结肠腺瘤发生的危险因素及和幽门螺杆菌感染的相关性分析

目的:分析结肠腺瘤发生的危险因素及和幽门螺杆菌(Hp)感染的相关性。方法:选择我院2018年6月～2018年12月收治的180例结肠腺瘤患者,同时选择我院接受结肠镜检查无异常者152例作为对照组。收集和比较两组患者的一般资料,采用14C尿氮呼气试验检测Hp的感染情况,多因素Logistic回归分析结肠腺瘤发生的危险因素。结果:多因素Logistic逐步回归分析结果显示男性、年龄、体质指数24 kg/m~2、腹型肥胖、饮酒、吸烟、喜食红肉、喜食果蔬、高脂血症、糖尿病、粪便隐血阳性、肿瘤家族史及Hp阳性是结肠腺瘤发生的危险因素,喜食果蔬为其发生的保护因素。HP阳性率组腺瘤1 cm、腺瘤数目多发、左结肠率高于Hp阴性组(P0.05);Hp阳性组和Hp阴性组肠腺瘤患者腺瘤蒂部分型、腺瘤病理类型比较差异无统计学意义(P0.05)。结论:结肠腺瘤的发生和多种危险因素有关,其中Hp感染可增加结肠腺瘤发生发展风险,临床应将此类高危人群作为结肠腺瘤的重点筛查对象,以降低结肠癌的潜在发生风险。     

Adenomas – Genetic factors in colorectal cancer prevention

Colorectal cancer is the second most common type of cancer both in Europe and Poland. During the last 30 years more than a 3-fold increase has been observed in Poland due to environmental and genetic factors. Almost all colorectal malignancies are related to the formation and malignant transformation of colorectal dysplasia and adenoma. Efforts aiming to decrease the number of colorectal cancer deaths are focused on the disease early detection. Genetic diagnosis for hereditary syndromes predisposing to colorectal cancer has been developed and is a part of the routine treatment. Most cancers are sporadic. They often develop from polyps in the colon. In addition to the genetic events described in the 1990s, showing the adenoma transformation into carcinoma that has been a prime example of malignant transformation for a long time, there are also other possibilities of neoplastic transformation. The recognition of colorectal cancer risk factors make sense as their nature is lifestyle- and diet-related. In this review paper those risk factors are presented and the prevention of colorectal cancer is discussed taking into account genetic factors.     

Fluorescent multiplexing of 3D spheroids: Analysis of biomarkers using automated immunohistochemistry staining platform and multispectral imaging

In preclinical cancer studies, three-dimensional (3D) cell spheroids and aggregates are preferred over monolayer cell cultures due to their architectural and functional similarity to solid tumors. We performed a proof-of-concept study to generate physiologically relevant and predictive preclinical models using non–small cell lung adenocarcinoma, and colon and colorectal adenocarcinoma cell line-derived 3D spheroids and aggregates. Distinct panels were designed to determine the expression profiles of frequently studied biomarkers of the two cancer subtypes. The lung adenocarcinoma panel included ALK, EGFR, TTF-1, and CK7 biomarkers, and the colon and colorectal adenocarcinoma panel included BRAF V600E, MSH2, MSH6, and CK20. Recent advances in immunofluorescence (IF) multiplexing and imaging technology enable simultaneous detection and quantification of multiple biomarkers on a single slide. In this study, we performed IF staining of multiple biomarkers per section on formalin-fixed paraffin-embedded 3D spheroids and aggregates. We optimized protocol parameters for automated IF and demonstrated staining concordance with automated chromogenic immunohistochemistry performed with validated protocols. Next, post-acquisition spectral unmixing of the captured fluorescent signals were utilized to delineate four differently stained biomarkers within a single multiplex IF image, followed by automated quantification of the expressed markers. This workflow has the potential to be adapted to preclinical high-throughput screening and drug efficacy studies utilizing 3D spheroids from cancer cell lines and patient-derived organoids. The process allows for cost, time, and resource savings through concurrent staining of several biomarkers on a single slide, the ability to study the interactions of multiple expressed proteins within a single region of interest, and enable quantitative assessment of biomarkers in cancer cells.     

Role of mast cells in colorectal cancer development, the jury is still out

The link between inflammation and colorectal cancer development is becoming increasingly clear. It had long been recognized that patients with inflammatory bowel disease are at an increased risk of colon cancer. Evidence from experimental animals now also implicates the innate immune system in the development of sporadically occurring intestinal adenomas, the precursors to colorectal cancer. Here we discuss the interaction between the immune system and the adenoma to carcinoma sequence with a special emphasis on the role of mast cells which may play a key role in adenoma development. This article is part of a Special Issue entitled: Mast cells in inflammation.     

Colon cancer specific nuclear matrix protein alterations in human colonic adenomatous polyps

Most colon cancers arise within preexisting adenomatous polyps or adenomas. The slow evolution from the non-invasive premalignant lesion, the adenomatous polyp, to invasive cancer supports a strategy of early detection. Recently, we identified unique nuclear matrix proteins (NMPs) specific for colon cancer (CC2, CC3, CC4, CC5). Most of the NMPs identified are common to all cell types, but several identified NMPs are tissue and cell line specific. The objective of this study is to describe and characterize the NMP profile of premalignant adenomatous colon polyps. Specifically when in the adenoma-carcinoma sequence four specific colon cancer NMPs, previously described, appear. Using two-dimensional (2-D) gel analysis 20 colon polyps (one juvenile polyp, six tubular adenoma (TA), seven tubulovillous adenoma (TVA), six TVA with focal high-grade dysplasia (HGD), were analyzed for the presence of four (CC2, CC3, CC4, CC5) specific NMPs. CC2 was not seen in any of the premalignant polyps. CC5 was present in only two premalignant TVA with HGD and in one TA. CC3 and CC4 were present in most adenomas. None of the NMPs were seen in the juvenile polyp, which is not considered to be a precursor of colon cancer. CC2 and CC5 are NMPs expressed at the junction of an advanced adenoma and invasive colorectal cancer. CC3 and CC4 are expressed earlier in the evolution of adenomatous polyps. Development of an assay to these proteins may serve as a new method for early detection of colorectal cancer.     

Differential expression of mimecan and thioredoxin domain-containing protein 5 in colorectal adenoma and cancer: a proteomic study

Adenoma is the major precursor lesion of colorectal cancer, one of the most common cancers worldwide. The elucidation of the molecular mechanism underlying adenoma is essential for early detection, prevention, and intervention of colorectal cancer. Using a combination of two-dimensional gel electrophoresis and mass spectrometry, we identified 27 differentially expressed proteins in adenoma, compared with matched normal mucosa and cancer tissue. Seventeen proteins were upregulated and six downregulated in adenoma when compared with the same proteins in individual-matched normal mucosa. Four were downregulated, but none upregulated in adenoma when compared with the same proteins in matched cancer tissue. Two novel proteins, mimecan and thioredoxin domain-containing protein 5 (TXNDC5), were further validated by Western blot in 8 colorectal adenomas and 19 cancers that were matched with normal mucosa. All adenoma and cancer tissues did not express mimecan, but all normal mucosa did (P < 0.01). In contrast, TXNDC5 was significantly upregulated in colorectal adenoma and cancer tissues as compared with that in normal mucosa (P < 0.05). This study clearly demonstrated that absence of mimecan and upregulation of TXNDC5 are involved in the early development of colorectal cancer. Thus, the differentially expressed proteins might serve as potential biomarkers for colorectal cancer detection and intervention.     

Biomarkers in nutritional epidemiology: applications, needs and new horizons

Modern epidemiology suggests a potential interactive association between diet, lifestyle, genetics and the risk of many chronic diseases. As such, many epidemiologic studies attempt to consider assessment of dietary intake alongside genetic measures and other variables of interest. However, given the multi-factorial complexities of dietary exposures, all dietary intake assessment methods are associated with measurement errors which affect dietary estimates and may obscure disease risk associations. For this reason, dietary biomarkers measured in biological specimens are being increasingly used as additional or substitute estimates of dietary intake and nutrient status. Genetic variation may influence dietary intake and nutrient metabolism and may affect the utility of a dietary biomarker to properly reflect dietary exposures. Although there are many functional dietary biomarkers that, if utilized appropriately, can be very informative, a better understanding of the interactions between diet and genes as potentially determining factors in the validity, application and interpretation of dietary biomarkers is necessary. It is the aim of this review to highlight how some important biomarkers are being applied in nutrition epidemiology and to address some associated questions and limitations. This review also emphasizes the need to identify new dietary biomarkers and highlights the emerging field of nutritional metabonomics as an analytical method to assess metabolic profiles as measures of dietary exposures and indicators of dietary patterns, dietary changes or effectiveness of dietary interventions. The review will also touch upon new statistical methodologies for the combination of dietary questionnaire and biomarker data for disease risk assessment. It is clear that dietary biomarkers require much further research in order to be better applied and interpreted. Future priorities should be to integrate high quality dietary intake information, measurements of dietary biomarkers, metabolic profiles of specific dietary patterns, genetics and novel statistical methodology in order to provide important new insights into gene-diet-lifestyle-disease risk associations.     

Site-specific risk factors for colorectal cancer in a Korean population

We investigated the association of colorectal cancer risk factors with different colorectal cancer subsites to assess etiological differences for cancers of the proximal colon, distal colon, and rectum. Included in this study were 869,725 men and 395,501 women who participated in a health examination provided by the Korean National Health System between 1996 and 1997. During up to 7 years of follow-up, 4,144 incident colorectal cancer cases were detected (3,051 men and 1,093 women). Greater height was associated with elevated risk for distal colon cancer and rectal cancer in both men and women. Family history of cancer was associated with higher risk for cancers of the proximal colon in men and distal colon in both men and women. Frequent alcohol consumption and consuming high amounts of alcohol were associated with elevated risk for distal colon cancer in men and higher risk for rectal cancer in women. Frequent meat consumption was associated with risk for proximal colon cancer in men and for rectal cancer in women. Our findings suggest that risk factors for colorectal cancer are different by subsites of colon and rectum, as well as by sex.     

Bulky DNA adduct levels in normal-appearing colon mucosa,and the prevalence of colorectal adenomas

Abstract

Purpose: Examine the association between bulky DNA adduct levels in colon mucosa and colorectal adenoma prevalence, and explore the correlation between adduct levels in leukocytes and colon tissue.

Methods: Bulky DNA adduct levels were measured using ³²P-postlabelling in biopsies of normal-appearing colon tissue and blood donated by 202 patients. Multivariable logistic regression was used to examine associations between DNA adducts, and interactions of DNA adduct-DNA repair polymorphisms, with the prevalence of colorectal adenomas. Correlation between blood and tissue levels of DNA adducts was evaluated using Spearman’s correlation coefficient.

Results: An interaction between bulky DNA adduct levels and XPA rs1800975 on prevalence of colorectal adenoma was observed. Among individuals with lower DNA repair activity, increased DNA adduct levels were associated with increased colorectal adenoma prevalence (OR?=?1.41 per SD increase, 95%CI: 0.92–2.18). Conversely, among individuals with normal DNA activity, an inverse association was observed (OR?=?0.60 per SD increase, 95%CI: 0.34–1.07). Blood and colon DNA adduct levels were inversely correlated (ρ?=??0.20).

Conclusions: Among genetically susceptible individuals, higher bulky DNA adducts in the colon was associated with the prevalence of colorectal adenomas. The inverse correlation between blood and colon tissue measures demonstrates the importance of quantifying biomarkers in target tissues.     

Early detection of colon cancer: new tests on the horizon

This year, the American Cancer Society reported that the rate of decline in both the incidence and mortality of colorectal cancer has increased over the last two decades. This success is felt to be attributable to the early detection and treatment of colonic adenomas and early-stage colorectal cancers. However, the current recommended 'menu of options' for screening is limited by poor patient acceptance, low sensitivity, and both high cost and poor accessibility for application to a large general screening population (colonoscopy). Computerized tomography and magnetic resonance colonography offer an alternative method for the identification of polyps and early lesions in certain patients, but have cost, access, and acceptance limitations that are similar to those of colonoscopy; thus, they present similar barriers to their use in broad population screening. These limitations provide a strong rationale for the development of early colorectal cancer detection biomarkers that are simple to use and are cost effective. A successful biomarker or biomarker panel, coupled with the colonoscopic follow-up of only those patients with positive results, would reduce the burden and morbidity associated with the screening of colonoscopy. This would most likely result in enhanced adherence to colorectal screening, as well as a dramatic reduction in the incidence and mortality rates of colorectal cancer. In this paper, we review recent advances in the discovery of potential colorectal cancer biomarkers. Their applicability to clinical population screening will require large prospective validation.     

Discovery and Validation of New Potential Biomarkers for Early Detection of Colon Cancer

Background

Accurate detection of characteristic proteins secreted by colon cancer tumor cells in biological fluids could serve as a biomarker for the disease. The aim of the present study was to identify and validate new serum biomarkers and demonstrate their potential usefulness for early diagnosis of colon cancer.

Methods

The study was organized in three sequential phases: 1) biomarker discovery, 2) technical and biological validation, and 3) proof of concept to test the potential clinical use of selected biomarkers. A prioritized subset of the differentially-expressed genes between tissue types (50 colon mucosa from cancer-free individuals and 100 normal-tumor pairs from colon cancer patients) was validated and further tested in a series of serum samples from 80 colon cancer cases, 23 patients with adenoma and 77 cancer-free controls.

Results

In the discovery phase, 505 unique candidate biomarkers were identified, with highly significant results and high capacity to discriminate between the different tissue types. After a subsequent prioritization, all tested genes (N = 23) were successfully validated in tissue, and one of them, COL10A1, showed relevant differences in serum protein levels between controls, patients with adenoma (p = 0.0083) and colon cancer cases (p = 3.2e-6).

Conclusion

We present a sequential process for the identification and further validation of biomarkers for early detection of colon cancer that identifies COL10A1 protein levels in serum as a potential diagnostic candidate to detect both adenoma lesions and tumor.

Impact

The use of a cheap serum test for colon cancer screening should improve its participation rates and contribute to decrease the burden of this disease.     

Plasma levels of resistin-like molecule beta in humans

Background: Resistin-like molecules (RELM) are expressed in many tissues and among those, RELMβ is most abundantly expressed in the colon. Based on animal studies, RELMβ is induced by high fat diets, obesity, and intestinal microflora and may play a role in insulin resistance and intestinal inflammation. In the present study, we evaluated whether RELMβ could be measured in human plasma and the influence of selected host and behavioral factors on RELMβ levels, including known risk factors for colorectal cancer. Methods: The subjects for this pilot study were derived from healthy controls who participated in a population-based case–control study of colorectal cancer in Metropolitan Detroit. The subjects were 45–80 years of age without history of cancer or colorectal resection. Results: RELMβ was present in human plasma, with levels in the range of 0.08–0.26 ng/mL. Lower RELMβ levels were found in subjects with non-Caucasian race, lower pack-years of smoking, and higher physical activity index scores. Other variables such as dietary intakes, gender, obesity, use of non-steroidal anti-inflammatory agents and history of polyps were not associated with RELMβ levels. Conclusions: The direct association of RELMβ with smoking and inverse association with physical activity, both of which are risk factors for colon cancer, indicates that RELMβ may be involved in mediating the effects of these two lifestyle factors on risk of colon cancer.     

Exocyclic DNA adducts as oxidative stress markers in colon carcinogenesis: potential role of lipid peroxidation,dietary fat and antioxidants

Molecular pathways to colorectal cancer involve multiple genetic changes, whereby extensive oxyradical damage causes mutations in cancer-related genes and leads to a cycle of cell death and regeneration. Besides direct oxidative DNA-damage, reactive oxygen and nitrogen species can induce etheno (epsilon)-DNA adducts mainly via trans-4-hydroxy-2-nonenal, generated as the major aldehyde by lipid peroxidation (LPO) of omega-6 PUFAs. Patients with familial adenomatous polyposis (FAP) develop multiple colorectal adenomas. In affected tissues increased LPO could be triggered due to increased arachidonic acid metabolism as a result of elevated cyclooxygenases. Our studies demonstrated an increased epsilon-DNA adduct level in affected colon epithelia of FAP patients. Epsilon-DNA adducts are promutagenic and can cause genomic instability that drives colorectal adenoma to malignancy. We have further investigated the potential chemopreventive properties of olive oil and its polyphenolic components. 'Mediterranean diet', of which olive oil is a major fatty acid source, has protective effects against human breast and colorectal cancers. Olive oil extracts and the newly identified lignan fractions showed high antioxidant capacity in vitro. As epsilon-DNA adducts are biomarkers for oxidative stress and LPO induced DNA damage, they can verify the efficacy of newly identified antioxidants, e.g. from olive oil, as chemopreventive agents against colon carcinogenesis.     

Progress in the identification of plasma biomarkers of colorectal cancer

Proteomic analysis of human tissue and plasma samples has been a useful tool in recent years for the identification of potential biomarkers to aid in the early diagnosis of colorectal cancer. However, biomarkers relating to the crucial transition between adenomatous lesions and invasive colorectal malignancy have not previously been described. The work of Choi et al. (Proteomics 2013, 13, 2361–2374) attempts to address this issue. Using plasma samples from age‐matched patients with colorectal adenomas or invasive disease this group identified a range of plasma proteins and cytokines that were differentially expressed. This information not only provides insights into the biology of the adenoma to carcinoma progression sequence but it also represents a step towards the goal of achieving diagnostically accurate and clinically acceptable biomarkers in early colorectal cancer.     

Use of Genome-Wide Association Studies for Cancer Research and Drug Repositioning

Although genome-wide association studies have identified many risk loci associated with colorectal cancer, the molecular basis of these associations are still unclear. We aimed to infer biological insights and highlight candidate genes of interest within GWAS risk loci. We used an in silico pipeline based on functional annotation, quantitative trait loci mapping of cis-acting gene, PubMed text-mining, protein-protein interaction studies, genetic overlaps with cancer somatic mutations and knockout mouse phenotypes, and functional enrichment analysis to prioritize the candidate genes at the colorectal cancer risk loci. Based on these analyses, we observed that these genes were the targets of approved therapies for colorectal cancer, and suggested that drugs approved for other indications may be repurposed for the treatment of colorectal cancer. This study highlights the use of publicly available data as a cost effective solution to derive biological insights, and provides an empirical evidence that the molecular basis of colorectal cancer can provide important leads for the discovery of new drugs.