this genetically aberrant but pre-neoplastic clone is more widespread and can be more easily detectable than histological dysplasia [24].…”

Section: Surveillancementioning

confidence: 99%

“…Loss of p53 is present in 89% of patients exhibiting DALM, 71% of patients with PSC, 35% of patients with pancolitis, and 9% of patients with left colitis [75]. The extent of LOH directly correlates with severity of neoplasia and gradually increases as UC stage becomes more prone to cancer development, as significant LOH occurs in 63% of patients with HGD and 33% with LGD [75,77]. Allelic loss in the p53 gene is an early molecular event in dysplasia/carcinoma and may be connected to malignant change and mutations closely correlate with aneuploidy that precedes dysplasia [12,28,30,55].…”

Section: Surveillancementioning

confidence: 99%

Ulcerative colitis and cancer

Kulaylat

Dayton

2010

Journal of Surgical Oncology

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Patients with ulcerative colitis (UC) are at an increased risk for the development of colorectal cancer (CRC). Unlike sporadic CRC, the cancer in UC patients arises from a focal or multifocal dysplastic mucosa in areas of inflammation. The clinical features of UC-associated cancer are similar to those found in patients with hereditary non-polyposis colorectal cancer. As with other varieties of CRC, UC-associated cancer exhibits a variety of genetic and molecular changes/abnormalities. These abnormalities are however clustered in areas of mucosae with histological abnormalities. The magnitude and timing of these changes are however significantly different. Surveillance and identification of patients at risk for cancer are a challenging problem.

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Neoplastic progression in ulcerative colitis: Histology, DNA content, and loss of a p53 allele

Cited by 267 publications

References 20 publications

The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

Aberrant Crypt Foci as Precursors of the Dysplasia-Carcinoma Sequence in Patients with Ulcerative Colitis

Ulcerative colitis and cancer

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