The frequency of colorectal lesions in the first-degree relatives of patients with colorectal lesions among PERSIAN Guilan Cohort Study population (PGCS).

BACKGROUND: This study aimed to investigate the frequency of colorectal lesions in the first-degree relatives of patients with colorectal lesions among the Prospective Epidemiological Research Studies in Iran (PERSIAN )Guilan Cohort Study (PGCS) population. METHODS: In this cross-sectional study, 162 first-degree relatives with a history of colorectal lesions were randomly selected from 52 participants in PGCS. All subjects underwent total colonoscopy by a gastroenterologist, and a pathologist evaluated colorectal biopsies. Also, individuals' demographic information, clinical data, and dietary habits were recorded. RESULTS: The mean age of the participants was 56.55 ± 7.04. Of 86 colon polyps, 52 neoplastic and 34 non-neoplastic polyps were observed in 56 patients (34.6%). Individuals with age > 60 years had 3.29-fold increased odds of developing colorectal polyps (OR = 3.29, 95% CI: 1.13-9.56, P = 0.029). The smokers were 2.73 times more susceptible to developing colorectal polyps than non-smokers (OR = 2.73, 95% CI: 1.24-6.02, P = 0.013). Moreover, consumption of vegetables more than three times per day was associated with decreased OR of colorectal polyp development (OR = 0.43, CI: 0.19-0.98, P = 0.045). CONCLUSIONS: Considering the high prevalence of neoplastic colorectal polyps among the first-degree relatives of patients with colorectal lesions, early screening is recommended for individuals with a family history of colorectal lesions.

Macrophage Inflammatory Proteins (MIPs) Contribute to Malignant Potential of Colorectal Polyps and Modulate Likelihood of Cancerization Associated with Standard Risk Factors.

Better understanding of molecular changes leading to neoplastic transformation is prerequisite to optimize risk assessment and chemopreventive and surveillance strategies. Data on macrophage inflammatory proteins (MIPs) in colorectal carcinogenesis are scanty and their clinical relevance remains unknown. Therefore, transcript and protein expression of CCL3, CCL4, CXCL2, and CCL19 were determined in 173 and 62 patients, respectively, using RT-qPCR and immunohistochemistry with reference to polyps' characteristics. The likelihood of malignancy was modeled using probit regression. With the increasing malignancy potential of hyperplastic-tubular-tubulo-villous-villous polyps, the expression of CCL3, CCL4, and CCL19 in lesions decreased. CCL19 expression decreased also in normal mucosa while that of CXCL2 increased. Likewise, lesion CCL3 and lesion and normal mucosa CCL19 decreased and normal CXCL2 increased along the hyperplasia-low-high dysplasia grade. The bigger the lesion, the lower CCL3 and higher CXCL2 in normal mucosa. Singular polyps had higher CCL3, CCL4, and CCL19 levels in normal mucosa. CCL3, CCL4 and CXCL2 modulated the likelihood of malignancy associated with traditional risk factors. There was no correlation between the protein and mRNA expression of CCL3 and CCL19. In summary, the polyp-adjacent mucosa contributes to gaining potential for malignancy by polyps. MIPs may help in specifying cancerization probability estimated based on standard risk factors.

Characterization of sessile serrated adenomas with dysplasia including intramucosal adenocarcinoma and colorectal carcinoma with a microsatellite instability phenotype.

Recent studies have shown that sessile serrated lesions (SSLs) lead to the development of colorectal cancer (CRC) with a microsatellite instability (MSI) phenotype via a dysplasia-carcinoma sequence. However, the pathological and molecular mechanisms of SSL with dysplasia (SSLD) are unclear. Here, we aimed to examine the clinicopathological and molecular alterations in SSLD and to evaluate the significance of such alterations with regard to lesion progression. Fifty-four SSLDs (20 serrated dysplasia cases and 17 intestinal dysplasia cases, including 30 low-grade dysplasia [LGD] cases, 7 high-grade dysplasia [HGD] cases, and 17 intramucosal adenocarcinomas [IMAs]) were evaluated. Molecular alterations, including immunohistochemical expression of various markers, DNA methylation status, and multiple genetic mutations (using next-generation sequencing), were assessed. Additionally, such alterations were also investigated in 41 CRCs with an MSI phenotype (invasion beyond submucosa). The frequency of mismatch repair (MMR) deficiency in SSLD was 12 of 39 cases (32.4 %), whereas the MMR proficient type was observed in 17 of 39 SSLD cases. SSLD with serrated dysplasia showed a significantly higher frequency of loss of MMR protein expression and methylation status. Moreover, loss of MMR protein expression differed significantly between LGD and IMA. Furthermore, the frequency of TP53 mutation was significantly higher in IMA than in LGD. The current findings demonstrated that SSL with serrated dysplasia may be associated with an increased risk of malignant transformation compared with intestinal dysplasia. Loss of MMR proteins and mutation of TP53 may play important roles in tumor progression from dysplasia to carcinomatous lesions.

Causal association between telomere length and colorectal polyps: A bidirectional two-sample Mendelian randomization study.

We performed a bidirectional 2-sample Mendelian randomization (MR) design to explore the causal relation between telomere length (TL) and colorectal polyps. Genome-wide association study summary data of TL and colorectal polyps were extracted from the IEU open genome-wide association study database. Single nucleotide polymorphisms were served as instrumental variables at the significance threshold of P < 5 × 10-8. The inverse variance weighted method, MR-Egger method, and weight median method were performed for causal estimation in MR. Cochran Q test, MR-Egger intercept test, and leave-one-out analyses were performed to evaluate the pleiotropy of the MR results. One hundred and twenty-four single nucleotide polymorphisms were selected as instrumental variables. We found significant casual association between TL and colorectal polyps. Long TL increased the risk of colorectal polyps using the inverse variance weighted method [ukb-a-521: odds ratio (OR): 1.004, 95% confidence interval (CI): 1.001-1.007, P = .004; ukb-d-D12: OR: 1.008, CI: 1.004-1.012, P < .001; finn-b-CD2_BENIGN_COLORECANI_EXALLC2: OR: 1.170, CI: 1.027-1.332, P = .018]. Sensitivity analyses validated that the causality between TL and colorectal polyps was robust. The study provided a causal association between TL and colorectal polyps which indicated that TL might be served as a potential biomarker of colorectal polyps for screening and prevention. Nonetheless, the conclusions need further validation.

Cronkhite‒Canada syndrome as inflammatory hamartomatous polyposis: new evidence from whole transcriptome sequencing of colonic polyps.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare, nonhereditary disease characterized by diffuse gastrointestinal polyposis and ectodermal abnormalities. Although it has been proposed to be a chronic inflammatory condition, direct evidence of its pathogenesis is lacking. This study aims to investigate the pathophysiology of CCS by analyzing transcriptomic changes in the colonic microenvironment. METHODS: Next-generation sequencing-based genome-wide transcriptional profiling was performed on colonic hamartomatous polyps from four CCS patients and normal colonic mucosa from four healthy volunteers. Analyses of differential expression and multiple enrichment analyses were conducted from the molecular level to the cellular level. Quantitative real-time PCR (qRT-PCR) was carried out to validate the sequencing accuracy in samples from six CCS patients and six healthy volunteers. RESULTS: A total of 543 differentially expressed genes were identified, including an abundance of CC- and CXC-chemokines. Innate immune response-related pathways and processes, such as leukocyte chemotaxis, cytokine production, IL-17, TNF, IL-1 and NF-kB signaling pathways, were prominently enhanced in CCS colonic polyps. Upregulation of wound healing, epithelial-mesenchymal transition, Wnt, and PI3K-Akt signaling pathways were also observed. Enrichment analyses at different levels identified extracellular structure disorganization, dysfunction of the gut mucosal barrier, and increased angiogenesis. Validation by qRT-PCR confirmed increased expression of the LCN2, IL1B, CXCL1, and CXCL3 genes in CCS colonic polyps. CONCLUSIONS: This case-control whole transcriptome analysis of active CCS colonic hamartomatous polyps revealed intricate molecular pathways, emphasizing the role of the innate immune response, extracellular matrix disorganization, inflammatory cell infiltration, increased angiogenesis, and potential epithelial to mesenchymal transition. These findings supports CCS as a chronic inflammatory condition and sheds light on potential therapeutic targets, paving the way for more effective and personalized management of CCS in the future.

Identification of LncPVT1 and CircPVT1 as prognostic biomarkers in human colorectal polyps.

LncPVT1 and CircPVT1 are isoforms for the PVT1 gene and are associated with cancer progression and carcinogenesis. Our study investigated the expression of LncPVT1 and CircPVT1 in colon adenoma polyps. 40 tissues of colorectal polyps and 40 normal-adjacent tissues (NATs) were taken. The expression of LncPVT1 and CircPVT1 was evaluated through qRael-Time PCR. The relation between expression and features of clinicopathological was explored. The ceRNA network was constructed by LncPVT1 and CircPVT1 and predicted miRNAs and miRNAs targets. Further, hub nodes in this network were determined using the cytoHubba package. Over-expressed LncPVT1 and CircPVT1 were differentiated in polyp and NATs. The expression level of LncPVT1 and CircPVT1 were significantly higher in adenoma polyps than in hyperplastic polyps. The area under the curve of the ROC estimate for the LncPVT1 and CircPVT1 was 0.74 and 0.77, respectively. A positive correlation was observed between the LncPVT1 expression and CircPVT1. Three miRNAs, including hsa-miR-484, hsa-miR-24-3p, hsa-miR-423-5p, and CircPVT1, were detected as ceRNA hub nodes. In this study, expression profiles of LncPVT1 and CircPVT1 were significantly higher in precancerous polyps. In addition, based on our in silico analysis, LncPVT1, CircPVT1/miR-484, miR-24-3p, miR-423-5p/PLAGL2 axis might be involved in colon cancer development. LncPVT1 and CircPVT1 can be prescribed as warning problems as potential prognostic biomarkers in patients with pre-CRC colon polyps.

Integrated bioinformatics and wet-lab analysis revealed cell adhesion prominent genes CDC42, TAGLN and GSN as prognostic biomarkers in colonic-polyp lesions.

Colorectal cancers are derived from intestinal polyps. Normally, alterations in cell adhesion genes expression cause deviation from the normal cell cycle, leading to cancer development, progression, and invasion. The present study aimed to investigate the elusive expression pattern of CDC42, TAGLN, and GSN genes in patients with high and low-risk polyp samples, and also colorectal cancer patients and their adjacent normal tissues. In upcoming study, 40 biopsy samples from Taleghani Hospital (Tehran, Iran) were collected, consisting of 20 colon polyps and 20 paired adjacent normal tissues. The expression of the nominated genes CDC42, TAGLN, and GSN was analyzed using quantitative polymerase chain reaction (Q-PCR) and relative quantification was determined using the 2-ΔΔCt method. ROC curve analysis was performed to compare high-risk and low-risk polyps for the investigated genes. The expression of adhesion molecule genes was also evaluated using TCGA data and the correlation between adhesion molecule gene expression and immunophenotype was analyzed. The role of mi-RNAs and lncRNAs in overexpression of adhesion molecule genes was studied. Lastly, GO and KEGG were performed to identify pathways related to adhesion molecule genes expression in healthy, normal adjacent, and COAD tissues. The results showed that the expression patterns of these genes were significantly elevated in high-risk adenomas compared to low-risk polyps and normal tissues and were associated with various clinicopathological characteristics. The estimated AUC for CDC42, TAGLN, and GSN were 0.87, 0.77, and 0.80, respectively. The study also analyzed COAD cancer patient data and found that the selected gene expression in cancer patients was significantly reduced compared to high-risk polyps and healthy tissues. Survival analysis showed that while the expression level of the GSN gene had no significant relationship with survival rate, the expression of CDC42 and TAGLN genes did have a meaningful relationship, but with opposite effects, suggesting the potential use of these genes as diagnostic or prognostic markers for colorectal cancer. The present study's findings suggest that the expression pattern of CDC42, TAGLN, and GSN genes was significantly increased during the transformation of normal tissue to polyp lesions, indicating their potential as prognostic biomarkers for colorectal polyp development. Further results provide valuable insights into the potential use of these genes as diagnostic or prognostic markers for colorectal cancer. However, further studies are necessary to validate these findings in larger cohorts and to explore the underlying mechanisms of these genes in the development and progression of colorectal cancer.

Sessile serrated lesions with dysplasia: is it possible to nip them in the bud?

The serrated neoplasia pathway constitutes an "alternative route" to colorectal cancer (CRC), and sessile serrated lesions with dysplasia (SSLDs) are an intermediate step between sessile serrated lesions (SSLs) and invasive CRC in this pathway. While SSLs show indolent growth before becoming dysplastic (> 10-15 years), SSLDs are considered to rapidly progress to either immunogenic microsatellite instable-high (MSI-H) CRC (presumably 75% of cases) or mesenchymal microsatellite stable (MSS) CRC. Their flat shapes and the relatively short window of this intermediate state make it difficult to detect and diagnose SSLDs; thus, these lesions are potent precursors of post-colonoscopy/interval cancers. Confusing terminology and the lack of longitudinal observation data of serrated polyps have hampered the accumulation of knowledge about SSLDs; however, a growing body of evidence has started to clarify their characteristics and biology. Together with recent efforts to incorporate terminology, histological studies of SSLDs have identified distinct dysplastic patterns and revealed alterations in the tumor microenvironment (TME). Molecular studies at the single-cell level have identified distinct gene alterations in both the epithelium and the TME. Mouse serrated tumor models have demonstrated the importance of TME in disease progression. Advances in colonoscopy provide clues to distinguish pre-malignant from non-malignant-SSLs. Recent progress in all aspects of the field has enhanced our understanding of the biology of SSLDs. The aim of this review article was to assess the current knowledge of SSLDs and highlight their clinical implications.

Long non­coding RNA LINC00460 contributes as a potential prognostic biomarker through its oncogenic role with ANXA2 in colorectal polyps.

BACKGROUND: Long intergenic non-coding RNA 460 (LINC00460) as a potential oncogene and Annexin A2 (ANXA2) as a promoter in different cancer progression processes was considered. A significant relationship between the LINC00460 and ANXA2 has been recently discovered in colorectal cancer (CRC). Therefore, defining molecular biomarkers accompanied by lesion histopathologic features can be a suggestive prognostic biomarker in precancerous polyps. This study aimed to investigate the elusive expression pattern of ANXA2 and LINC00460 in polyps. MATERIALS AND METHODS: The construction of the co-expression and correlation network of LINC00460 and ANXA2 was plotted. LINC00460 and ANXA2 expression in 40 colon polyps was quantified by reverse transcription-real-time polymerase chain reaction. The receiver operating characteristic (ROC) curve was designed for distinguishing the high-risk precancerous lesion from the low-risk. Further, bioinformatics analysis was applied to find the shared MicroRNA-Interaction-Targets (MITs) between ANXA2 and LINC00460, and the associated pathways. RESULTS: ANXA2 has a high co-expression rank with LINC00460 in the lncHUB database. Overexpression of ANXA2 and LINC00460 was distinguished in advanced adenoma polyps compared to the adjacent normal samples. The estimated AUC for ANXA2 and LINC00460 was 0.88 - 0.85 with 93%-90% sensitivity and 81%-70% specificity. In addition, eight MITs were shared between ANXA2 and LINC00460. Enrichment analysis detected several GO terms and pathways, including HIF-1α associated with cancer development. CONCLUSION: In conclusion, the expression of the ANXA2 and LINC00460 were significantly elevated in pre-cancerous polyps, especially in high-risk adenomas. Collectively, ANXA2 and LINC00460 may be administered as potential prognostic biomarkers in patients with a precancerous large intestine lesion as an alarming issue.

Microvesicular hyperplastic polyp and sessile serrated lesion of the large intestine: a biological continuum or separate entities?

The range of lesions with a serrated appearance within the large intestine has expanded and become more complex over the last 30 years. The majority of these were previously known as metaplastic polyps but are today called hyperplastic polyps (HPs). HPs show two main growth patterns: microvesicular and goblet cell-rich. The former type shows morphological and molecular similarities (eg, BRAF mutations) to the more recently described sessile serrated lesion (SSL). In this review, we debate whether these lesions represent a biological spectrum or separate entities. Whichever view is held, microvesicular HPs and SSLs are distinct from the goblet cell-rich HP and the traditional serrated adenoma (TSA), which may themselves share molecular changes (eg, KRAS mutations), with the goblet cell-rich HP representing a precursor to the TSA. Both SSLs and the goblet cell-rich HP-TSA pathway are routes to colorectal cancer within the serrated pathway and overlaps between them can occur, for example, a (BRAF-mutated) TSA may arise from an SSL.

A Case of Sporadic Multiple Colonic Polyps in a Young Woman.

Sporadic colorectal cancer arises from an adenoma. As mutations in the adenomatous polyposis coli (APC) tumor suppressor gene have been frequently detected in colorectal adenomas, the APC gene is considered a gatekeeper in colorectal carcinogenesis. Here, we report a case of sporadic multiple colonic adenomas that were accompanied by an APC-truncating mutation. A 25-year-old Korean woman presented with dozens of incidentally found colonic polyps. There was no family history of colorectal polyposis or colon cancer in her first or second-degree relatives. All the polyps were removed endoscopically at once, and their pathological examination revealed tubular adenoma. Mutational analysis showed a 2-bp deletion mutation at codon 443, which generates a premature stop codon at codon 461 of the APC gene, and Western blot analysis demonstrated both wild-type and truncated APC proteins in adenoma tissue. This study suggests that a single truncating mutation of the APC gene may initiate adenoma formation.

Germline mutations in WNK2 could be associated with serrated polyposis syndrome.

BACKGROUND: Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts. METHODS: After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion. RESULTS: We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2. CONCLUSION: After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease.

Serrated polyposis syndrome; epidemiology and management.

Serrated colorectal polyps, long considered innocent, are currently recognized as the precursors to one-third of all colorectal cancers (CRC). Serrated polyposis syndrome (SPS), characterized by accumulation of multiple and/or large serrated polyps, symbolizes the highest expression of serrated pathway of carcinogenesis, leading to a high risk of CRC when it is not detected or treated on time. Although previously considered uncommon, SPS is now acknowledged as the most prevalent colorectal polyposis. This syndrome has attracted increasing interest over the past decade and has become a hot topic in the field of gastrointestinal oncology. Besides a small proportion of cases caused by germline mutations in RNF43, no clear genetic cause has been identified. Both epigenetic and environmental factors, especially smoking, have been related to this syndrome, but the etiology of SPS remains uncertain and diagnosis is based on endoscopic criteria. Recent studies on SPS have focused on identifying the underlying risk-factors for CRC, defining the best endoscopic techniques for surveillance and establishing optimal preventive strategies aimed at reducing CRC-incidence without exposing patients to unnecessary procedures. The purpose of this chapter is to review, from a practical perspective, current knowledge and future directions in the diagnosis and management of serrated polyposis syndrome.

Investigation of the Association between High Arachidonic Acid Synthesis and Colorectal Polyp Incidence within a Generally Healthy UK Population: A Mendelian Randomization Approach.

BACKGROUND: Arachidonic acid (ARA) is associated with colorectal cancer (CRC), a major public health concern. However, it is uncertain if ARA contributes to the development of colorectal polyps which are pre-malignant precursors of CRC. OBJECTIVE: The study aimed to investigate the association between lifelong exposure to elevated ARA and colorectal polyp incidence. METHODS: Summary-level GWAS data from European, Singaporean, and Chinese cohorts (n = 10,171) identified 4 single-nucleotide polymorphisms (SNPs) associated with blood ARA levels (p < 5 × 10-8). After pruning, 1 SNP was retained (rs174547; p = 3.0 × 10-971) for 2-stage Mendelian randomization. RESULTS: No association between ARA and colorectal polyp incidence was observed (OR = 1.00; 95% CI: 0.99, 1.00; p value = 0.50) within the UK Biobank (1,391 cases; 462,933 total). CONCLUSIONS: Blood levels of ARA do not associate with colorectal polyp incidence in a general healthy population. Although not providing direct evidence, this work supports the contention that downstream lipid mediators, such as PGE2 rather than ARA itself, are key for polyp formation during early-stage colorectal carcinogenesis.

Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA.

BACKGROUND: Current noninvasive assays have limitations in the early detection of colorectal cancer. We evaluated the clinical utility of promoter methylation of the long noncoding RNA LINC00473 as a noninvasive biomarker to detect colorectal cancer and associated precancerous lesions. METHODS: We evaluated the epigenetic regulation of LINC00473 through promoter hypermethylation in colorectal cancer cell lines using bisulfite genomic sequencing and expression analyses. DNA methylation of LINC00473 was analyzed in primary colorectal tumors using 450K arrays and RNA-seq from The Cancer Genome Atlas (TCGA). Tissue-based findings were validated in several independent cohorts of colorectal cancer and advanced colorectal polyp patients by pyrosequencing. We explored the clinical utility of LINC00473 methylation for the early detection of colorectal cancer in plasma cell-free DNA by quantitative methylation-specific PCR and droplet digital PCR. RESULTS: LINC00473 showed transcriptionally silencing due to promoter hypermethylation in colorectal cancer cell lines and primary tumors. Methylation of the LINC00473 promoter accurately detected primary colorectal tumors in two independent clinical cohorts, with areas under the receiver operating characteristic curves (AUCs) of 0.94 and 0.89. This biomarker also identified advanced colorectal polyps from two other tissue-based clinical cohorts with high diagnostic accuracy (AUCs of 0.99 and 0.78). Finally, methylation analysis of the LINC00473 promoter in plasma cell-free DNA accurately identified patients with colorectal cancer and advanced colorectal polyps (AUCs of 0.88 and 0.84, respectively), which was confirmed in an independent cohort of patients. CONCLUSIONS: Hypermethylation of the LINC00473 promoter is a new promising biomarker for noninvasive early detection of colorectal cancer and related precancerous lesions.

Somatic targeted mutation profiling of colorectal cancer precursor lesions.

BACKGROUND: Most colorectal cancers (CRC) arise from precursor lesions. This study aimed to characterize the mutation profile of colorectal cancer precursor lesions in a Brazilian population. METHODS: In total, 90 formalin-fixed paraffin-embedded colorectal precursor lesions, including 67 adenomas, 7 sessile serrated lesions, and 16 hyperplastic polyps, were analyzed by next-generation sequencing using a panel of 50 oncogenes and tumor suppressor genes. The genetic ancestry of the patients was estimated. RESULTS: Somatic driver mutations were identified in 66.7% of cases, including alterations in APC (32.2%), TP53 (20.0%), KRAS (18.9%), BRAF (13.3%) and EGFR (7.8%). Adenomas displayed a higher number of mutations, mainly in APC, compared to serrated polyps (73.1% vs. 47.8%, p = 0.026). Advanced adenomas had a significantly higher frequency of mutation in KRAS and a high overall mutation rate than early adenomas (92.9% vs. 59%, p = 0.006). A high degree of ancestry admixture was observed in the population studied, with a predominance of European components (mean of 73%) followed by African (mean of 11.3%). No association between genetic ancestry and type of lesions was found. The mutation profile of Brazilian colorectal precursor lesions exhibits alteration in APC, KRAS, TP53, and BRAF at different frequencies according to lesion type. CONCLUSIONS: These results bestow the knowledge of CRC's biologic history and support the potential of these biomarkers for precursor lesions detection in CRC screening of the Brazilian population.

Genome-wide analysis of mRNA expression identified the involvement of trefoil factor 1 in the development of sessile serrated lesions.

Precursor lesions that progress into colorectal cancer (CRC) could be largely classified into sessile serrated lesions (SSLs), traditional serrated adenoma (TSA), and tubular adenoma (TA). We aimed to determine whether high expression of trefoil factor 1 (TFF1) is closely associated with serrated lesions, particularly SSLs. The samples were divided into the first (12 SSLs, 5 TSAs, and 15 TAs) and second cohorts (15 SSLs, 9 TSAs, and 15 TAs). First, we investigated TFF1 expression in isolated gland samples using array-based and reverse-transcription PCR. Second, we performed immunohistochemical analysis of TFF1 expression in paraffin-embedded tissues obtained from SSL, TSA, TA, and hyperplastic polyp (HP) samples. In addition, we compared TFF1 mRNA levels between SSLs and HPs. TFF1 expression was significantly higher in SSLs than in TSA and TA in both cohorts. Additionally, immunohistochemical staining of TFF1 in the HP, SSL, TSA, and TA samples revealed significant differences in the immunohistochemical scores of TFF1 among the four types of lesions (higher expression in SSLs than in the other three lesions). Finally, there were significant differences in TFF1 mRNA expression levels between SSLs and HPs in paraffin-embedded tissues. However, there was considerable overlap in the immunohistochemical scores and expression levels of TFF1 transcripts between SSLs and HPs. The current findings may help elucidate the molecular mechanisms involved in serrated lesion development. In addition, we suggest that despite the limited practical application, upregulation of TFF1 transcripts may help differentiate SSLs from other lesions.

Characterization of mucin gene expression and goblet cell proportion in inflammatory colorectal polyps in miniature dachshunds.

Hyperplastic goblet cells and abundant mucus are significant characteristics of inflammatory colorectal polyps (ICRPs) in miniature dachshunds. In this study, selected mucin gene expressions and goblet cell proportions were evaluated in miniature dachshunds with ICRPs and in healthy dogs. Mucin 2 (MUC2) gene expression was not significantly different among the groups, whereas mucin 5AC (MUC5AC) gene expression was significantly higher in the polypoid lesions than in healthy colonic mucosa. Although the percentage of goblet cells in the upper crypt regions did not significantly differ between the groups, that in the lower crypt regions was significantly decreased in polypoid lesions. In conclusion, increased MUC5AC gene expression and goblet cell proportion changes may be associated with the pathogenesis of ICRPs.

Transcriptome of sessile serrated adenoma/polyps is associated with MSI-high colorectal cancer and decreased expression of CDX2.

The objective of this study was to elucidate the molecular background of sessile serrated adenoma/polyp (SSA/P) endoscopically resected with comprehensive gene expression analysis. Gene expression profiling was performed for 10 tumor-normal pairs of SSA/P. Cluster analysis, gene set enrichment analysis (GSEA), and consensus molecular subtype (CMS) classification of colorectal cancer (CRC) were applied to our transcriptome analysis. Unsupervised cluster analysis showed that the gene expression profile of SSA/Ps is different from that of adjacent normal epithelial cells, even in the very early stage of tumorigenesis. According to the CMS classification, our microarray data indicated that SSA/Ps were classified as CMS1. GSEA demonstrated a strong association between SSA/P and microsatellite instability-high (MSI-H) CRC (p < 10-5 ). Transcriptome analysis of five MSI-related genes (MSH2, MSH6, MLH1, PMS1, and PMS2) and five CRC-related genes (BRAF, KRAS, APC, TP53, and CDX2) showed that CDX2 expression was most severely decreased in SSA/P. Immunohistochemical staining confirmed that CDX2 protein was reduced compared with the surrounding mucosa. Direct sequencing of the BRAF gene showed that the BRAF V600E mutation was detected in only nine of 36 cases. In a mouse model, BRAF, APC, or CDX2 deficiency indicated that the gene expression pattern with loss of CDX2 is more similar to our SSA/Ps compared with those induced by BRAF or APC mutation. Transcriptome analysis of SSA/Ps showed characteristic gene expression with a strong resemblance to MSI-H CRC. Downregulation of CDX2 expression is an essential molecular mechanism involved in the initial stage of SSA/P tumorigenesis. (UMIN000027365).

Cause, Epidemiology, and Histology of Polyps and Pathways to Colorectal Cancer.

Colorectal cancer is the second leading cause of cancer-associated mortality, with a lifetime risk of approximately 4% to 5%. Colorectal cancer develops from the sequential acquisition of defined genetic mutations in the colonic epithelium. Tumorigenesis from normal tissue to cancer occurs largely through 3 pathways: the chromosomal instability pathway, the microsatellite instability pathway, and the sessile serrated pathway. Colorectal cancer incidence and mortality have decreased by approximately 35% since the beginning of screening programs in the 1990s, although other factors such as use of aspirin for coronary disease prevention and decreased smoking rates may also be important. In this review, we discuss the etiology, epidemiology, and histology of colorectal polyps and cancer.