p53 protein expression in ulcerative colitis-associated colorectal dysplasia and carcinoma

doi:10.1016/0046-8177(94)90067-1

Human Pathology

Volume 25, Issue 10, October 1994, Pages 1069-1074

https://doi.org/10.1016/0046-8177(94)90067-1 Get rights and content

Abstract

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.

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Traditional serrated adenoma-like lesions in patients with inflammatory bowel disease: Serrated dysplasia in IBD
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Abnormal p53 expression was present in 48% of these lesions and in 70% of those with high-grade serrated dysplasia. These results are in agreement with previous studies reporting p53 overexpression in 22% to 45% of all IBD-associated dysplastic lesions and up to 80% of high-grade lesions and IBD-associated CRCs [28,29]. In sporadic TSA, p53 overexpression has been reported in advanced lesions with superimposed dysplasia but was rare in ordinary TSAs [15,30,31].
Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal carcinoma. The significance of serrated lesions resembling traditional serrated adenoma (TSA) in IBD patients is unclear. In this retrospective study, we analyzed 52 TSA-like lesions arising in 30 IBD patients and diagnosed in colectomy or endoscopic specimens. The 27 colectomy lesions presented predominantly as ill-defined areas with granular appearance, with a median size of 15 mm, located throughout the large bowel and associated with synchronous advanced colorectal lesions in 58%. Low-grade serrated dysplasia was present in 56%, high-grade serrated dysplasia in 37%, and TSA-type cytology in 7%. Increased Ki-67 immunostaining and abnormal p53 expression were identified in 96% and 48%, respectively; 74% had a KRAS mutation, and 4% had a BRAF mutation. Endoscopically resectable TSA-like lesions were all discrete polypoid lesions, smaller in size (median 9 mm), predominantly in the distal large bowel, with an adjacent precursor polyp in 24%, and associated with synchronous and metachronous advanced colorectal lesions in 6%. Most (92%) show TSA-type cytology. p53 overexpression was present in 4%, KRAS mutation in 41%, and BRAF mutation in 32%. None of the 52 TSA-like lesions demonstrated loss of MLH1 or SATB2 expression by immunohistochemistry. On follow-up, 4 patients were diagnosed with colorectal carcinoma or high-grade adenomatous IBD-associated dysplasia. None of the patients with lesions showing TSA-type cytology only developed an advanced lesion. Our findings suggest that some TSA-like lesions, essentially from colectomy, may represent a form of IBD-associated dysplasia associated with an increased risk of advanced neoplasia.
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Although various studies have been conducted on colitis-associated cancer (CAC), few have assessed the differences in the clinical and endoscopic features, treatment, and prognosis of CAC and sporadic neoplasia (SN) in the inflamed mucosa of ulcerative colitis (UC) patients.
To compare the characteristics of CAC and SN within the previously or currently inflamed mucosa.
Between 1997 and 2017, we retrospectively analyzed the endoscopic chart data of 348 colonic lesions from 266 UC patients. Non-dysplastic lesions and lesions located outside the inflamed mucosa were excluded. The diagnosis of CAC or SN was confirmed by conventional histopathological and immunohistochemical evaluation of p53 and Ki67.
In total, 74 patients with CAC (97 lesions) and 46 with SN (58) were enrolled. The proportions of patients with a younger age of onset of UC, with chronic persistent UC, and with severe inflamed mucosa were significantly higher in the CAC group. In the SN group, no flat lesions were found, whereas 26% of the lesions in the CAC group were flat. Sixteen patients died during a median follow-up of 6.1 years (interquartile range (IQR) 1.8–11.1)in the CAC group, whereas 1 patient died during a median follow-up 3.2 years(IQR 1.4–4.6) in the SN group. Mortality from colorectal cancer was significantly higher (P = 0.015) in the CAC group (12/68; 17.6%) than in the SN group (1/44; 2.3%). The 5-year survival rate was 100% in the SN group and 97% in the CAC group for lesions located in the mucosa or submucosa.
Recognizing differences in the characteristics of CAC and SN within the inflamed mucosa is critical to avoid unnecessary total colectomy in patients with SN.
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In a population-based study of patients in Denmark with IBD and SBC, we found risk of adenocarcinomas and neuroendocrine tumors to be increased among persons with Crohn’s disease. Most patients with IBD-SBC had extensive IBD of moderate-to-severe activity. Adenocarcinomas appeared to develop via an inflammation-dysplasia-carcinoma pathway, but differed from IBD-related colorectal adenocarcinomas in their molecular features.
The molecular landscape of colitis-associated carcinogenesis
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In UC patients, telomere shortening has been documented in mucosa adjacent to dysplasia and cancer, and it has been detected more frequently in patients who subsequently develop cancer [57,58]. In contrast with the late involvement of TP53 dysregulation in sporadic colon carcinogenesis, seminal mutational profiling and LOH studies addressing IBD-associated oncogenesis have consistently pinpointed TP53 mutations and TP53 gene locus loss as early molecular changes already underway in intraepithelial neoplastic lesions [59–65]. TP53 mutations have also been observed in non-dysplastic UC-affected mucosa, further supporting the early involvement of TP53 [66].
In spite of the well-established histopathological phenotyping of IBD-associated preneoplastic and neoplastic lesions, their molecular landscape remains to be fully elucidated. Several studies have pinpointed the initiating role of longstanding/relapsing inflammatory insult on the intestinal mucosa, with the activation of different pro-inflammatory cytokines (TNF-α, IL-6, IL-10, IFN-γ), chemokines and metabolites of arachidonic acid resulting in the activation of key transcription factors such as NF-κB. Longstanding inflammation may also modify the intestinal microbiota, prompting the overgrowth of genotoxic microorganisms, which may act as further cancer promoters. Most of the molecular dysregulation occurring in sporadic colorectal carcinogenesis is documented in colitis-associated adenocarcinoma too, but marked differences have been established in both their timing and prevalence. Unlike sporadic cancers, TP53 alterations occur early in IBD-related carcinogenesis, while APC dysregulation emerges mainly in the most advanced stages of the oncogenic cascade. From the therapeutic standpoint, colitis-associated cancers are associated with a lower prevalence of KRAS mutations than the sporadic variant. Epigenetic changes, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, are significantly involved in colitis-associated cancer development and progression. The focus now is on identifying diagnostic and prognostic biomarkers, with a view to ultimately designing patient-tailored therapies.
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The suppressor of cytokine signaling SOCS1 is a member of the cytokine signaling pathway inhibitor family, which is induced by the IFN-γ induced JAK signaling pathway. The expression of SOCS1 has been found to increase in Crohn's disease (CD) patients, but the role of SOCS1 in intestinal epithelium is unclear. This study was designed to investigate whether SOCS1 has a role in the death of intestinal epithelial cells and intestinal injury. The results showed that the expression of SOCS1 increased in CD patients, and the expression of SOCS1, p-p53 and PUMA increased in the mouse TNBS induced colitis model. Using IFN-γ treated HT-29 cells as an apoptotic model of intestinal epithelial cells in vitro, we confirmed that SOCS1 promoted apoptosis of intestinal epithelial cells by activating p53. In HT-29 cells which were treated with IFN-γ, the interaction between p53 and SOCS1 and phosphorylation of p53 were significantly higher than untreated cells. When knocking SOCS1 down by using SOCS1 siRNA, phosphorylation of p53 and apoptosis of intestinal epithelial cells which was induced by IFN-γ were significantly inhibited. In summary, our findings suggest that SOCS1 may promote apoptosis of intestinal epithelial cells at least partly through mediating p53 signaling.

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^☆: Supported in part by a National Institutes of Health, Bethesda, MD, grant no. DK47717-01 and a grant from the Crohn's and Colitis Foundation of America, NY, NY.

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Original contributionp53 protein expression in ulcerative colitis-associated colorectal dysplasia and carcinoma☆

Abstract

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

J Am Acad Dermatol

Hazard rates for dysplasia and cancer in ulcerative colitis. Results from a surveillance program

Dig Dis Sci

Dysplasia in inflammatory bowel disease: Standardized classification with provisional clinical applications

Hum Pathol

Genetic alterations during colorectal-tumor development

N Engl J Med

Prevalence of ras gene mutations in human colorectal cancers

Nature

Detection of high incidence of K-ras oncogenes during human colon tumorigenesis

Nature

Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients

Science

Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers

Science

Identification of a chromosome 18q gene that is altered in colorectal cancers

Science

Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas

Science

Original contribution
p53 protein expression in ulcerative colitis-associated colorectal dysplasia and carcinoma☆