A transforming growth factor beta 1 receptor type II mutation in ulcerative colitis-associated neoplasms
Abstract
BACKGROUND & AIMS: Numerous gastrointestinal tumors, notably sporadic and ulcerative colitis (UC)-associated colorectal carcinomas and dysplasias, gastric cancers, and esophageal carcinomas, manifest microsatellite instability. Recently, a transforming growth factor beta 1 type II receptor (TGF-beta 1RII) mutation in a coding microsatellite was described in colorectal carcinomas showing instability. One hundred thirty-eight human neoplasms (61 UC-associated, 35 gastric, 26 esophageal, and 16 sporadic colorectal) were evaluated for this TGF- beta 1RII mutation. METHODS: Whether instability was present at other chromosomal loci in these lesions was determined. In lesions manifesting or lacking instability, the TGF-beta 1RII coding region polydeoxyadenine (poly A) microsatellite tract was polymerase chain reaction amplified with 32P-labeled deoxycytidine triphosphate. Polymerase chain reaction products were electrophoresed on denaturing gels and exposed to radiographic film. RESULTS: Three of 18 UC specimens with instability at other chromosomal loci (17%) showed TGF- beta 1RII poly A tract mutation, including 2 cancers and 1 dysplasia; moreover, 2% of UC specimens without instability (1 of 43) (1 cancer), 81% of unstable sporadic colorectal cancers (13 of 16), and none of the 61 stable or unstable gastric or esophageal cancers contained TGF-beta 1RII mutations. CONCLUSIONS: Mutational inactivation of the poly A microsatellite tract within TGF-beta 1RII occurs early and in a subset of unstable UC neoplasms and commonly in sporadic colorectal cancers but may be rare in unstable gastric and esophageal tumors. (Gastroenterology 1997 Jan;112(1):40-5)
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Loss of MMR and TGFBR2 Increases the Susceptibility to Microbiota-Dependent Inflammation-Associated Colon Cancer
2022, Cellular and Molecular Gastroenterology and HepatologyCitation Excerpt :The IBD-CRCs in VCMsh2/Tgfbr2 mice showed no Apc mutations either during spontaneous or DSS-induced colorectal tumorigenesis in contrast to the DSS-induced CRCs in VCMsh2 mice or SI tumors in both mouse lines. This is reminiscent of most IBD-CRCs in human patients that do not harbor APC mutations or seem to acquire them at later stages during tumor development and indicates that TGFBR2 loss at the early stages of tumorigenesis is crucial for their etiology or progression.15,17 However, other genes with known roles in intestinal homeostasis or colorectal tumorigenesis carried mutations in VCMsh2/Tgfbr2 CRCs.
Mutations in DNA mismatch repair (MMR) genes are causative in Lynch syndrome and a significant proportion of sporadic colorectal cancers (CRCs). MMR-deficient (dMMR) CRCs display increased mutation rates, with mutations frequently accumulating at short repetitive DNA sequences throughout the genome (microsatellite instability). The TGFBR2 gene is one of the most frequently mutated genes in dMMR CRCs. Therefore, we generated an animal model to study how the loss of both TGFBR2 signaling impacts dMMR-driven intestinal tumorigenesis in vivo and explore the impact of the gut microbiota.
We generated VCMsh2/Tgfbr2 mice in which Msh2loxP and Tgfbr2loxP alleles are inactivated by Villin-Cre recombinase in the intestinal epithelium. VCMsh2/Tgfbr2 mice were analyzed for their rate of intestinal cancer development and for the mutational spectra and gene expression profiles of tumors. In addition, we assessed the impact of chemically induced chronic inflammation and gut microbiota composition on colorectal tumorigenesis.
VCMsh2/Tgfbr2 mice developed small intestinal adenocarcinomas and CRCs with histopathological features highly similar to CRCs in Lynch syndrome patients. The CRCs in VCMsh2/Tgfbr2 mice were associated with the presence of colitis and displayed genetic and histological features that resembled inflammation-associated CRCs in human patients. The development of CRCs in VCMsh2/Tgfbr2 mice was strongly modulated by the gut microbiota composition, which in turn was impacted by the TGFBR2 status of the tumors.
Our results demonstrate a synergistic interaction between MMR and TGFBR2 inactivation in inflammation-associated colon tumorigenesis and highlight the crucial impact of the gut microbiota on modulating the incidence of inflammation-associated CRCs.
Molecular basis of diseases of the gastrointestinal tract
2018, Molecular Pathology: The Molecular Basis of Human DiseaseMuch of the progress in the understanding of gastrointestinal disorders has continued to center on the molecular underpinning of gastrointestinal neoplasia in the 21st century. First, the development of cancer in the setting of inflammatory conditions is well represented by the association of Helicobacter pylori with gastric cancer and of inflammatory bowel diseases with colorectal cancer. Second, the development of cancer in patients with hereditary predisposition syndromes has shed light not only in the mechanisms of hereditary neoplasia, but has also led to major progress in the understanding of the molecular basis of the more common forms of sporadic cancer. The molecular characterization of the steps of gastrointestinal neoplastic development and progression has led to advances in disease diagnosis and treatment and has opened the opportunity for development of more targeted approaches to cancer prevention, surveillance, and novel therapeutics. This chapter focuses on the disease processes that most clearly illustrate the concepts and advances in molecular pathology of the gastrointestinal tract. It includes neoplastic diseases associated with a background of chronic inflammation, well-characterized gastrointestinal hereditary cancer syndromes, and the so-called sporadic cancers of the gastrointestinal tract, primarily reviewing gastric and colonic carcinogenesis.
Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers
2016, GastroenterologyA 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.
Transforming growth factor-β1 and its receptors in patients with ulcerative colitis
2009, International ImmunopharmacologyTransforming growth factor-β1 (TGF-β1) plays a role in the pathogenesis of ulcerative colitis (UC) by activating its specific receptors (TβRI–TβRIII). We investigated the expression of genes encoding for TGF-β1 and TβRI–III using RT-QPCR in patients with active and inactive UC and non-IBD controls. The localization and level of TGF-β1 protein in intestinal tissue was estimated by immunohistochemistry, and serum TGF-β1 concentrations were determined using ELISA. We found a significant increase in TGF-β1 gene expression and increase in the expression of genes encoding receptor TβRI in patients with active UC when compared with controls. The expression of genes encoding TβRII was found to be higher in patients with both active and inactive UC when compared to controls. Specific staining for TGF-β1 in fibroblasts was significantly greater in both active and inactive UC as compared to controls. The serum concentration of TGF-β1 was significantly higher in patients with active UC when compared with controls as well as in UC patients with left side/total colonic extension when compared with those with disease limited to rectum/rectosigmoid area. However, no correlation between TGF-β1 serum concentrations and UC activity index was found. Increases in TGF-β1 gene expression and its protein level, associated with altered TGF-β1 receptor profile indicate a functional role for TGF-β1 in intestinal inflammatory/repair processes in UC. Increases in TGF-β1 serum concentrations correlate with extension of disease.
Molecular Basis of Diseases of the Gastrointestinal Tract
2009, Molecular Pathology: The Molecular Basis of Human DiseaseMuch of the progress in the understanding of gastrointestinal disorders has continued to center on the molecular underpinning of gastrointestinal neoplasia in the 21st century. First, the development of cancer in the setting of inflammatory conditions is well represented by the association of H. pylori with gastric cancer and of inflammatory bowel diseases with colorectal cancer. Second, the development of cancer in patients with hereditary predisposition syndromes has shed light not only in the mechanisms of hereditary neoplasia, but has also led to major progress in the understanding of the molecular basis of the more common forms of sporadic cancer. The molecular characterization of the steps of gastrointestinal neoplastic development and progression has led to advances in disease diagnosis and treatment and has opened the opportunity for development of more targeted approaches to cancer prevention, surveillance, and novel therapeutics. This chapter focuses on the disease processes that most clearly illustrate the concepts and advances in molecular pathology of the gastrointestinal tract. It includes neoplastic diseases associated with a background of chronic inflammation, well characterized gastrointestinal hereditary cancer syndromes, and the so- called sporadic cancers of the gastrointestinal tract, primarily reviewing gastric and colonic carcinogenesis.
Smad3 knockout mice exhibit impaired intestinal mucosal healing
2008, Laboratory InvestigationAltered transforming growth factor-β (TGFβ) expression may contribute to inflammatory bowel disease and modulate epithelial cell restitution. Interference with TGFβ-mediated signaling inhibits excisional skin wound healing, but accelerates healing of incisional cutaneous wounds and wounds in some other tissues. Therefore, we sought to clarify the potential role of Smad3-dependent TGFβ signaling in intestinal mucosal healing in Smad3 null mice. Jejunal serosal application of filter disks saturated with 75% acetic acid yielded a circumscribed reproducible ischemic mucosal ulcer 1 day later. We compared ulcer area at 3 and 5 days to day 1 in Smad3 knockout mice and syngeneic wild-type mice, and evaluated mucosal immunoreactivity at the ulcer edge for TGFβ, phosphorylated (activated) focal adhesion kinase (pFAK), phosphorylated extracellular signal-related kinase (pERK), proliferating cell nuclear antigen and apoptosis by TUNEL. Ulcer healing in Smad3 null mice was 17% less at day 3 (n=14, P=0.022) and 15% less at day 5 (n=14, P=0.004) than in wild-type littermates. In wild-type mice, pFAK, pERK and TGFβ immunoreactivity were elevated in epithelium immediately adjacent to the ulcer compared with more distant mucosa. However, this pattern of immunoreactivity for pFAK, pERK and TGFβ was not observed in Smad3 null mice. Smad3 null mice exhibited increased epithelial proliferation and no differences in apoptotic cell death compared with wild types, suggesting that ulcer healing may reflect differences in restitutive cell migration. Thus, Smad3-dependent disruption of the TGFβ signaling pathway impairs the healing of murine intestinal mucosal ulcers and alters patterns of activated FAK and ERK immunoreactivity important for cell migration at the ulcer edge. These studies suggest a significant role for Smad3-dependent TGFβ signaling in intestinal mucosal healing.