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.     

Molecular genetics of colorectal cancer: An overview

Colorectal cancer (CRC) is a major cause of morbidity and mortality from cancers in the United States. Recent studies have revealed the paradigm in which sequential genetic changes (mutations) result in the progression from normal colonic tissues to frank carcinoma. In particular, the study of hereditary colorectal cancer and polyposis syndromes such as familial adenomatous polyposis and hereditary nonpolyposis colon cancer has contributed enormously to the understanding of the pathogenesis of CRC. Here we describe some of the common genetic pathways in CRC and the mechanisms of action for some of the key genes involved in the formation of CRC. The understanding of the genetic pathways and functions in CRC may lead to the development of novel therapeutic approaches for treating this deadly disease.     

Epigenetics/epigenomics and prevention by curcumin of early stages of inflammatory-driven colon cancer

Colorectal cancer (CRC) is associated with significant morbidity and mortality in the US and worldwide. CRC is the second most common cancer-related death in both men and women globally. Chronic inflammation has been identified as one of the major risk factors of CRC. It may drive genetic and epigenetic/epigenomic alterations, such as DNA methylation, histone modification, and non-coding RNA regulation. Current prevention modalities for CRC are limited and some treatment regimens such as use the nonsteroidal anti-inflammatory drug aspirin may have severe side effects, namely gastrointestinal ulceration and bleeding. Therefore, there is an urgent need of developing alternative strategies. Recently, increasing evidence suggests that several dietary cancer chemopreventive phytochemicals possess anti-inflammation and antioxidative stress activities, and may prevent cancers including CRC. Curcumin (CUR) is the yellow pigment that is found in the rhizomes of turmeric (Curcuma longa). Many studies have demonstrated that CUR exhibit strong anticancer, antioxidative stress, and anti-inflammatory activities by regulating signaling pathways, such as nuclear factor erythroid-2-related factor 2, nuclear factor-κB, and epigenetics/epigenomics pathways of histones modifications, and DNA methylation. In this review, we will discuss the latest evidence in epigenetics/epigenomics alterations by CUR in CRC and their potential contribution in the prevention of CRC.     

The implications of colorectal cancer molecular biology in clinical practice

Colorectal cancer (CRC) is the third most common malignancy in the United States. Advances in molecular biology have enhanced the understanding of colorectal carcinogenesis. Approximately 75% of CRCs are sporadic; the rest are hereditary or belong to a familial syndrome. Identification of familial forms of CRC have enabled the development of several models of carcinogenesis and made CRC a well-studied malignancy in terms of molecular pathogenesis. Pathways containing multiple mutations and genetic alterations that play a role in hereditary CRC pathogenesis have been elucidated. Many of the molecular changes seen in these pathways also are involved in the development of sporadic cancers.     

Epigenetics Offer New Horizons for Colorectal Cancer Prevention

In recent years, colorectal cancer (CRC) incidence has been increasing to become a major cause of morbidity and mortality worldwide from cancers, with high rates in westernized societies and increasing rates in developing countries. Epigenetic modifications including changes in DNA methylation, histone modifications, and non-coding RNAs play a critical role in carcinogenesis. Epidemiological data suggest that, in comparison to other cancers, these alterations are particularly common within the gastrointestinal tract. To explain these observations, environmental factors and especially diet were suggested to both prevent and induce CRC. Epigenetic alterations are, in contrast to genetic modifications, potentially reversible, making the use of dietary agents a promising approach in CRC for the development of chemopreventive strategies targeting epigenetic mechanisms. This review focuses on CRC-related epigenetic alterations as a rationale for various levels of prevention strategies and their potential modulation by natural dietary compounds.     

Combining targeted therapeutics in the era of precision medicine

Colorectal cancer (CRC) is one of the most common cancers in the western world and is characterised by deregulation of the Wnt signalling pathway. Mutation of the adenomatous polyposis coli (APC) tumour suppressor gene, which encodes a protein that negatively regulates this pathway, occurs in almost 80% of CRC cases. The progression of this cancer from an early adenoma to carcinoma is accompanied by a well-characterised set of mutations including KRAS, SMAD4 and TP53. Using elegant genetic models the current paradigm is that the intestinal stem cell is the origin of CRC. However, human histology and recent studies, showing marked plasticity within the intestinal epithelium, may point to other cells of origin. Here we will review these latest studies and place these in context to provide an up-to-date view of the cell of origin of CRC.     

HNPCC and Sporadic MSI-H Colorectal Cancer: A Review of the Morphological Similarities and Differences

Morphological features may serve as diagnostically useful markers of colorectal cancer (CRC) with the microsatellite instability-high (MSI-H) phenotype. The most important of these are lymphocytic infiltration, mucin secretion and poor differentiation. These features are apparent in both sporadic MSI-H CRC and CRC occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). There is now strong evidence that that the two principal subtypes of MSI-H CRC evolve through different pathways. Sporadic MSI-H CRC orginate within serrated polyps with BRAF mutation and DNA methylation while CRC in HNPCC arise within conventional adenomas in which there is frequent mutation of APC or beta -catenin and/or K- ras. These early differences in pathogenesis translate into multiple morphological distinctions in the cancers developing through the two pathways. Lymphocytic infiltration, tumour budding (de-differentiation), and co-existing adenomas are more evident in HNPCC while mucin secretion, poor differentiation, tumour heterogeneity and glandular serration, and co-existing serrated polyps are more evident in sporadic MSI-H CRC. Sporadic MSI-H CRC are also characterized by cytoplasmic eosinophilia and nuclei that are large, round, vesicular and contain a prominent nucleolus while in HNPCC the cytological features recapitulate the basophilia and nuclear characteristics of conventional adenomas. In practice, lymphocytic infiltration is the most sensitive marker of MSI-H status in both sporadic CRC and HNPCC. The crucial distinction between HNPCC and sporadic MSI-H CRC should be achieved by means of all available data including family history, age at onset of malignancy and molecular features. There is increasing evidence that genetic factors may predispose to DNA methylation. This can result in familial clustering of MSI-H CRC in which the underlying mechanism is methylation of hMLH1 rather than germline mutation. Morphological features can assist is distinguishing such families from bona fide HNPCC families which they closely mimic.     

Diversity of axin in signaling pathways and its relation to colorectal cancer

Colorectal cancer is one of the commonest cancers in western world, while majority of cases of CRC are sporadic, a significant minority occurs as a result of inherited genetic mutations. Various studies have demonstrated that tumorigenesis of colon arises as a result of accumulation of multiple genetic alterations targeting the single signal transduction pathway. Genetic alteration of axin has been implicated in different cancers including colorectal cancers. Axin being a multidomain protein interacts with multiple proteins and acts as major scaffold protein in signaling pathways like c-jun/SAPK, TGF-β, and Wnt. In different signaling pathways, axin utilizes different domains and hence exerts distinct roles.

     

Systems biology and OMIC data integration to understand gastrointestinal cancers

Gastrointestinal (GI) cancers are a set of diverse diseases affecting many parts/ organs. The five most frequent GI cancer types are esophageal, gastric cancer (GC), liver cancer, pancreatic cancer, and colorectal cancer (CRC); together, they give rise to 5 million new cases and cause the death of 3.5 million people annually. We provide information about molecular changes crucial to tumorigenesis and the behavior and prognosis. During the formation of cancer cells, the genomic changes are microsatellite instability with multiple chromosomal arrangements in GC and CRC. The genomically stable subtype is observed in GC and pancreatic cancer. Besides these genomic subtypes, CRC has epigenetic modification (hypermethylation) associated with a poor prognosis. The pathway information highlights the functions shared by GI cancers such as apoptosis; focal adhesion; and the p21-activated kinase, phosphoinositide 3-kinase/Akt, transforming growth factor beta, and Toll-like receptor signaling pathways. These pathways show survival, cell proliferation, and cell motility. In addition, the immune response and inflammation are also essential elements in the shared functions. We also retrieved information on protein-protein interaction from the STRING database, and found that proteins Akt1, catenin beta 1 (CTNNB1), E1A binding protein P300, tumor protein p53 (TP53), and TP53 binding protein 1 (TP53BP1) are central nodes in the network. The protein expression of these genes is associated with overall survival in some GI cancers. The low TP53BP1 expression in CRC, high EP300 expression in esophageal cancer, and increased expression of Akt1/TP53 or low CTNNB1 expression in GC are associated with a poor prognosis. The Kaplan Meier plotter database also confirmed the association between expression of the five central genes and GC survival rates. In conclusion, GI cancers are very diverse at the molecular level. However, the shared mutations and protein pathways might be used to understand better and reveal diagnostic/prognostic or drug targets.     

Undefined familial colorectal cancer

Colorectal cancer (CRC), one of the most common cancers of the world, is actually a spectrum of several subtypes, with different molecular profiles, clinico-pathological characteristics and possibly separate pathways of progression. It is estimated that in approximately 25%-35% of cases, a familial component exists, so they are classified as familial CRC (fCRC). However the known hereditary CRC syndromes justify only up to 5%. The rest are attributed to some inherited genetic predisposition passed to offspring through low-penetrance genes, which in the proper environmental setting can bring on tumorigenesis. Furthermore, part of the familial clustering may be attributed to chance. Because of the complexity regarding the etiology of CRC, the clinician is sometimes faced with obscure patient data, and cannot be sure if they are dealing with fCRC or sporadic CRC. The elucidation of what is going on with the as yet "undefined" portion of CRC will aid not only in the diagnosis, classification and treatment of CRC, but more importantly in the proper adjustment of the screening guidelines and in genetic counselling of patients.     

Colorectal cancer carcinogenesis: From bench to bedside

Colorectal cancer (CRC) remains one of the main causes of cancer death in developed countries. Yet, it is potentially preventable, by removing the precursor lesions - adenomas or serrated lesions. Several studies proved that this intervention reduces CRC mortality and that the first colonoscopy’s results can guide surveillance strategies. More recently, it became clear that several carcinogenesis pathways may lead to sporadic CRC. CRC is a heterogeneous disease, characterized by multiple molecular subtypes. Three main pathways have been implicated in the development of CRC: Chromosomal instability, microsatellite instability, and the “serrated” pathways, with overlapping features between them. This and other molecular and genetic based CRC classifications are known to have clinical implications, spanning from familial risk assessment to therapy choices. The authors review basic science data and provide insight on current implications for the management of patients with CRC.     

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.     

Molecular pathogenesis ofsporadic colorectal cancers

Colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic mucosa to adenocarcinoma. Approximately 75% of CRCs are sporadic and occur in people without genetic predisposition or family history of CRC. During the past two decades, sporadic CRCs were classiifed into three major groups according to frequently altered/mutated genes. These genes have been identiifed by linkage analyses of cancer-prone families and by individual mutation analyses of candidate genes selected on the basis of functional data. In the ifrst half of this review, we describe the genetic pathways of sporadic CRCs and their clinicopathologic features. Recently, large-scale genome analyses have detected many infrequently mutated genes as well as a small number of frequently mutated genes. These infrequently mutated genes are likely described in a lim-ited number of pathways. Gene-oriented models of CRC progression are being replaced by pathway-oriented models. In the second half of this review, we summarize the present knowledge of this research ifeld and discuss its prospects.     

Diversity of axin in signaling pathways and its relation to colorectal cancer

Colorectal cancer is one of the commonest cancers in western world, while majority of cases of CRC are sporadic, a significant minority occurs as a result of inherited genetic mutations. Various studies have demonstrated that tumorigenesis of colon arises as a result of accumulation of multiple genetic alterations targeting the single signal transduction pathway. Genetic alteration of axin has been implicated in different cancers including colorectal cancers. Axin being a multidomain protein interacts with multiple proteins and acts as major scaffold protein in signaling pathways like c-jun/SAPK, TGF-β, and Wnt. In different signaling pathways, axin utilizes different domains and hence exerts distinct roles.     

Evolving molecular classification by genomic and proteomic biomarkers in colorectal cancer: potential implications for the surgical oncologist

Colorectal cancer (CRC) is one of the most frequent cancers in the Western world and represents a major health burden. CRC development is a multi-step process that spans 10-15years, thereby providing an opportunity for early detection and even prevention. As almost half of all patients undergoing surgery develop recurrent disease, surveillance is advocated, albeit with various means and intervals. Current screening and surveillance efforts have so far only had limited impact due to suboptimal compliance. Currently, CEA is the only biomarker in clinical use for CRC, but has suboptimal sensitivity and specificity. New and better biomarkers are therefore strongly needed. Non-invasive biomarkers may develop through the understanding of colorectal carcinogenesis. Three main pathways occur in CRC, including chromosomal instability (CIN), microsatellite instability (MSI) and epigenetic silencing through the CpG Island Methylator Phenotype (CIMP). These pathways have distinct clinical, pathological, and genetic characteristics, which can be used for molecular classification and comprehensive tumour profiling for improved diagnostics, prognosis and treatment in CRC. Molecular-biological research has advanced with the sequencing of the human genome and the availability of genomic and proteomic high-throughput technologies using different chip platforms, such as tissue microarrays, DNA microarrays, and mass spectrometry. This review aims to give an overview of the evolving biomarker concepts in CRC, with concerns on methods, and potential for clinical implications for the surgical oncologist.     

DNA Methylation and Colorectal Cancer

Colorectal cancer (CRC) is one of the major cancers in the world and the second death-causing cancer in the USA. CRC development involves genetic and epigenetic alterations. Changes in DNA methylation status are believed to be involved at different stages of CRC. Promoter silencing via DNA methylation and hypomethylation of oncogenes alters gene expression and can be used as a tool for the early detection of colonic lesions. DNA methylation use as a diagnostic and prognostic marker has been described for many cancers including CRC. CpG island methylator phenotype (CIMP) is one of the underlying CRC mechanisms. This review aims to define methylation signatures in CRC. The analysis of DNA methylation profile in combination with the pathological diagnosis would be useful in predicting CRC tumor evolution and their prognostic behavior.     

Single nucleotide polymorphisms in sporadic colorectal cancer

Colorectal cancer (CRC) etiology involves multiple disease pathways. An important research element for unraveling these carcinogenic pathways to CRC is to gain an understanding of genetic susceptibility to CRC at the population level; single nucleotide polymorphisms (SNPs) are central to this research. Examination of a broad spectrum of SNPs along multiple disease pathways should help our understanding of cancer biology and the carcinogenic process. However, one of the greatest research challenges today will be to implement and interpret studies that utilize SNPs to gain insight into the genetic susceptibility of CRC.     

Colorectal carcinogenesis: Insights into the cell death and signal transduction pathways: A review

Colorectal carcinogenesis (CRC) imposes a major health burden in developing countries. It is the third major cause of cancer deaths. Despite several treatment strategies, novel drugs are warranted to reduce the severity of this disease. Adenomatous polyps in the colon are the major culprits in CRC and found in 45% of cancers, especially in patients 60 years of age. Inflammatory polyps are currently gaining attention in CRC, and a growing body of evidence denotes the role of inflammation in CRC. Several experimental models are being employed to investigate CRC in animals, which include the APC^min/+ mouse model, Azoxymethane, Dimethyl hydrazine, and a combination of Dextran sodium sulphate and dimethyl hydrazine. During CRC progression, several signal transduction pathways are activated. Among the major signal transduction pathways are p53, Transforming growth factor beta, Wnt/β-catenin, Delta Notch, Hippo signalling, nuclear factor erythroid 2-related factor 2 and Kelch-like ECH-associated protein 1 pathways. These signalling pathways collaborate with cell death mechanisms, which include apoptosis, necroptosis and autophagy, to determine cell fate. Extensive research has been carried out in our laboratory to investigate these signal transduction and cell death mechanistic pathways in CRC. This review summarizes CRC pathogenesis and the related cell death and signal transduction pathways.     

Early-onset gastric cancer: Learning lessons from the young

There is by no means a clear-cut pattern of mutations contributing to gastric cancers, and gastric cancer research can be hampered by the diversity of factors that can induce gastric cancer, such as Helicobacter pylori infection, diet, ageing and other environmental factors. Tumours are unquestionably riddled with genetic changes yet we are faced with an unsolvable puzzle with respect to a temporal relationship. It is postulated that inherited genetic factors may be more important in early-onset gastric cancer (EOGC) than in gastric cancers found in older patients as they have less exposure to environmental carcinogens. EOGC, therefore, could provide a key to unravelling the genetic changes in gastric carcinogenesis. Gastric cancers occurring in young patients provide an ideal background on which to try and uncover the initiating stages of gastric carcinogenesis. This review summarizes the literature regarding EOGC and also presents evidence that these cancers have a unique molecular-genetic phenotype, distinct from conventional gastric cancer.