Specific Clinical and Biological Features Characterize Inflammatory Bowel Disease–Associated Colorectal Cancers Showing Microsatellite Instability

Purpose Microsatellite instability (MSI) due to mismatch repair (MMR) deficiency has been reported to occur at variable frequencies in inflammatory bowel disease–associated intestinal neoplasias (IBD-Ns). We investigated a large series of IBD-N for associations between MSI and several biologic and clinical parameters related to tumors, patients, and their treatment. Patients and Methods A total of 277 IBD-Ns in 205 patients were screened for MSI. Biologic and clinical variables of patients with high levels of DNA microsatellite instability high (MSI-H) were collected and compared with those associated with 33 MSI-H non-IBD colorectal cancers (CRCs). Results A total of 27 IBD-Ns from 17 patients were found to be MSI-H. Compared with sporadic MSI-H CRCs, patients presented with a younger age at diagnosis, and there was no female predominance and no right-sided predominance. Unlike sporadic MSI-H CRCs, MSI-H IBD-Ns presented with heterogeneous mismatch repair defects involving MLH1, MSH2, MSH6, or PMS2, and a low frequency of MLH1 promoter methylation. They exhibited frequent BRAF mutations and frameshift mutations in genes containing coding repeat sequences. Conclusion The mechanisms underlying MMR deficiency in MSI-H IBD-Ns are different from those in sporadic MSI-H tumors and seem to be more related to those observed in hereditary MSI-H tumors. However, BRAF mutations were observed in MSI-H IBD-Ns, similar to sporadic MSI-H tumors, but unlike hereditary MSI-H tumors. Finally, the mutational events in target genes for instability are the same in MSI-H IBD-N tumors as in non-IBD sporadic and hereditary colorectal MSI-H cancers, indicating a colon-related repertoire of target gene alterations.

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Inflammatory Bowel Disease–associated Colorectal Cancers and Microsatellite Instability

The American Journal of Surgical Pathology ◽

10.1097/pas.0b013e31827ae150 ◽

2013 ◽

Vol 37 (3) ◽

pp. 460-462 ◽

Cited By ~ 2

Author(s):

Magali Svrcek ◽

Jacqueline Fontugne ◽

Alex Duval ◽

Jean-François Fléjou

Keyword(s):

Inflammatory Bowel Disease ◽

Microsatellite Instability ◽

Bowel Disease ◽

Colorectal Cancers ◽

Inflammatory Bowel

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Noncanonical NF-κB Signaling Upregulation in Inflammatory Bowel Disease Patients is Associated With Loss of Response to Anti-TNF Agents

Frontiers in Pharmacology ◽

10.3389/fphar.2021.655887 ◽

2021 ◽

Vol 12 ◽

Author(s):

Vu Q. Nguyen ◽

Kristin Eden ◽

Holly A. Morrison ◽

Megan B. Sammons ◽

Kristin K. Knight ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Signaling Pathway ◽

Bowel Disease ◽

Target Genes ◽

Preliminary Evidence ◽

Lymphocyte Migration ◽

Clinical Criteria ◽

Number Of Patients ◽

Effective Therapeutic Strategy ◽

Inflammatory Bowel

Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-κB signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-κB signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn’s disease (CD) and ulcerative colitis (UC) patients.Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-κB signaling and IBD.Results: Noncanonical NF-κB signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-κB signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3.Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-κB signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response.

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Microsatellite Instability, Mismatch Repair Deficiency, and BRAF Mutation in Treatment-Resistant Germ Cell Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.8623 ◽

2009 ◽

Vol 27 (13) ◽

pp. 2129-2136 ◽

Cited By ~ 125

Author(s):

Friedemann Honecker ◽

Hendrik Wermann ◽

Frank Mayer ◽

Ad J.M. Gillis ◽

Hans Stoop ◽

...

Keyword(s):

Germ Cell ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Braf Mutation ◽

Cisplatin Resistance ◽

Germ Cell Tumors ◽

Braf V600e ◽

Braf Mutations ◽

Kras Mutations ◽

Mmr Deficiency

Purpose Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown. Patients and Methods Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations. Results Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P < .0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P < .0001). BRAF mutations were highly correlated with MSI (P = .006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P = .017 and P = .008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P < .001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P = .001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P = .068). Conclusion We report for the first time a correlation between a gene mutation—BRAF V600E—and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed.

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