C-Ki-ras mutations in chronic ulcerative colitis and sporadic colon carcinoma

doi:10.1016/0016-5085(90)91024-Z

Gastroenterology

Volume 99, Issue 2, August 1990, Pages 416-420

https://doi.org/10.1016/0016-5085(90)91024-Z Get rights and content

Abstract

Mutations in the first exon of the c-Ki-ras protooncogene were analyzed in carcinomas and dysplasias from patients with sporadic colon cancer and chronic ulcerative colitis by a combination of histological enrichment, cell sorting, polymerase catalyzed chain reaction, and direct sequencing. In contrast to sporadic colon carcinomas, where 52% (11 of 21) contained mutations in codon 12, only 1 of 28 samples of ulcerative colitis associated carcinoma or dysplasia contained a c-Ki-ras mutation, despite the presence of aneuploid cell populations. These results suggest that a different genetic pathway for tumor progression may exist between sporadic colon carcinoma and carcinomas arising in chronic ulcerative colitis.

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The molecular landscape of colitis-associated carcinogenesis
2017, Digestive and Liver Disease
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.
Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers
2016, Gastroenterology
Citation Excerpt :
Three of the 4 IBD-CRC tumors with APC mutation were from CD patients, and the fourth was from a patient with indeterminate colitis. Mutations in KRAS were also less prevalent in IBD-CRC compared with sporadic CRC, again concordant with previous single-gene studies18–21,60 (adjusted P = .019). No NRAS mutations were found in IBD-CRC tumors, although this gene is often altered in sporadic CRC.60
A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors.
We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn’s disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the microdissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies.
Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD.
Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer.
The gross pathology of inflammatory bowel disease
2015, Diagnostic Histopathology
Citation Excerpt :
In patients with pancolitis, the risk of CRC begins to increase 8–10 years following the onset of symptoms. The mechanism of carcinogenesis in the setting of IBD is unclear, but evidence suggests that it arises through molecular pathways different than sporadic CRC.13,14 Patients with IBD tend to develop cancer at a younger age when compared to sporadic cases.
Inflammatory bowel disease is a broad term that describes conditions with chronic or recurring immune response, and inflammation of the gastrointestinal tract. The two major types are Crohn's disease and ulcerative colitis. Considering the evaluation of inflammatory bowel disease requires a multidisciplinary approach, gross pathologic examination represents an integral component in its diagnosis and classification. The purpose of this review is to address the following: (1) describe the main gross findings of inflammatory bowel disease that facilitate discrimination between Crohn's disease and ulcerative colitis; (2) discuss atypical/non-classical presentations of inflammatory bowel disease; (3) highlight the importance of gross inspection in detecting and sampling suspicious areas for dysplasia and/or malignancy in the setting of inflammatory bowel disease; and (4) offer practical guidelines for grossing inflammatory bowel disease specimens.
The interrelationships of the gut microbiome and inflammation in colorectal carcinogenesis
2014, Clinics in Laboratory Medicine
Citation Excerpt :
Although the pathogenesis of CRC in the setting of IBD is poorly understood, studies suggest that there are differences from sporadic CRC. In contrast to sporadic CRC, mutations in the ras proto-oncogene are less frequently observed in CRC associated with UC and occur as a late event.15–17 In CRC associated with IBD, loss of heterozygosity for p53 and SRC activation occur earlier.15,17
Molecular alterations in colitis-associated colorectal neoplasia: Study from a low prevalence area using magnifying chromo colonoscopy
2012, Journal of Crohn's and Colitis
Citation Excerpt :
Frequent mutations are observed in codons 12, 13 and 61 resulting in the increased and unregulated cellular proliferation. Several studies have reported the frequency of KRAS mutations in UC-CRN to be 8–24% which is lower than that reported for sporadic neoplasms (40–50%).27,28 Mutations in BRAF have been described in about 15% of all human tumours, especially in malignant melanomas.29,30
Longstanding ulcerative colitis (UC) predisposes to colorectal cancer (CRC). To understand the molecular pathogenesis of colitis-associated colorectal neoplasia (UC-CRN), we studied the frequency of microsatellite instability (MSI) and mutations in p53, BRAF and KRAS genes in the tissues of patients with long standing UC with or without neoplasia and compared them with colitis patients without risk of neoplasia, and those with sporadic colorectal neoplasia (S-CRN) in an area with lower prevalence for either disease.
Biopsies were obtained during magnifying chromo colonoscopy or routine colonoscopy in consecutive UC patients with high risk (UC-HR) and low risk (UC-LR) of neoplasia, and those with S-CRN. MSI (NCI-Bethesda panel) and mutations in p53, KRAS and BRAF genes were analysed.
Twenty-eight patients with UC-HR, 30 with UC-LR and 30 with S-CRN were included. Six (21.4%) of UC-HR had neoplasia (Progressors). MSI was not detected in the UC-CRN group as compared to 5 (16.7%) in the S-CRN group. p53 mutations occurred in 1 (3.3%) of UC-LR, increasing to 6 (27.3%, P < 0.05) and 3 (50%, P < 0.05) in the UC-HR subgroups without and with neoplasia respectively, as against 10 (33.3%) in sporadic neoplasia group. KRAS mutations were found only in the presence of neoplasia. None showed the BRAF mutation.
In a population with a lower prevalence for UC and CRC, the molecular pathogenesis of colitis-associated colorectal neoplasia is comparable to that reported from areas with a higher prevalence of these diseases, MSI being an exception.

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: This work was supported by the NIH NIDDKD Grant No. DK32971 to Drs. Glenna Burmer, Douglas Levine, Peter Rabinovitch, Rodger Haggitt, and Cyrus Rubin, and by the National Institute on Aging Grant No. AG07359 to Dr. Glenna Burmer.

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C-Ki-ras mutations in chronic ulcerative colitis and sporadic colon carcinoma

Abstract

Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centers

Gut

Ulcerative colitis and colon cancer

Clin Gastroenterol

The clonal evolution of tumor cell populations

Science

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 in the c-Kiras oncogene during progressive stages of human colon carcinoma