Focus on genetic and epigenetic events of colorectal cancer pathogenesis: implications for molecular diagnosis

Originally, colorectal cancer (CRC) tumorigenesis was understood as a multistep process that involved accumulation of tumor suppressor genes and oncogenes mutations, such as APC, TP53 and KRAS. However, this assumption proposed a relatively limited repertoire of genetic alterations. In the last decade, there have been major advances in knowledge of multiple molecular pathways involved in CRC pathogenesis, particularly regarding cytogenetic and epigenetic events. Microsatellite instability, chromosomal instability and CpG island methylator phenotype are the most analyzed cytogenetic changes, while DNA methylation, modifications in histone proteins and microRNAs (miRNAs) were analyzed in the field of epigenetic alterations. Therefore, CRC development results from interactions at many levels between genetic and epigenetic amendments. Furthermore, hereditary cancer syndrome and individual or environmental risk factors should not be ignored. The difficulties in this setting are addressed to understand the molecular basis of individual susceptibility to CRC and to determine the roles of genetic and epigenetic alterations, in order to yield more effective prevention strategies in CRC patients and directing their treatment. This review summarizes the most investigated biomolecular pathways involved in CRC pathogenesis, their role as biomarkers for early CRC diagnosis and their possible use to stratify susceptible patients into appropriate screening or surveillance programs.     

Association of screening status,polygenic risk score and environmental risk factors with colorectal cancer incidence and mortality risks

Whether screening can attenuate the influence of genetic risk and environmental risk factors for colorectal cancer (CRC) mortality risk remains unknown. Our study is to investigate the association of the screening history, genetic risk and environmental risk factors with CRC incidence and mortality risks using UK Biobank data. Screening history was associated with lower CRC incidence (hazard ratio [HR]: 0.63, 95% confidence interval [CI]: 0.58-0.69) and mortality risk (HR: 0.56, 95% CI: 0.49-0.63). Compared to the HRs of participants with a low genetic risk, low environmental risk and no screening history, the HRs of participants with a high genetic risk, high environmental risk and no screening history were 3.42 (95% CI: 2.76-4.24) for CRC incidence and 3.36 (95% CI: 2.48-4.56) for CRC mortality. In contrast, the HRs of participants with a high genetic risk and no screening history, but a low environmental risk, were 1.92 (95% CI: 1.55-2.36) for CRC incidence and 1.88 (95% CI: 1.39-2.53) for CRC mortality. Furthermore, the HRs of participants with a high genetic risk and a low environmental risk, but a screening history were 1.62 (95% CI: 1.15-2.28) for CRC incidence and 1.77 (95% CI: 1.08-2.89) for CRC mortality. Participants benefited more substantially from screenings for CRC mortality than for CRC incidence risk. A higher environmental risk was associated with higher risk of CRC incidence and mortality within each category of genetic risk. These findings emphasize the importance of CRC screening and identifying environmental factors to reduce CRC incidence and mortality risks.     

Young Patients with Colorectal Cancer: Risk,Screening, and Treatment

Purpose of Review

While the incidence and mortality of colorectal cancer have been declining in the USA in the last decades, there is a considerable increase in the incidence of this malignancy in the young adult patients. Several environmental and genetic factors have been studied and known to be associated with colorectal cancer. However, the exact causes of this increase are not clear. Therefore, in this review, we aimed to provide insights in terms of novel findings and avenues of research that may lead to a better way to treat this population of patients.

Recent Findings

Obesity and its associated behaviors, such as unhealthy dietary patterns and sedentary lifestyles, as well as gut microbiota may play a crucial role in colorectal cancer (CRC) risk for young adults. Recently, the American Cancer Society recommends that adults aged 45 years and older with an average risk of CRC undergo regular screening with either a high-sensitivity stool-based test or a structural examination, depending on patient preference and test availability. It is important to note that data on outcomes associated with systemic cytotoxic and biologic therapy specifically in young patients with CRC are lacking.

Summary

In this review, we provide an overview on the most recent evidence regarding incidence, screening, molecular features, and management of young patients with colorectal cancer.

     

The role of gut microbiota in the pathogenesis of colorectal cancer

The human gastrointestinal tract harbors a complex and abundant microbial community that can reach levels as high as 10¹³–10¹⁴ microorganisms in the colon. These microorganisms are essential to a host’s well-being in terms of nutrition and mucosa immunity. However, numerous studies have also implicated members of the colonic microbiota in the development of colorectal cancer (CRC). While CRC involves a genetic component where damaged DNA and genetic instability initiates a malignant transformation, environmental factors can also contribute to the onset of CRC. Furthermore, considering the constant exposure of the colonic mucosa to the microbiome and/or its metabolites, the mucosa has long been proposed to contribute to colon tumorigenesis. However, the mechanistic details of these associations remain unknown. Fortunately, due to technical and conceptual advances, progress in characterizing the taxonomic composition, metabolic capacity, and immunomodulatory activity of human gut microbiota have been made, thereby elucidating its role in human health and disease. Furthermore, the use of experimental animal models and clinical/epidemiological studies of environmental etiological factors has identified a correlation between gut microbiota composition and gastrointestinal cancers. Bacteria continuously stimulate activated immunity in the gut mucosa and also contribute to the metabolism of bile and food components. However, the highest levels of carcinogen production are also associated with gut anaerobic bacteria and can be lowered with live lactobacilli supplements. In this review, evidence regarding the relationship between microbiota and the development of CRC will be discussed, as well as the role for microbial manipulation in affecting disease development.     

The role ofantioxidants andpro-oxidants in colon cancer Stone WL,Krishnan K,Campbell SE,Palau VE简

This review focuses on the roles antioxidants and pro-oxidants in colorectal cancer (CRC). Considerable evidence suggests that environmental factors play key roles in the incidence of sporadic CRC. If pro-oxidant factors play an etiological role in CRC it is reasonable to expect causal interconnections between the well-characterized risk factors for CRC, oxidative stress and genotoxicity. Cigarette smoking, a high dietary consumption of n-6 polyunsaturated fatty acids and alcohol intake are all associated with increased CRC risk. These risk factors are all pro-oxidant stressors and their connections to oxidative stress, the intestinal microbiome, intestinal microfold cells, cyclooxygenase-2 and CRC are detailed in this review. While a strong case can be made for pro-oxidant stressors in causing CRC, the role of food antioxidants in preventing CRC is less certain. It is clear that not every micronutrient with antioxidant activity can prevent CRC. It is plausible, however, that the optimal food antioxidants for preventing CRC have not yet been critically evaluated. Increasing evidence suggests that RRR-gamma-tocopherol (the primary dietary form of vitamin E) or other “non-alpha-tocopherol” forms of vitamin E (e.g., tocotrienols) might be effective. Aspirin is an antioxidant and its consumption is linked to a decreased risk of CRC.     

Meat,vegetables and genetic polymorphisms and the risk of colorectal carcinomas and adenomas

Background  

The risk of sporadic colorectal cancer (CRC) is mainly associated with lifestyle factors, particularly dietary factors. Diets high in red meat and fat and low in fruit and vegetables are associated with an increased risk of CRC. The dietary effects may be modulated by genetic polymorphisms in biotransformation genes. In this study we aimed to evaluate the role of dietary factors in combination with genetic factors in the different stages of colorectal carcinogenesis in a Norwegian population.     

Environmental Exposures,Tumor Heterogeneity,and Colorectal Cancer Outcomes

Considerable progress has been made in colorectal cancer (CRC) over the past two decades but it still remains the third commonest and third most deadly cancer in the USA. Epidemiologic and experimental studies have continued to describe links between environmental risk factors for developing nonhereditary CRC. However, the most significant recent advances have come through the understanding of CRC tumor heterogeneity and its impact on the variability of treatment efficacy. Using the KRAS mutation as a predictive biomarker for anti-epidermal growth factor receptor therapy is an example of how the genetic diversity of tumors can lead to a more individual or so-called personalized medicine with the goal of providing more benefits to patients, without unnecessary adverse side effects. Most recent reviews on this topic have focused on the key cancer pathways for which targeted therapies for CRC already exist. Less attention has recently been given to the three major genetic subtypes of CRC. Chromosomal instability, microsatellite instability, and CpG island methylator phenotype are thought to be the three major genetic and epigenetic alterations that drive tumorigenesis. In the past, these genetic alterations were used as a prognostic indicator, but recent data have demonstrated their correlation with treatment response.     

Association between pre-diagnostic circulating adipokines and colorectal cancer and adenoma in the CLUE II cohort

Objective

Obesity is a known risk factor for colorectal cancer (CRC) and adenoma. Obese individuals have higher circulating concentrations of certain endocrine and immune factors produced by adipocytes thought to partially underlie the association between obesity and colorectal neoplasia. Thus, we evaluated the association of plasma concentrations of adiponectin, leptin, and soluble tumor necrosis factor receptor-2 (sTNFR2) with CRC and adenoma.

Methods

We ascertained 193 CRC cases and 193 matched controls, and 131 colorectal adenoma cases and 131 matched controls who had had an endoscopy nested in the CLUE II cohort of Washington County, MD. Plasma markers were measured using ELISA. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression for quartiles of the plasma markers separately for CRC and adenoma.

Results

Adjusting for leptin and adiponectin, sTNFR2 was positively associated with CRC only in men (Q4 vs. Q1: OR?=?3.14, 95% CI 1.11–8.86), which was unchanged adjusting for BMI (3.46, 95% CI 1.19–10.06). Leptin and adiponectin were not associated with CRC risk overall or in men or women. Adiponectin, leptin, and sTNFR2 were not associated with adenoma risk overall or in men or women.

Conclusion

In this study, leptin and adiponectin were not associated with colorectal carcinogenesis and thus do not appear to underlie the association between obesity and colorectal carcinogenesis. sTNFR2, which we measured as a correlate of TNF-α, was positively associated with CRC in men adjusting for BMI, suggesting that TNF-α may influence colorectal carcinogenesis independent of adipocyte production.

     

Interaction between interleukin-10 (IL-10) polymorphisms and dietary fibre in relation to risk of colorectal cancer in a Danish case-cohort study

ABSTRACT: BACKGROUND: More than 50% of the colorectal cancer (CRC) etiology has been attributed to diet. Established or suspected dietary factors modifying risk of CRC are red meat, cereals, fish, and fibre. Diet and lifestyle may be linked to cancer through inflammation. Interleukin-10 (IL-10) is an anti-inflammatory cytokine. We wanted to test if dietary factors and IL10 polymorphisms interact in relation to colorectal carcinogenesis. METHODS: The functional IL10 polymorphism C-592A (rs1800872) and the marker rs3024505 were assessed in relation to diet and lifestyle in a nested case-cohort study of 378 CRC cases and 775 randomly selected participants from a prospective study of 57,053 persons. Genotyping data on the IL10 polymorphism C-592A, smoking and non-steroidal anti-inflammatory drugs (NSAID) was retrieved from Vogel et al (Mutat Res, 2007; 624:88). Incidence rate ratios (IRR) and 95% Confidence Interval (95% CI) were calculated. RESULTS: No associations were found between the IL10 rs3024505 polymorphism and risk of CRC. There was interaction between rs3024505 and dietary fibre (P-value for interaction=0.01). IL10 rs3024505 homozygous wildtype carriers were at 27% reduced risk of CRC per 10 g fibre per day (95% CI: 0.60-0.88) whereas variant carriers had no risk reduction by fibre intake. Also, interaction between IL10 C-592A and intake of fibre was found (P-value for interaction=0.02). Among those eating <17.0 grams of fibre per day, carriers of an C-592A variant allele had a statistically significantly higher risk of colorectal cancer compared to homozygous wildtypes. No significant differences in colorectal cancer risk were observed between the reference group (CC and <17.0 g/day) and carriers of one C-592A variant allele eating 17.0 or more grams of dietary fibre per day. This suggests that the increased risk due to carrying the variant allele can be overcome by higher fibre intake. No interactions between IL10 polymorphisms and dietary meat, cereal, or fish intake, or between IL10 rs3024505 and smoking or NSAID use were found. CONCLUSIONS: In this northern Caucasian cohort we found interaction between IL10 and dietary fibre in CRC carcinogenesis. High intake of fibre seems to protect against CRC among individuals with IL10 related genetic susceptibility to CRC. This finding should be evaluated in other prospective and population-based cohorts with different ethnic groups.     

The role of proteomics in the diagnosis and outcome prediction in colorectal cancer

Colorectal cancer is the second most frequent cancer in Western countries. Exogenous factors play a major role in the aetiology of sporadic colorectal cancer representing about 90% of all cases, hereditary cancers accounting for about 10% of patients. Thus, in the large majority of cases, cell dysfunction in CRC results from multiple rather than single, gene interactions. Numerous cellular events and environmental influences modify gene expression or post-translational protein modifications. Changes like glycosylation of proteins and lipids which are a common feature in colorectal cancer and influence cancer cell behaviour, cannot be directly detected by genetic studies. Better than genomics studies, functional proteomics studies allow the investigation of environmental factors over time, allowing the monitoring of metabolic responses to various stimuli. However, proteomics studies also have several drawbacks: a) current tools only allow narrow-range analyses, b) identification of proteins of interest remains cumbersome, c) protein studies address multiple compounds of high complexity, d) large amount of proteins are necessary to allow analysis, e) protein research require specific tools, e.g. tagged antibodies, that first have to be developed. Some protein tests are already in application for CRC: a classical prognostic test in colorectal cancer is based on the detection and quantification of a single protein (CEA) in body fluids. Recently, a screening assay based on APC protein truncation test has also been proposed. However, studies linking large protein expression patterns with clinical outcome in colorectal cancer are still in their infancy. To be able to predict occurrence of disease, and treatment outcome, more studies on genotype-phenotype correlations are needed both in sporadic and in hereditary colorectal cancer.     

Effect Modification of Meat Intake by Genetic Polymorphismson Colorectal Neoplasia Susceptibility

Colorectal cancer incidences differ considerably between Western and non-Western countries. In recentyears, a dramatic increase in colorectal cancer incidence has been reported in several Asian countries.Immigration studies have suggested that environmental rather than genetic factors are primarily responsiblefor the international variability and secular trends of colorectal cancer incidence rates. Therefore, not only themain effect of a gene but also the inflkuence of gene-environment interactions on cancer risk are important fromthe public health perspective. This review encompasses the literature on gene-diet interactions, particularlyfocusing on meat intake and its association with the risk of colorectal carcinoma or adenomas. It is generallyaccepted that genotypes which are associated with the higher enzyme activity for metabolic activation or loweractivity for detoxification would affect individual’s susceptibility to meat carcinogens. The most intensivelystudied genes were those involved in xenobiotic metabolism, including N-acetyltransferase (NAT), cytochromeP450 (CYP) families, glutathione S-transferase (GST), and sulfotransferase (SULT). However, the associationswere not consistent across studies. The role of genetic polymorphisms and their role in effect modificationof environmental carcinogens should be assessed in well-designed large-scale epidmiological studies withcomprehensive information for risk factors for better understanding the etiologic role of dietary factors and indeveloping personalized cancer prevention strategy in the genome-wide association study era.     

散发性结直肠癌发病分子机制研究进展

结直肠癌是最常见的消化系统恶性肿瘤之一,其病因和发病机制十分复杂。自1974年Morson提出结直肠腺瘤癌变序贯学说以来,随着现代分子生物学技术的飞速发展,研究者对结直肠癌发病的分子机制进行了深入研究。目前认为,结直肠癌的发生是一个多因素、多步骤、内外因交互作用的结果,且具有鲜明的分子特征,主要包括癌基因的激活、抑癌基因的失活及基因组不稳定现象等。全文主要围绕结直肠癌发病分子机制的最新研究进展作一综述。     

Clinical significance of tumor microsatellite instability and immunohistochemistry for mismatch repair deficiency in colorectal cancers

Referrals to genetics services are becoming increasingly common for patients who are diagnosed with early-onset colorectal cancer (CRC) or patients who have a family history of CRC. Microsatellite instability (MSI) testing and immunohistochemical analysis (IHC) of the patient’s tumor tissue, which assess indirectly the cellular status of DNA mismatch repair, have proven important tools for geneticists and genetic counselors to determine whether or not these individuals may be at risk for an inherited cancer syndrome, Lynch syndrome (a subset of hereditary nonpolyposis colorectal cancer). The application of tumor MSI/ IHC also extends to the group of providers involved in the diagnosis and management of CRC, demonstrating the growing clinical applicability of MSI/IHC testing. This review discusses the clinical utility of MSI/IHC analysis, including its benefits and limitations, and addresses some of the current debates surrounding testing.     

Environmental Exposure and Tumor Heterogeneity in Colorectal Cancer Risk and Outcomes

Colorectal cancers are a group of heterogeneous disorders that involve interactions among environmental influences, germ-line susceptibility factors, and accumulated genetic and epigenetic changes in the colorectal epithelium. This review provides background on environmental exposure and molecular pathways during colorectal cancer pathogenesis. Additionally, the review discusses the interplay between these risk factors in the context of colorectal cancer development and progression. Smoking, obesity, and regular aspirin use appear to have profound effects on colorectal cancer initiation and prognosis through the activation of pathways targeting gene methylation, inflammation, insulin mitogenesis, and cell proliferation. New data on other types of exposure and molecular changes will continue to improve our understanding of the cause of colorectal cancer, leading to novel therapeutic and preventive strategies and ultimate reduction in disease burden.     

Lifestyle factors and risk of sporadic colorectal cancer by microsatellite instability status: a systematic review and meta-analyses

IntroductionThe association of lifestyle factors with molecular pathological subtypes of colorectal cancer (CRC), such as microsatellite instability (MSI), could provide further knowledge about the colorectal carcinogenic process. The aim of this review was to evaluate possible associations between lifestyle factors and risk of sporadic CRC by MSI status.MethodsPubMed and Web of Science were searched for studies investigating the association between alcohol, body mass index, dietary fiber, hormone replacement therapy (HRT), non-steroidal anti-inflammatory drugs, physical activity, red meat, smoking, or statin use, with MSI-high (MSI-H) and microsatellite stable (MSS) CRC. Meta-analyses were carried out to calculate summary relative risks (sRR).ResultsOverall, 31 studies reporting on the association between lifestyle factors and CRC according to MSI status were included in this review. Ever smoking was associated with MSI-H (sRR = 1.62; 95% CI: 1.40–1.88) and MSS/MSI-low CRC (sRR = 1.10; 95% CI: 1.01–1.20), but the association was significantly stronger for MSI-H CRC. The use of HRT was associated with a 20% decrease (sRR = 0.80; 95% CI: 0.73–0.89) in the risk of MSS CRC, but was not associated with MSI-H CRC. An increase in body mass index per 5 kg/m² was equally associated with MSS and MSI-H CRC (sRR = 1.22, in both cases), but was statistically significant for MSS CRC only (95% CI: 1.11–1.34 and 0.94–1.58, respectively). Limited evidence for associations between other lifestyle factors and CRC by MSI status exists.ConclusionsLifestyle factors, such as HRT and smoking are differentially associated with the risk of MSI-H and MSS CRC. Further research on associations of lifestyle factors and CRC subtypes is necessary to provide a better understanding of the CRC disease pathway.     

Combinations of cytochrome P450 gene polymorphisms enhancing the risk for sporadic colorectal cancer related to red meat consumption.

Susceptibility to sporadic colorectal cancers (CRC) is generally thought to be the sum of complex interactions between environmental and genetic factors, all of which contribute independently, producing only a modest effect on the whole phenomenon. However, to date, most research has concealed the notion of interaction and merely focused on dissociate analyses of risk factors to highlight associations with CRC. By contrast, we have chosen a combinative approach here to explore the joint effects of several factors at a time. Through an association study based on 1,023 cases and 1,121 controls, we examined the influence on CRC risk of environmental factors coanalyzed with combinations of six single nucleotide polymorphisms located in cytochrome P450 genes (c.-163A>C and c.1548T>C in CYP1A2, g.-1293G>C and g.-1053C>T in CYP2E1, c.1294C>G in CYP1B1, and c.430C>T in CYP2C9). Whereas separate analyses of the SNPs showed no effect on CRC risk, three allelic variant combinations were found to be associated with a significant increase in CRC risk in interaction with an excessive red meat consumption, thereby exacerbating the intrinsic procarcinogenic effect of this dietary factor. One of these three predisposing combinations was also shown to interact positively with obesity. Provided that they are validated, our results suggest the need to develop robust combinative methods to improve genetic investigations into the susceptibility to CRC.     

Familial transmission of prostate,breast and colorectal cancer in adoptees is related to cancer in biological but not in adoptive parents: A nationwide family study

AimFamilial clustering of prostate, breast and colorectal cancer is well established, but the familial risk of these cancers has not been determined among adoptees. The aim was to disentangle the contributions of genetic and environmental factors to the familial transmission of prostate, breast and colorectal cancer.MethodsThe Swedish Multi-Generation Register was used to follow all adoptees born between 1932 and 1969 (n = 70,965) for prostate, breast and colorectal cancer from January 1958 up to December 2010. The risk of prostate, breast and colorectal cancer was estimated in adoptees with at least one biological parent with the same cancer type compared with adoptees without a biological parent with the same cancer type. The risk of cancer was also determined in adoptees with at least one adoptive parent with cancer compared with adoptees with an adoptive parent without cancer.ResultsAdoptees with at least one biological parent with prostate, breast or colorectal cancer were more likely to have cancer of the same type than adoptees with biological parents not affected by these respective cancer types (standardised incidence ratio = SIR: 1.8 [95% confidence interval 1.2–2.7], 2.0 [1.6–2.5] and 1.9 [1.2–2.9], respectively). In contrast, adoptees with at least one adoptive parent with prostate, breast or colorectal cancer were not at an increased risk of these respective cancer types (SIR = 1.2 [0.94–1.6], 0.97 [0.71–1.3], and 1.1 [0.71–1.5], respectively).ConclusionsThe findings of the study support the importance of genetic/biological factors in the familial transmission of prostate, breast and colorectal cancer.     

Genetic pathways in colorectal and other cancers

Cells from cancers show aberrant behaviour such as unrestrained growth, invasion into adjacent tissue and metastasis. All these features of cancer cell behaviour can be explained in terms of genetic changes and the functional impact of these changes. In this review, colorectal cancer (CRC) is examined as a classical example of multistep carcinogenesis. First there is an overview which shows that cancers develop by a process of somatic evolution. This gives rise to preferred genetic pathways of tumorigenesis. The factors which may influence the development and ultimate choice of genetic pathways are then examined. Next, CRC is studied as a specific disease and the putative genetic pathways are described. The mutations that comprise these pathways and the possible functional sequelae of these are explored. The review concludes with a look at those avenues which may further elucidate the natural history of CRC and lead to improved therapy. ©     

Brain Metastases from Colorectal Cancer: Risk Factors,Incidence, and the Possible Role of Chemokines

BackgroundBrain metastases from colorectal cancer (CRC) are uncommon. There has been relatively little published on the host and tumor factors that might lead to this clinical scenario. We reviewed all cases of brain metastases from CRC at Dartmouth-Hitchcock Medical Center over a more than 20-year period to establish incidence and to identify patient and cancer characteristics which were associated with their development.Patients and MethodsWe present a retrospective review of 39 confirmed cases of brain metastases from CRC diagnosed between 1984 and 2006. Immunohistochemical staining for CXCR4 was performed on all available brain metastasis biopsy specimens.ResultsThe incidence of brain metastases from CRC was 2.3%. Left-sided primary colon tumors predominated. The majority of patients had pulmonary metastases at the time brain metastases were identified, and those with preexisting pulmonary metastases had progression of that disease. All patients were symptomatic from brain metastases, and the cerebellum was the most common area of brain involvement. Immunohistochemical analysis confirmed strong expression of CXCR4 in all brain metastases sampled.ConclusionThe incidence of brain metastases from CRC is low. Primary tumor in the left colon, long-standing pulmonary metastases, especially those with recent progression, and CXCR4 expression by tumor cells are all associated with increased risk of brain metastases. Increased survival among patients with metastatic CRC will likely result in an increased incidence of brain metastases. Further characterization of the role of tumor and host factors might yield better insight into the development, and potentially the prevention, of this devastating situation.