Limits of Diagnosis and Molecular Markers for Early Detection of Ulcerative Colitis-Associated Colorectal Neoplasia

Abstract Objective.—To present recent advances in the use of molecular markers in diagnosis, in prognosis, in early detection, in novel therapies, and in understanding the molecular pathogenesis of colorectal neoplasia. Data and Literature Sources.—A review of studies of molecular markers in colorectal neoplasia, published in English and available on MEDLINE and BioMednet, indicates that molecular markers are being increasingly studied to predict clinical outcomes in patients with colorectal adenocarcinoma (CRC). We have used this resource, together with our published and unpublished observations at the University of Alabama at Birmingham, to provide an overview of translational research related to molecular markers in colorectal neoplasia. Conclusions.—Currently, the prognosis of patients with CRC is predicted primarily on the basis of clinicopathologic staging; however, pathologists and oncology surgeons have recently begun to investigate the use of molecular markers to diagnose and/or understand the progression of CRC. In recent years, much has been learned about the molecular events responsible for the development of CRC. Also, several studies have reported the implication of some molecular markers in metastasis and tumor aggression and their usefulness in predicting clinical outcome. In this article, we discuss the use of specific molecular markers, including tumor-associated glycoprotein 72 (TAG-72), carcinoembryonic antigen (CEA), and oncofetal tumor antigens (Lewis X and Y) in diagnosis and as targets for novel therapies, as well as the phenotypic expression of bcl-2, mucin antigens (MUC1 and MUC2), and nuclear accumulation of p53 in predicting the clinical outcome of patients with CRC. We also review the ways in which molecular markers may aid the early detection of colorectal neoplasia and promote our understanding of the earliest changes in colorectal neoplasia.

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P266 Risk factors for colorectal neoplasia in ulcerative colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjx002.391 ◽

2017 ◽

Vol 11 (suppl_1) ◽

pp. S212-S212

Author(s):

H. Saoula ◽

A. Boutaleb ◽

M. Aissaoui ◽

A. Salah ◽

K. Belhocine ◽

...

Keyword(s):

Risk Factors ◽

Ulcerative Colitis ◽

Colorectal Neoplasia

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Histologic Inflammation Is a Risk Factor for Progression to Colorectal Neoplasia in Ulcerative Colitis: A Cohort Study

Yearbook of Gastroenterology ◽

10.1016/s0739-5930(08)79065-2 ◽

2008 ◽

Vol 2008 ◽

pp. 157-158

Author(s):

G.R. Lichtenstein

Keyword(s):

Ulcerative Colitis ◽

Risk Factor ◽

Cohort Study ◽

Colorectal Neoplasia

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Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: A meta-analysis

Gastrointestinal Endoscopy ◽

10.1067/mge.2002.125367 ◽

2002 ◽

Vol 56 (1) ◽

pp. 48-54 ◽

Cited By ~ 371

Author(s):

Roy M. Soetikno ◽

Otto S. Lin ◽

Paul A. Heidenreich ◽

Harvey S. Young ◽

Michael O. Blackstone

Keyword(s):

Ulcerative Colitis ◽

Primary Sclerosing Cholangitis ◽

Sclerosing Cholangitis ◽

Colorectal Neoplasia ◽

Meta Analysis ◽

Increased Risk

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Genomic Landscape of Early-stage Colorectal Neoplasia Developing From the Ulcerative Colitis Mucosa in the Japanese Population

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa268 ◽

2020 ◽

Author(s):

Kenta Matsumoto ◽

Yuji Urabe ◽

Shiro Oka ◽

Katsuaki Inagaki ◽

Hidenori Tanaka ◽

...

Keyword(s):

Ulcerative Colitis ◽

Early Stage ◽

Colorectal Neoplasia ◽

Genomic Analysis ◽

The Cancer Genome Atlas ◽

Sequencing Data ◽

Kras Mutations ◽

Tp53 Mutations ◽

Amino Terminal ◽

Cancer Genome Atlas

Abstract Backgrounds Colorectal neoplasias (CRN)s developing from the ulcerative colitis (UC) mucosa include both colitic and sporadic neoplasias. Although several genomic analyses of advanced colitis-associated cancer are available, such studies do not distinguish between colitic and sporadic cases, and the early-stage genomic alterations involved in the onset of colitic cancer remain unclear. To address this, we performed a genomic analysis of early-stage CRN developing from the UC mucosa (CRNUC). Methods We extracted DNA from 36 early-stage CRNUCs (T1 cancer, 10; dysplasia, 26) from 32 UC patients and performed targeted sequencing of 43 genes commonly associated with colitis-associated cancer and compared the results with sequencing data from the Japanese invasive colitis-associated cancer. Results The most frequently mutated gene in the CRNUC cohort was APC (mutated in 47.2% of the cases), followed by TP53 (44.4%), KRAS (27.8%), and PRKDC (27.8%). None of the TP53 mutations occurred at any of the hotspot codons. Although the TP53 mutations in The Cancer Genome Atlas of Colorectal Cancer were dispersed throughout the gene, those detected here in CRNUC cases were concentrated in the amino terminal part of the DNA-binding domain. Interestingly, the mutations in KRAS and TP53 were mutually exclusive in CRNUC, and CRNUCs with KRAS mutations had histologically serrated lesions in the gland duct. Mayo endoscopic subscore was higher in TP53-mutated CRNUCs and lower in KRAS-mutated CRNUCs. Conclusions Our findings suggest that early-stage CRNUC can be classified into 2 groups: those developing through the carcinogenic pathway via TP53 mutations and those developing through the carcinogenic pathway via KRAS mutations.

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Early detection and follow‐up of colorectal neoplasia based on faecal volatile organic compounds

Colorectal Disease ◽

10.1111/codi.15009 ◽

2020 ◽

Vol 22 (9) ◽

pp. 1119-1129 ◽

Cited By ~ 1

Author(s):

S. Bosch ◽

R. Bot ◽

A. Wicaksono ◽

E. Savelkoul ◽

R. Hulst ◽

...

Keyword(s):

Volatile Organic Compounds ◽

Early Detection ◽

Organic Compounds ◽

Colorectal Neoplasia ◽

Volatile Organic

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P078 Efficiency of evaluating the expression of Toll-like receptors 2, 4, 6 and proteins proteomic profiling as integral indicators for predicting the risk of early relapse of ulcerative colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.207 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S174-S174

Author(s):

G Tarasova ◽

A Volkov ◽

A Iakovlev ◽

T Ghazudin ◽

I Shcherbakova

Keyword(s):

Ulcerative Colitis ◽

Molecular Markers ◽

Molecular Characteristics ◽

Colon Mucosa ◽

Proteomic Profiling ◽

Blood Monocytes ◽

Early Relapse ◽

Risk Of Recurrence ◽

Flight Mass Spectrometry ◽

Mass Spectrogram

Abstract Background Success was made in the study of TLR in congenital and adaptive immunity, which determined a new look at immune processes at ulcerative colitis (UC). Modern achievements of proteomic methods of analysis research allow to define molecular characteristics of the inflammation in colon mucosa of patients with UC. Methods The study included 86 patients with UC, an average age of 39.0 ± 1.4 years. Groups: 1–15 (17.4%) patients with distal form of UC, 2–42 (48%) left-sided form, 3–29 (33.7%) patients with total UC. The expression of TLR on peripheral blood monocytes was determined in the immunofluorescence test. Two-colour analysis was performed on a flow-through laser cytofluorimeter (Cytomics FC500, Beckman Coulte). The percentage of monocytes (CD14 + cells) carrying TLR2, TLR4, TLR6 on their surface was assessed. The separation of proteins of colon mucosa was based on technologies of IEF, SDS–PAGE, 2DPAGE (Bruker, USA). The getting of mass spectrogram was determined by matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-TOF-MS/MS, Ultraflex II, Bruker, USA). Statistical analysis was performed using the software Statistica 10.0 (Statsoft). Results The direct average relationship was established between the number of monocytes expressing CD14 + CD282 +, CD14 + CD284 +, CD14 + CD286 + and the area of inflammation (r = 0.49, r = 0.55, r = 0.42, p < 0.05). The nonlinear regression equation was used. Calculation example: the risk of recurrence UC = exp (−26.1 + (0.4) × TLR 2)/(1 + exp (−26.1 + (0.4) × TLR 2)), χ2 = 130, 59, p < 0.0001. Thus, when the number of monocytes expressing TLR2 is not more than 60%, the risk of recurrence of the UC is not more than 11%, with values above 70%, the probability of recurrence exceeds 80%. We identified potentially new molecular markers of the early relapse of ulcerative colitis: SMAD2 activates the transcription of TFG1β and leads to development of fibrosis in colon submucosa in patients with UC; significant decrease of the expression of PPARγ promotes the activation of STAT and AP-1 signalling pathways that promotes the increase of the synthesis of IL-2,6,8,12,TNFα, the activity of immune and inflammation processes in colon mucosa; the reduction of expression of β-defensin-1 in cells of colon mucosa are accompanied with increased expression of CCR6, that promotes the formation of inflammatory infiltrates in colonic submucosa in UC. Conclusion Expression of TLR 2,4,6 in blood monocytes (the risk of recurrence UC ratio) and new protein molecular markers of colon mucosa (SMAD2, PPARγ and apoС-III) can be used as a tool for prediction of early relapse UC.

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Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study

Gut ◽

10.1136/gutjnl-2017-314190 ◽

2017 ◽

Vol 68 (3) ◽

pp. 414-422 ◽

Cited By ~ 38

Author(s):

Chang-Ho Ryan Choi ◽

Ibrahim Al Bakir ◽

Nik-Sheng (John) Ding ◽

Gui-Han Lee ◽

Alan Askari ◽

...

Keyword(s):

Ulcerative Colitis ◽

Risk Stratification ◽

Cox Regression ◽

Colorectal Neoplasia ◽

Single Centre ◽

Centre Study ◽

Unit Increase ◽

Single Centre Study ◽

Microscopic Inflammation ◽

Inflammatory Burden

ObjectiveUlcerative colitis (UC) is a dynamic disease with its severity continuously changing over time. We hypothesised that the risk of colorectal neoplasia (CRN) in UC closely follows an actuarial accumulative inflammatory burden, which is inadequately represented by current risk stratification strategies.DesignThis was a retrospective single-centre study. Patients with extensive UC who were under colonoscopic surveillance between 2003 and 2012 were studied. Each surveillance episode was scored for a severity of microscopic inflammation (0=no activity; 1=mild; 2=moderate; 3=severe activity). The cumulative inflammatory burden (CIB) was defined as sum of: average score between each pair of surveillance episodes multiplied by the surveillance interval in years. Potential predictors were correlated with CRN outcome using time-dependent Cox regression.ResultsA total of 987 patients were followed for a median of 13 years (IQR, 9-18), 97 (9.8%) of whom developed CRN. Multivariate analysis showed that the CIB was significantly associated with CRN development (HR, 2.1 per 10-unit increase in CIB (equivalent of 10, 5 or 3.3 years of continuous mild, moderate or severe active microscopic inflammation); 95% CI 1.4 to 3.0; P<0.001). Reflecting this, while inflammation severity based on the most recent colonoscopy alone was not significant (HR, 0.9 per-1-unit increase in severity; 95% CI 0.7 to 1.2; P=0.5), a mean severity score calculated from all colonoscopies performed in preceding 5 years was significantly associated with CRN risk (HR, 2.2 per-1-unit increase; 95% CI 1.6 to 3.1; P<0.001).ConclusionThe risk of CRN in UC is significantly associated with accumulative inflammatory burden. An accurate CRN risk stratification should involve assessment of multiple surveillance episodes to take this into account.

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