Neoplastic Progression In Ulcerative Colitis Research Articles

P042 Distinct gene expression profile associated to inflammation and neoplastic progression in longstanding ulcerative colitis

Abstract Background One of the main drivers of colitis associated colorectal cancer (CA-CRC) is suspected to be long-standing mucosal inflammation, but far from all colitis patients develop cancer. We analyzed mucosal gene expression profiles in ulcerative colitis (UC) patients who have progressed to neoplasia (progressors) compared to those who have not (non-progressors) in order to identify underlying mechanisms for neoplastic progression in UC patients. Methods We performed transcriptome profiling on 143 mucosal samples from non-neoplastic colon segments of 14 UC progressors and 30 UC non-progressors from the prospective CA-CRC cohorts from Lovisenberg Diakonale- and Akershus University Hospitals in Norway. Differentially expressed genes were determined using SurePrint G3 human gene expression 60K microarray (Agilent Tech Inc.). Results 609 genes were differentially expressed between non-progressor- and progressor inflamed tissue, 24 genes between non-progressor- and progressor non-inflamed tissue, 404 genes between non-progressor non-inflamed- and -inflamed tissue and 26 genes between progressor non-inflamed- and inflamed tissue. In inflamed mucosa, genes related to metabolic processes such as xenobiotic- as well as carbohydrate and lipid metabolism were significantly higher expressed in progressors compared to non-progressors. Genes related to innate and adaptive immune responses were expressed at significantly lower levels. These main traits were not influenced by type of inflammation but apparent in both, chronic- and chronic active inflammation. However, chronic inflamed mucosa of progressors were also characterised by dysregulation of processes related to chromatin organization. Treatment with immunomodulators and biologics were equally distributed in the groups. Restriction of the analysis to patients without treatment of these drugs did not significantly influence the main results. In non-inflamed mucosa, the gene expression profile of progressors and non-progressors were remarkably similar. In fact, within the positively and negatively enriched gene ontologies, only the gene S100P was significantly deregulated with a higher expression in non-inflamed mucosa of the progressors. Conclusion Upregulated detoxification as well as dysregulated immune response and chromatin organization may be underlying processes for neoplastic progression in ulcerative colitis. Our findings warrant further evaluation.

Differentially Deregulated MicroRNAs as Novel Biomarkers for Neoplastic Progression in Ulcerative Colitis.

Colorectal cancer (CRC) is a potentially life-threatening complication of long-standing ulcerative colitis (UC). MicroRNAs (miRNA) are epigenetic regulators that have been involved in the development of UC-associated CRC. However, their role as potential mucosal biomarkers of neoplastic progression has not been adequately studied. In this study, we analyzed the expression of 96 preselected miRNAs in human formalin-fixed and paraffin-embedded tissue of 52 case biopsies (20 normal mucosa, 20 dysplasia, and 12 UC-associated CRCs) and 50 control biopsies (10 normal mucosa, 21 sporadic adenomas, and 19 sporadic CRCs) by using Custom TaqMan Array Cards. For validation of deregulated miRNAs, we performed individual quantitative real-time polymerase chain reaction in an independent cohort of 50 cases (13 normal mucosa, 25 dysplasia, and 12 UC-associated CRCs) and 46 controls (7 normal mucosa, 19 sporadic adenomas, and 20 sporadic CRCs). Sixty-four miRNAs were found to be differentially deregulated in the UC-associated CRC sequence. Eight of these miRNAs were chosen for further validation. We confirmed miR-31, -106a, and -135b to be significantly deregulated between normal mucosa and dysplasia, as well as across the UC-associated CRC sequence (all P < 0.01). Notably, these miRNAs also confirmed to have a significant differential expression compared with sporadic CRC (all P < 0.05). UC-associated and sporadic CRCs have distinct miRNA expression patterns, and some miRNAs indicate early neoplastic progression.

Epigenetic biomarkers in progression from non-dysplastic Barrett's oesophagus to oesophageal adenocarcinoma: a systematic review protocol

IntroductionBarrett's oesophagus (BO), a metaplastic condition affecting the lower oesophagus due to long-standing gastro-oesophageal reflux and chronic inflammation, is a precursor lesion for oesophageal adenocarcinoma (OADC). There is no clinical...

Investigating Neoplastic Progression of Ulcerative Colitis with Label-Free Comparative Proteomics

Patients with extensive ulcerative colitis (UC) have an increased risk of colorectal cancer. Although UC patients generally undergo lifelong colonoscopic surveillance to detect dysplasia or cancer in the colon, detection of cancer in this manner is expensive and invasive. An objective biomarker of dysplasia would vastly improve the clinical management of cancer risk in UC patients. In the current study, accurate mass and time methods with ion intensity-based label-free proteomics are applied to profile individual rectal and colon samples from UC patients with dysplasia or cancer (UC progressors) compared to rectal samples from patients that are dysplasia/cancer free (UC nonprogressors) to identify a set of proteins in the rectum mucosa that differentiate the two groups. In addition to the identification of proteins in UC dysplastic colon tissue, we for the first time identified differentially expressed proteins in nondysplastic rectal tissue from UC progressors. This provides a candidate pool of biomarkers for dysplasia/cancer that could be detected in a random nondysplastic rectal biopsy. Mitochondrial proteins, cytoskeletal proteins, RAS superfamily, proteins relating to apoptosis and metabolism were important protein clusters differentially expressed in the nondysplastic and dysplastic tissues of UC progressors, suggesting their importance in the early stages of UC neoplastic progression. Among the differentially expressed proteins, immunohistochemistry analysis confirmed that TRAP1 displayed increased IHC staining in UC progressors, in both dysplastic and nondysplastic tissue, and CPS1 showed a statistically significant difference in IHC staining between the nonprogressor and progressor groups. Furthermore, rectal CPS1 staining could be used to predict dysplasia or cancer in the colon with 87% sensitivity and 45% specificity, demonstrating the feasibility of using surrogate biomarkers in rectal biopsies to predict dysplasia and/or cancer in the colon.

Abstract 4562: Alteration of mitochondrial proteome in neoplastic progression of ulcerative colitis

Abstract Patients with extensive ulcerative colitis (UC) have an increased risk of colon cancer. Current colonoscopic surveillance of these patients is expensive, time consuming, and invasive. An objective biomarker of dysplasia would aid the clinical management of cancer risk in UC patients. The purpose of this study is to investigate alterations in mitochondrial proteome during UC neoplastic progression to: 1) better understand the underlying mechanisms of neoplastic progression in UC; and 2) employ this knowledge for improved, more cost effective surveillance for UC cancer. Stable isotope labeling and tandem mass spectrometry were used to identify differential mitochondrial proteins associated with UC neoplastic progression. We identified 23, 31 and 32 mitochondrial proteins dysregulated in the colonic epithelium of UC non-progressors (UC patients who do not progress to dysplasia), and the non-dysplastic and dysplastic epithelium of UC progressors (UC patients who have dysplasia/cancer), respectively by at least 1.5-fold change. Nine of the mitochondrial proteins displayed gradually increasing dysregulation from UC non-progressor mucosa to UC progressor non-dysplastic mucosa and finally the worst changes were present in the dysplasia itself. One of the dysregulated mitochondrial proteins, carbamoyl-phosphate synthase 1 (CPS1) was further studied by immunohistochemistry (IHC) analysis. The expression level of CPS1 was significantly higher in UC progressors (in both dysplastic N=9 and non-dysplastic biopsies N=10) than non-progressors (N=29, P&amp;lt;0.003). If the IHC score of 1+ or higher was used as a cutoff, CPS1 could achieve 90% sensitivity and 59% specificity in distinguishing a rectal UC progressor non-dysplastic biopsy from a rectal UC non-progressor biopsy. To further evaluate the mechanism for mitochondrial protein changes in UC, a disease of chronic inflammation, we investigated protein oxidation and carbonylation of the mitochondria during UC neoplastic progression. Carbonyl-modified proteins in UC dysplastic biopsies were enriched using hydrazide-based chemistry and identified by proteomics analysis. We identified 19 carbonylated mitochondrial proteins in UC dysplasia. Several heat shock proteins were among these oxidized mitochondrial proteins. Oxidation of mitochondrial proteins can cause dysfunction of mitochondria, which may in turn contribute to neoplastic progression. In summary, we discovered that mitochondrial proteins are dysregulated in UC neoplastic progression and this is likely caused by chronic oxidation. The mitochondrial proteins become dysregulated early in tumorigenesis, with the changes present in non-dysplastic mucosa of patients with dysplasia. One of these proteins, CPS1, is significantly overexpressed in the normal appearing mucosa of UC progressors and may serve as a biomarker of dysplasia elsewhere in the colon. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4562.

Proteins that underlie neoplastic progression of ulcerative colitis

Patients with ulcerative colitis (UC) have an increased risk for developing colorectal cancer. Because UC tumorigenesis is associated with genomic field defects that can extend throughout the entire colon, including the non-dysplastic mucosa; we hypothesized that the same field defect will include abnormally expressed proteins. Here we applied proteomics to study the protein expression of UC neoplastic progression. The protein profiles of colonic epithelium were compared from 1) UC patients without dysplasia (non-progressors); 2) none-dysplastic colonic tissue from UC patient with high-grade dysplasia or cancer (progressors); 3) high-grade dysplastic tissue from UC progressors and 4) normal colon. We identified protein differential expression associated with UC neoplastic progression. Proteins relating to mitochondria, oxidative activity, calcium-binding proteins were some of interesting classes of these proteins. Network analysis discovered that Sp1 and c-myc proteins may play roles in UC early and late stages of neoplastic progression, respectively. Two over-expressed proteins in the non-dysplastic tissue of UC progressors, CPS1 and S100P, were further confirmed by IHC analysis. Our study provides insight into the molecular events associated with UC neoplastic progression, which could be exploited for the development of protein biomarkers in fields of non-dysplastic mucosa that identify a patient's risk for UC dysplasia.

Quantitative proteomics profiling of neoplastic progression of ulcerative colitis

Quantitative proteomics profiling of neoplastic progression of ulcerative colitis

Quantitative proteomics profiling of neoplastic progression of ulcerative colitis

Quantitative proteomics profiling of neoplastic progression of ulcerative colitis

Molecular profiling of ulcerative colitis-associated neoplastic progression

Fundamental differences exist between ulcerative colitis (UC)-associated and sporadic forms of colorectal cancer, including preexisting inflammation, type of dysplasia, and timing of molecular events in carcinogenesis. Transcriptional alterations that occur in UC-associated neoplasia in the progression from normal mucosa through dysplastic epithelium to invasive cancer have not been described. We used Affymetrix U95Av2 microarrays to assess differential gene expression in the neoplastic progression of UC tissue from the colonic mucosa of individuals with benign UC, UC-dysplasia-associated lesions or masses, and UC adenocarcinoma. By correlating transcript alterations across tissue types using a mixed statistical model, we identified 699 genes exhibiting altered expression with dysplasia development. A different expression profile was observed in progression to adenocarcinoma with 392 transcripts exhibiting differential expression. There were 224 transcripts common to both dysplasia and adenocarcinoma. Most of the differentially expressed genes described herein were not previously known to play a role in neoplastic progression in UC, including transcripts affecting cell proliferation and apoptosis, signal transduction and signaling, and DNA repair. The altered expression of five transcripts was confirmed by quantitative real-time reverse-transcription polymerase chain reaction. Based on comparisons with previous studies on sporadic colorectal carcinoma, several similarities were found. There were, however, important differences that suggest that different molecular events may occur in the development of UC-associated neoplasia. Several of these genes demonstrated similar changes in dysplastic and cancerous tissue and may be involved in early cancer formation. Identification of these genes as potential clinical biomarkers may lead to improved early disease diagnosis.

Preventing Neoplastic Progression in Ulcerative Colitis

Patients with ulcerative colitis (UC) and Crohn's colitis carry an increased risk for developing colorectal cancer (CRC). Patients with more extensive colitis, greater duration of disease, concomitant primary sclerosing cholangitis, and a family history of CRC are at greatest risk among UC patients. Young age at disease onset and greater inflammatory burden have also been proposed as risk factors. Maneuvers that limit the impact of cancer in colitis include prophylactic colectomy, which is unacceptable to most UC and Crohn's colitis patients, and dysplasia surveillance. Although recommended in a number of practice guidelines, surveillance has not yet been demonstrated to reduce CRC mortality or morbidity. A number of factors, including low levels of agreement among pathologists interpreting surveillance specimens, patients lost to follow-up, failure to recommend colectomy once dysplasia has been discovered, and others, hinder the success of surveillance. In an effort to compensate for the limitations of surveillance, chemoprevention and newer endoscopic and molecular techniques are being assessed for their effectiveness in augmenting or replacing conventional surveillance.

Preventing neoplastic progression in ulcerative colitis: Role of meaalamine

Preventing neoplastic progression in ulcerative colitis: Role of meaalamine

Promoter hypermethylation of the tumor suppressor gene p16/INK4A during neoplastic progression in ulcerative colitis

Promoter hypermethylation of the tumor suppressor gene p16/INK4A during neoplastic progression in ulcerative colitis

Mutations in the p53 gene: An early marker of neoplastic progression in ulcerative colitis

Background/Aims: In long-term extensive ulcerative colitis, aneuploidy occurs earlier and loss of heterozygosity for p53(p53 LOH) later during histological progression towards carcinoma. This study determined the time of onset of p53 mutation in this progression. Methods: We developed a rapid, sensitive screening assay for p53 mutations at codon 248. The geographic distribution of this p53 mutation was mapped in two fresh colectomy specimens with mutations of codon 248 (1 cancer, 1 dysplasia) and correlated with patterns of clonal expansion, histological progression, and allelic loss. Numerous samples from throughout both colons were analyzed (216 for histology, 142 for DNA content, 104 for mutation, and 41 for p53 LOH). Results: p53 mutation correlated highly with histological grade and was distributed more extensively than p53 LOH. Mutation, but not LOH, was also found in diploid, nondysplastic colonic mucosa adjacent to dysplastic areas. Conclusions: These findings suggest that p53 mutation appears to be an early genetic event that precedes p53 LOH. The very close correlation of p53 mutation with aneuploidy (P > 0.0001) emphasizes the role of normal p53 at the G1 checkpoint to help prevent entry of genetically damaged cells into the cell cycle.

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

Neoplastic progression in patients with chronic ulcerative colitis (UC) is characterized by the development of epithelial dysplasia, which is accompanied by genetic abnormalities that can be detected by flow cytometric and molecular biologic methods. Distribution of and correlation between histologic abnormalities, DNA content, and loss of heterozygosity for a p53 allele (p53 LOH) in the colons of nine UC patients were analyzed. Loss of a p53 allele was found in 85% (22/26) of biopsy specimens classified histologically as carcinoma, 63% (25/40) of biopsy specimens with high grade dysplasia, and 33% (7/21) of biopsy specimens with low grade dysplasia. Loss of heterozygosity for p53 was also found in 9% (5/57) of biopsy specimens indefinite for dysplasia and in 1/18 biopsy specimens negative for dysplasia, showing that this genetic change may occur early in the histological progression towards carcinoma. Aneuploid DNA contents were more common than p53 LOH in regions with negative, indefinite or low grade dysplastic histology; moreover, p53 LOH was detected only in aneuploid cells and not in diploid epithelium. Aneuploidy alone was not as specific a marker for the concomitant presence of dysplasia or carcinoma in a biopsy sample as aneuploidy combined with p53 LOH. These findings show that aneuploidy may precede both p53 LOH and epithelial dysplasia. Two UC patients' colons contained geographically separated clones of cells with different aneuploidies that also showed loss of different p53 alleles, suggesting that neoplasia may arise within different populations of cells in separate areas of the same colon.