Ulcerative Colitis-associated Colorectal Carcinoma Research Articles

A novel ceRNA-immunoregulatory axis based on immune cell infiltration in ulcerative colitis-associated colorectal carcinoma by integrated weighted gene co-expression network analysis

BackgroundPatients with ulcerative colitis are at an increased risk of developing colorectal cancer with a prolonged disease course. Many studies have shown that alterations in the immune microenvironment play a key role in ulcerative colitis-associated colorectal cancer. Additionally, competing endogenous RNAs have important functions in immunoregulation, affecting inflammation and tumorigenesis. However, the complexity and behavioral characteristics of the competing endogenous RNA immunoregulatory network in ulcerative colitis-associated colorectal cancer remain unclear. We constructed a competing endogenous RNA immunoregulatory network to discover and validate a novel competing endogenous RNA immunoregulatory axis to provide insight into ulcerative colitis-associated colorectal cancer progression.MethodsThe competing endogenous RNA immunoregulatory network was constructed using differential expression analysis, weighted gene co-expression network analysis, and immune-related genes. Cmap was used to identify small-molecule drugs with therapeutic potential in ulcerative colitis-associated colorectal cancer. The ulcerative colitis-associated colorectal cancer-related pathways were identified by gene set variation and enrichment analysis. CIBERSORT, single-sample Gene Set Enrichment Analysis, and xCell were used to evaluate the infiltration of immune cells and screen hub immunocytes. The competing endogenous RNA immunoregulatory axis was identified by correlation analysis.ResultsWe identified 130 hub immune genes and constructed a competing endogenous RNA immunoregulatory network consisting of 56 long non-coding RNAs, four microRNAs, and six targeted hub immune genes. Four small-molecule drugs exerted potential therapeutic effects by reversing the expression of hub immune genes. Pathway analysis showed that the NF-κB pathway was significantly enriched. Neutrophils were identified as hub immunocytes, and IL6ST was significantly positively correlated with the neutrophil count. In addition, NEAT1 may serve as a competing endogenous RNA to sponge miR-1-3p and promote IL6ST expression.ConclusionsThe competing endogenous RNA immunoregulatory axis may regulate neutrophil infiltration, affecting the occurrence of ulcerative colitis-associated colorectal cancer.

Molecular characterization of ulcerative colitis-associated colorectal carcinomas.

Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). In contrast to sporadic colorectal tumorigenesis, TP53 mutations occur early in the progression from inflamed colonic epithelium to dysplasia to CRC, and are sometimes readily detectable in inflamed, (yet) non-dysplastic mucosa. Here, we analyzed formalin-fixed paraffin-embedded tissue samples from 19 patients with long-standing UC (median 18 years, range 3 to 34) who had developed CRC as a consequence of chronic inflammation of the large bowel. We performed microsatellite instability testing, copy number analysis by array-based comparative genomic hybridization, mutation analysis by targeted next generation sequencing (48-gene panel) and TP53 immunostaining. The results were compared to The Cancer Genome Atlas (TCGA) data on sporadic CRC. All UC-CRC lesions in our cohort were microsatellite stable. Overall, genomic imbalances of UC-CRCs showed patterns of chromosomal aneuploidies characteristic for sporadic CRC with the exception of gains of chromosome arm 5p (12 of 23 UC-CRC, 52%), which are rare in sporadic CRCs from TCGA (21 of 144, 15%; FDR adjusted P = 0.006). UC-CRCs showed a predilection for TP53 alterations, which was the most frequently mutated gene in our cohort (20 of 23, 87%). Interestingly, spatially separated tumor lesions from individual patients tended to harbor distinct TP53 mutations. Similar to CRCs arising in a background of Crohn’s colitis, the genetic landscape of UC-CRCs was characterized by TP53 mutations and chromosomal aneuploidies including gains of chromosome arm 5p. Both alterations harbor the potential for early detection in precursor lesions, thus complementing morphologic diagnosis.

A Seven-NF-κB-Related Gene Signature May Distinguish Patients with Ulcerative Colitis-Associated Colorectal Carcinoma.

PurposeUlcerative colitis (UC) patients have an increased risk of colorectal cancer (CRC), and compared with sporadic CRC, ulcerative colitis-associated colorectal cancer (CAC) is more aggressive with a worse prognosis. This study aimed to identify a gene signature to predict the risk of CAC for patients with UC in remission.Patients and MethodsSeries of quiescent UC-related transcriptome data obtained from the Gene Expression Omnibus (GEO) data set were divided into a training set and a validation set. Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and \\Weighted Correlation Network Analysis (WGCNA) combined with protein–protein interaction (PPI) analysis were used to identify the pathways and gene signatures related to tumorigenesis among quiescent UC patients. A generalized linear model (GLM) of Poisson regression based on the training set was applied to estimate the diagnostic power of the gene signature in our validation set.ResultsThe tumor necrosis factor (TNF) signaling via NF-κB pathway was significantly augmented with the highest normalized enrichment score (NES). The genes in the brown module from WGCNA have shown a significant correlation with CAC (Pearson coefficient = 0.83, p = 6e-06). A subset of NF-κB related genes (FOS, CCL4, CXCL1, MYC, CEBPB, ATF3, and JUNB) were identified with a relatively higher expression level in CAC samples. The diagnostic value of this 7-gene biomarker was estimated by the receiver operating characteristic (ROC) curve with an area under the ROC curve (AUC) at 0.82 (p<0.0001, 95% CI: 0.7098–0.9400) in the validation cohort.ConclusionIn summary, the increased expression of this seven-NF-κB-related gene signature may act as a powerful index for tumorigenesis prediction among patients with UC in remission.

Abstract 1053: Potential utility of DNA methytlation as a biomarker for prediction of ulcerative colitis associated colitic cancer (UCAC)

Abstract Background: Patients with Ulcerative colitis (UC) have more increased risk for the development of colorectal cancers compared with the average-risk population. Methods or strategies other than intensive colonoscopic surveillance to diagnose ulcerative colitis-associated colorectal carcinoma (UCAC) at early stage are limited. DNA methylation is deeply involved in carcinogenesis in many tumor types and its potential utility as a biomarker has been suggested. Aim: To evaluate potential utility of DNA methylation as the risk marker for UCAC, we quantified DNA methylation of inflamed rectal mucosa, neoplastic tissue and adjacent colonic mucosa of UC patients. Method: Inflamed rectal mucosa (n = 84) and normal appealing proximal mucosa (n = 10) of 84 cancer-free UC patients were examined. Neoplastic tissue (n = 33) and adjacent colonic mucosa (n = 26) from 16 UC patients with neoplasia (UCAC or DALM) were also studied. Bisulfite pyro sequencing was performed for the quantification of 45 cancer or age-related candidate panels and LINE1 repetitive element. Illumina Infinium Human Methylation 450 platform was also used to determine 470,000 CpG sites distributed across the genome. Results: Inflamed mucosa in UC was characterized as hyper methylation in candidate panels using the helical unsupervised clustering. In several panels, hyper methylation was associated with severe clinical phenotypes including steroid dependent, refractory, longstanding severe inflammation etc. (DPYS and miR-1247: p&amp;lt;0.05. GSTP1: p&amp;lt;0.01. mean of three: p&amp;lt;0.0001). Notably, in many panels, hyper methylation was significantly associated with longer duration of disease in cancer-free patients. Among them, some panels showed hyper methyhlation in both neoplastic and adjacent tissue compared to rectal mucosa of cancer-free cases (DPYS and N33, both p values &amp;lt;0.0001). Genome scale analysis revealed that UC with severe inflammation or neoplasia was characterized as hyper methylation at CpG sites rather than outside CpG sites. Gene ontology analysis demonstrated frequently methylated promoter CpG sites in these cases frequently encoded protein related to biosynthetic process (Fold enrichment: 2.07. p value using Benjamini correction: 5.69E-05). Conclusion: Hyper methylation at CpG sites of non-neoplastic colonic mucosa in UC with severe inflammation and neoplasia suggested the potential utility of DNA methytlation as a biomarker for prediction of UCAC. Moreover, enrichment of specific pathway in methylated genes suggests the possibility of targeting therapy for treating UCAC. Citation Format: Tomomitsu Tahara, Naoko Nakano, Mitsuo Nagasaka, Yoshihito Nakagawa, Tomoyuki Shibata, Naoki Ohmiya, Ichiro Hirata. Potential utility of DNA methytlation as a biomarker for prediction of ulcerative colitis associated colitic cancer (UCAC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1053. doi:10.1158/1538-7445.AM2015-1053

HLA-DRB1*13:01 allele in the genetic susceptibility to colorectal carcinoma.

Increasing evidence suggests that HLA-DRB1 alleles reduce or increase the risk of developing ulcerative colitis-associated colorectal carcinoma (CRC) tumors. However, the role of HLA-DRB1 locus on the susceptibility to develop CRC tumor, in the absence of a history of inflammatory bowel diseases (IBDs), is unclear. The aim of our study was to determine whether HLA-DRB1 alleles are associated with IBD-independent CRC tumor. HLA-DRB1 allele polymorphisms were identified by sequence-based typing method in 53 CRC patients and 57 sex- and age-matched healthy Caucasian controls. Pearson's chi-squared analysis with Yate's correction or Fisher's exact test with Bonferroni's correction, as appropriate, were used to compare the allele frequency (AF) differences of HLA-DRB1 in patients and controls. A total of 29 HLA-DRB1 alleles were recognized. A detailed study of these alleles allowed to identify DRB1*13:01 and DRB1*11:01 alleles that were significantly associated with an increased and reduced risk to develop CRC tumor, respectively. AF of DRB1*13:01, in CRC patients, was significantly higher than that of healthy controls, even following Bonferroni's correction (p = 0.029). In contrast, the presence of the DRB1*11:01 allele was negatively associated with CRC tumor as evidenced by the significantly lower AF in CRC patients than that of healthy controls (p = 0.005). However, following Bonferroni's correction, the AF of DRB*11:01 lost its statistical significance. These results suggest that HLA-DRB1*13:01 allele could be a potential marker for predicting genetic susceptibility to CRC tumor. In contrast, the protective role of DRB1*11:01 remains unclear.

Mechanisms underlying development of ulcerative colitis-associated colorectal carcinoma

Mechanisms underlying development of ulcerative colitis-associated colorectal carcinoma

Synchronous multifocal colorectal carcinoma in a patient with delayed diagnosis of ulcerative pancolitis

Patients with ulcerative colitis face an increased lifetime risk of developing colorectal cancer. Relatively often, the patients present with multiple synchronous or metachronous tumors. Here, we report a case of ulcerative colitis-associated synchronous multifocal colorectal carcinomas. A 36-year-old male presented with symptoms of persisting abdominal pain that had lasted for several months. Histology of the colonic biopsies showed active ulcerative pancolitis with extensive multifocal low- and high-grade dysplasia. Regardless of the diagnosis and medical advice, the patient initially refused therapy, and proctocolectomy was delayed for 12 months. In the resection specimen, four clinically unsuspected, partly mucinous adenocarcinomas accompanied by several foci of low- and high-grade dysplasia were found in the left colon and rectum. At the time of colectomy, advanced tumor stage was diagnosed and classified as pT3c(4) pN1(2/120) M0 V1 R0, UICC stage IIIB, G2. Furthermore, a mucinous cystadenoma was found in the appendix in the setting of ulcerative colitis. We discuss the neoplastic transformation, current surveillance guidelines, and the therapeutic management in ulcerative colitis.

Is colonoscopy alone sufficient to screen for ulcerative colitis-associated colorectal carcinoma?

Patients with ulcerative colitis (UC) are at increased risk for colorectal carcinoma (CAC). Despite the fact that patients at risk are followed closely by colonoscopy to screen for dysplasia, the prevalence of CAC is still unacceptably high. The aim of this study was to evaluate the prevalence of risk factors for CAC, such as dysplasia, and to determine the relevance of colonoscopic surveillance in the group who went on to develop cancer. A series of 24 patients with UC were diagnosed with CAC. The patients' records were analyzed retrospectively for duration of UC, prevalence of preoperative dysplasia, and other cancer risk factors (CRFs) (e.g., pancolitis, primary sclerosing cholangitis, early onset of UC, and backwash ileitis). The mean age of the patients at the time of cancer diagnosis was 43 years with an average UC duration of 15 years (6 patients had had UC less than 8 years). CAC was identified preoperatively by colonoscopy in 15 of 24 patients, with an additional 7 of 15 showing flat dysplasia. Five of nine patients without preoperatively diagnosed CAC had flat dysplasia. Overall, 19 patients had additional CRFs, most of them with at least two more CRFs. Despite a regular colonoscopic follow-up for most patients with UC, flat dysplasia was missed in 12 patients preoperatively. Therefore we suggest that patient information should also always include surgical options in each case where significant cancer risk factors are found.

Metallothionein: early marker in the carcinogenesis of ulcerative colitis-associated colorectal carcinoma.

Metallothioneins (MTs) are zinc-binding proteins whose overexpression may lead to sequestration of zinc ions and consequently to functional inactivation of the p53 tumor suppressor gene. The aim of the study was to investigate the potential role of MTs in the carcinogenesis of ulcerative colitis (UC) as well as possible effects on p53 function. The monoclonal antibodies E9 (anti-MT), DO-7, and 1801 (anti-p53) and the polyclonal antibody CM-1 (anti-p53) were used to stain formalin-fixed, paraffin-embedded colon specimens obtained from 14 patients with UC-associated colorectal carcinoma (CAC), 13 with high-grade dysplasia (HGD), 10 with low-grade dysplasia (LGD), and 30 with UC without dysplasia or carcinoma. Statistical significance (p <0.05) was assessed using Fisher's exact test. Positive MT staining (> 20% of tumor, dysplastic, or epithelial cells) was found in most UC and LGD but in only a small percentage of HGD and CAC (p <0.01 for CAC vs. UC and LGD vs. HGD). Positive p53 immunoreactivity was observed predominantly in HGD and CAC but not in LGD and UC (p <0.01 for CAC vs. UC and HGD vs. LGD). In histologically normal tissue neighboring CAC, significant MT expression was found in six of seven specimens with simultaneous lack of p53 expression. MT overexpression may represent an important early step in the development of CAC independent of p53 expression and should be investigated in the long term as an independent cancer risk factor in UC.

Immunohistochemical expression of P53 and oncogenes in ulcerative colitis-associated colorectal carcinoma.

The role of the tumor suppressor gene p53 and proto-oncogenes mdm-2, waf-1,and bcl-2 in sporadic colorectal carcinoma (CRC) has been well investigated. However, little is known about the role of these genes in the development of ulcerative colitis-associated colorectal carcinoma (CAC). Colectomy specimens from patients with CAC, patients with ulcerative colitis (UC) and dysplasia, patients with long-standing UC without carcinoma or dysplasia, and patients with CRC were investigated in comparison to normal colon (NC) specimens from patients with diverticulosis without histologic signs of inflammation. Immunohistochemistry was performed with antibodies against p53, mdm-2, waf-1, and bcl-2; and staining was evaluated semiquantitatively with an expression of more than 20% of tumor cell nuclei or epithelial cell nuclei in nontumor specimens considered "positive." Statistical analysis was performed using Fisher's exact test. In carcinomas, p53 was positive in 50% of CRC tissues and 60% of CAC tissues without statistical difference. Positive expression of p53 was found in most high-grade dysplasia but not in low-grade dysplasia (p < 0.01). Whereas mdm-2 and bcl-2 were only sporadically expressed, waf-1 was observed in most specimens, with a high prevalence in UC without carcinoma or dysplasia (11/15). NC specimens were always negative for all antibodies. Immunohistochemical expression of p53, mdm-2, waf-1, and bcl-2 is similar for CAC and CRC. The malignant potential of dysplasia in UC is partially confirmed by a high prevalence of p53 and waf-1 expression, suggesting that CAC may develop along pathways that are different from CRC. High expression of waf-1 in nonmalignant long-standing UC has to be proved over a long-term course in its role as an independent cancer risk factor in UC patients.

Ulcerative colitis and colorectal carcinoma: DNA-profile, laminin-5 gamma2 chain and cyclin A expression as early markers for risk assessment.

Ulcerative colitis patients are at increased risk for developing colorectal carcinomas. Despite expensive surveillance programmes, clinical practice reflects an uncertainty in individual risk assessment. The aim of the study was to evaluate independent cellular features with possible predictive value. Two patient groups were selected: group A comprised 8 patients with ulcerative colitis-associated colorectal carcinomas, group B comprised 16 ulcerative colitis patients with risk factors (duration of disease, extent of inflammation, epithelial dysplasias). A total of 683 paraffin-embedded mucosal biopsies were retrospectively evaluated for inflammatory activity, grade of dysplasia, ploidy status, laminin-5 gamma2 chain and cyclin A expression. Mild or moderate inflammatory activity was present in 78% of all biopsies, low- or high-grade dysplasia in 5.5%. There was no difference in inflammatory activity and dysplasia between patient groups. In group A, 75% of the biopsies exhibited aneuploid DNA distribution patterns. Group B showed mainly proliferative-diploid cell populations (85% / P = 0.006). Laminin-5 gamma2 chain was expressed in 13% of all biopsies, with a higher frequency in group A (P = 0.002). Cyclin A expression was found in 98% of all biopsies, with a higher number of immunopositive cells in group A biopsies (P = 0.014). Combined nuclear DNA assessment, laminin-5 gamma2 chain and cyclin A expression may help to identify ulcerative colitis patients with an increased risk for cancer development.

Ulcerative colitis-associated colorectal carcinoma. DNA ploidy as indicator of impending malignant transformation?

The onset of a malignant transformation in long-standing ulcerative colitis is difficult to predict. The value of the clinical and histomorphological parameters in current use is limited. It was thus aim of the present study to investigate the value of DNA-ploidy for the early detection of a malignant transformation in long-standing ulcerative colitis. This retrospective study comprised 20 patients with long-standing ulcerative colitis. The average observation time was 7.3 years (range: four to twelve years). All patients took part in a surveillance program and had between four and seven colonoscopies within a minimum period of time of five years. At these instances mucosal biopsies were taken in a standardized manner at eight different locations throughout the colon. These paraffin-embedded specimens (n = 542) were analyzed histomorphologically and DNA-cytometrically. During the observation time five patients developed an ulcerative colitis-associated colorectal carcinoma (UCA). In these patients epithelial dysplasias were not more common than in the remaining 15 cases. The vast majority of the specimen of the patients with UCA showed distinct DNA-cytometrical alterations, i.e. they were aneuploid. Such aneuploid mucosal cell populations were distributed over the whole colon, irrespectively of the later site of the carcinoma. These aneuploid lesions were found in one case eleven years, in an average seven years prior to the final diagnosis of a UCA. In contrast, the colon epithelium of the patients without UCA showed only proliferative-diploid DNA-distribution patterns during the observation time. In summary, affected patients had multiple highly aneuploid lesions of the colon mucosa at an average of seven years prior to the final diagnosis of UCA. These lesions came from macroscopically chronic inflamed tissue, and where histomorphologically without signs of dysplastic transformation. DNA-cytometrical investigations could thus be of additional predictive value for the individual risk assessment as regards an impending malignant transformation.

Is dysplasie surveillance effective in the prevention of ulcerative colitis-associated colorectal carcinoma?

Is dysplasie surveillance effective in the prevention of ulcerative colitis-associated colorectal carcinoma?

Metallothionein—An early marker in the carcinogenesis of ulcerative colitis-associated colorectal carcinoma

A variety of imaging modalities have been developed to determine the characteristics of tumors in the colon. Endoscopic ultrasonography has been applied clinically to stage the depth of invasion of colon cancers and more recently, optical coherence tomography has been developed in the laboratory to increase imaging of the mucosal surface. We have initiated the first application of ultrasound modulated laser tomography to colonic tumors. This technique has the advantage of combining ultrasound and light to characterize tissue. Methods: The principle behind this technique is to use ultrasound waves to modulate laser light passing through a tissue. The modulated laser light can then be detected and amplified to generate a signal that is characteristic of that tissue. The system we used consists of a helium-neon laser to generate a 632-nm beam, which is focused on the tissue. A function generator is used to create a sinusoidal wave at I MHz, which is amplified to drive an ultrasound transducer placed perpendicular to the tissue. The signal is detected by a photodiode, which converts the modulated light to a current, which can be filtered using the current from the function generator. The time domain signal can then be processed and displayed. Results: The following graphs display the signal taken from 8 resected normal colon tissue and colon cancers. The X-axis represent wavelength while the Y-axis represents absorption in AU. The graph on the right represents colon cancer while the graph on the left represents the modulated signal from normal colon. The most prominant difference was noted between two samples at wave length of 350 nm. Conclusions: The signal received from ultrasound modulated optical tomography appears to differentiate between colonic cancer and normal tissue. This tool may be 6283

P53 immunohistochemistry of ulcerative colitis-associated with dysplasia and carcinoma.

In order to evaluate the usefulness of p53 immunohistochemistry (IHC) in the diagnosis of ulcerative colitis-associated colorectal carcinoma (UCACRC), ordinary paraffin sections were examined in 61 cases with ulcerative colitis (UC) and 29 control cases without UC. Among the 61 cases with UC, 11 were complicated by carcinoma coexisting with dysplasia, three with dysplasia, and two cases with adenoma. There were a total of 38 dysplasias, including 33 low grade dysplasias (LGD) and five mixed low and high grade dysplasias (LGD + HGD). The results of p53 IHC were divided into diffuse, nested, scattered and sporadic patterns for 29 control cases. Diffuse and nested patterns were presumed to reflect mutant forms of p53 protein and were defined as overexpression of p53 protein. In non-neoplastic mucosa of UC, the frequency of p53 positive tubules was significantly higher in active phase (13.5-17.9%) than in resolving phase (3.9-6.5%) and in remission (0.7-2.4%), regardless of association with neoplasia. Eight of the 37 lesions of dysplasia (21. 6%) showed p53 overexpression: 12.5% in LGD and 80.0% in LGD + HGD. The rate of p53 overexpression was significantly higher in UCACRC (90.9%) than in non-neoplastic mucosa of UC (0%), LGD and sporadic colorectal carcinoma (54.5%), but it did not differ between UCACRC and LGD + HGD. Interestingly, the mucosa without dysplasia showed p53 overexpression in one case of UCACRC. The biopsy specimen taken 4 years before the diagnosis of carcinoma revealed p53 overexpression in another case with UCACRC. These results suggest that p53 abnormalities play an important role in UC-associated tumorigenesis in its relatively early phase. For the diagnosis of dysplasia and carcinoma in UC, p53 IHC seems to be useful.

P53 expression in ulcerative colitis

p53 Mutation is a late event in the development of sporadic colorectal carcinoma (CRC). The timing of p53 mutations in the development of ulcerative colitis associated colorectal carcinoma (UCACRC) is, however, less certain and some reports suggest that it may be a relatively early event. This study sought to establish the timing of p53 mutations in neoplasia arising in ulcerative colitis. Blocks of 10 resected colorectal specimens from patients who had had a biopsy positive for dysplasia at least one year prior to resection were retrieved from the archives of St Mark's Hospital. Immunochemistry using the monoclonal antibody DO-7, specific for both mutant and wild type p53, was performed on sections from both the resection specimens and dysplastic biopsy specimens. Seven of the 10 resection specimens were positive for p53. Two of these seven specimens showed p53 overexpression in specimens taken two years before the development of carcinoma or high grade dysplasia. Five of the seven specimens were negative for p53 overexpression between one and four years prior to resection. These results suggest that p53 overexpression is usually a late event in the development of UCACRCs.

P53 expression in ulcerative colitis: a longitudinal study.

p53 Mutation is a late event in the development of sporadic colorectal carcinoma (CRC). The timing of p53 mutations in the development of ulcerative colitis associated colorectal carcinoma (UCACRC) is, however, less certain and some reports suggest that it may be a relatively early event. This study sought to establish the timing of p53 mutations in neoplasia arising in ulcerative colitis. Blocks of 10 resected colorectal specimens from patients who had had a biopsy positive for dysplasia at least one year prior to resection were retrieved from the archives of St Mark's Hospital. Immunochemistry using the monoclonal antibody DO-7, specific for both mutant and wild type p53, was performed on sections from both the resection specimens and dysplastic biopsy specimens. Seven of the 10 resection specimens were positive for p53. Two of these seven specimens showed p53 overexpression in specimens taken two years before the development of carcinoma or high grade dysplasia. Five of the seven specimens were negative for p53 overexpression between one and four years prior to resection. These results suggest that p53 overexpression is usually a late event in the development of UCACRCs.

P53 protein expression in ulcerative colitis-associated colorectal dysplasia and carcinoma

The frequency and timing of p53 inactivation in ulcerative colitis (UC)-associated tumorigenesis were investigated using immunohistochemistry (IHC) to detect p53 protein overexpression in 56 carcinomas and 40 dysplastic epithelia derived from 58 patients with UC undergoing colectomy for neoplasia. p53 DNA in 25 of the carcinomas also was evaluated by single-strand conformation polymorphism analysis (SSCP) to detect point mutations in exons 5–8 and by loss of heterozygosity analysis to detect allelic deletions. Point mutations were detected in 20 of the 25 carcinomas (80.0%) undergoing both IHC and DNA analysis. One carcinoma contained an allelic deletion but no mutations of the corresponding allele within the region tested. p53 overexpression occurred in 16 (76.2%) of the 21 carcinomas with point mutations and/or allelic deletions but not in any of those with wild type DNA. Of the 56 carcinomas evaluated by IHC, p53 overexpression occurred in 34 carcinomas (60.7%). The proportion of positive tumors was independent of stage, anatomic location, differentiation, and histological subtype. Overexpression was observed in nine of 20 dysplastic masses devoid of and situated remote from carcinoma (45.0%) and correlated positively with increasing grade of dysplasia ( P < .025). In contrast, overexpression occurred in 16 of 20 dysplastic epithelia situated adjacent to carcinoma (80.0%) and correlated with overexpression by the corresponding carcinomas but not with the grade of dysplasia present ( P = .013). It is concluded that p53 overexpression can be detected by IHC in most, although not all, UC-associated carcinomas with p53 mutations and/or allelic deletions. Based on this method, p53 overexpression occurs frequently in UC-associated carcinomas regardless of stage and pathological characteristics, in noncancerous dysplastic masses with high grade dysplasia, and in dysplasias of all grades situated adjacent to carcinomas. These findings implicate p53 inactivation in the progression from dysplasia to carcinoma in UC and suggest that its occurrence in dysplastic epithelium may be an independent marker of malignant potential.