<unk>  is a disease originating from the epithelial cells lining the colon or rectum of the gastrointestinal tract, most frequently as a result of mutations in the Wnt signaling pathway that increase signaling activity. The mutations can be inherited or acquired, and most probably occur in the intestinal crypt stem cell. The most commonly mutated gene in all<unk>  is the APC gene, which produces the APC protein. The APC protein prevents the accumulation of β-catenin protein. Without APC, β-catenin accumulates to high levels and translocates (moves) into the nucleus, binds to DNA, and activates the transcription of proto-oncogenes. These genes are normally important for stem cell renewal and differentiation, but when inappropriately expressed at high levels, they can cause cancer. While APC is mutated in most colon cancers, some cancers have increased β-catenin because of mutations in β-catenin (CTNNB1) that block its own breakdown, or have mutations in other genes with function similar to APC such as AXIN1, AXIN2, TCF7L2, or NKD1. Beyond the defects in the Wnt signaling pathway, other mutations must occur for the cell to become cancerous. The p53 protein, produced by the TP53 gene, normally monitors cell division and induces their programmed death if they have Wnt pathway defects. Eventually, a cell line acquires a mutation in the TP53 gene and transforms the tissue from a benign epithelial tumor into an invasive epithelial cell cancer. Sometimes the gene encoding p53 is not mutated, but another protective protein named BAX is mutated instead. Other proteins responsible for programmed cell death that are commonly deactivated in<unk> s are TGF-β and DCC (Deleted in<unk> . TGF-β has a deactivating mutation in at least half of<unk> s. Sometimes TGF-β is not deactivated, but a downstream protein named SMAD is deactivated. DCC commonly has a deleted segment of a chromosome in<unk> . Approximately 70% of all human genes are expressed in<unk> , with just over 1% of having increased expression in<unk>  compared to other forms of cancer. Some genes are oncogenes: they are overexpressed in<unk> . For example, genes encoding the proteins KRAS, RAF, and PI3K, which normally stimulate the cell to divide in response to growth factors, can acquire mutations that result in over-activation of cell proliferation. The chronological order of mutations is sometimes important. If a previous APC mutation occurred, a primary KRAS mutation often progresses to cancer rather than a self-limiting hyperplastic or borderline lesion. PTEN, a tumor suppressor, normally inhibits PI3K, but can sometimes become mutated and deactivated. Comprehensive, genome-scale analysis has revealed that<unk>  carcinomas can be categorized into hypermutated and non-hypermutated tumor types. In addition to the oncogenic and inactivating mutations described for the genes above, non-hypermutated samples also contain mutated CTNNB1, FAM123B, SOX9, ATM, and ARID1A. Progressing through a distinct set of genetic events, hypermutated tumors display mutated forms of ACVR2A, TGFBR2, MSH3, MSH6, SLC9A9, TCF7L2, and BRAF. The common theme among these genes, across both tumor types, is their involvement in Wnt and TGF-β signaling pathways, which results in increased activity of MYC, a central player in<unk> . Mismatch repair (MMR) deficient tumours are characterized by a relatively high amount of poly-nucleotide tandem repeats. This is caused by a deficiency in MMR proteins – which are typically caused by epigenetic silencing and or inherited mutations (e.g. Lynch syndrome). 15 to 18 percent of<unk>  tumours have MMR deficiencies, with 3 percent developing due to Lynch syndrome. The role of the mismatch repair system is to protect the integrity of the genetic material within cells (i.e.: error detecting and correcting). Consequently, a deficiency in MMR proteins may lead to an inability to detect and repair genetic damage, allowing for further cancer-causing mutations to occur and<unk>  to progress. The polyp to cancer progression sequence is the classical model of<unk>  pathogenesis. The polyp to cancer sequence describes the phases of transition from benign tumours into<unk>  over many years. Central to the polyp to<unk>  sequence are gene mutations, epigenetic alterations and local inflammatory changes. The polyp to<unk>  sequence can be used as an underlying framework to illustrate how specific molecular changes lead to various cancer subtypes. Field defects Longitudinally opened freshly resected colon segment showing a cancer and four polyps. Plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors. The term "field cancerization" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned (by what were largely unknown processes at the time) to predispose it towards development of cancer. Since then, the terms "field cancerization", "field carcinogenesis", "field defect", and "field effect" have been used to describe pre-malignant or pre-neoplastic tissue in which new cancers are likely to arise. Field defects are important in progression to colon cancer. However, as pointed out by Rubin, "The vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human<unk>  tumors occur before the onset of terminal clonal expansion." Similarly, Vogelstein et al. pointed out that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. Likewise, epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects. An expanded view of field effect has been termed "etiologic field effect", which encompasses not only molecular and pathologic changes in pre-neoplastic cells but also influences of exogenous environmental factors and molecular changes in the local microenvironment on neoplastic evolution from tumor initiation to death. Epigenetics Epigenetic alterations are much more frequent in colon cancer than genetic (mutational) alterations. As described by Vogelstein et al., an average cancer of the colon has only 1 or 2 oncogene mutations and 1 to 5 tumor suppressor mutations (together designated “driver mutations”), with about 60 further “passenger” mutations. The oncogenes and tumor suppressor genes are well studied and are described above under Pathogenesis. In addition to epigenetic alteration of expression of miRNAs, other common types of epigenetic alterations in cancers that change gene expression levels include direct hypermethylation or hypomethylation of CpG islands of protein-encoding genes and alterations in histones and chromosomal architecture that influence gene expression. As an example, 147 hypermethylations and 27 hypomethylations of protein coding genes were frequently associated with<unk> s. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers. In addition, 11 hypermethylations and 96 hypomethylations of miRNAs were also associated with<unk> s. Abnormal (aberrant) methylation occurs as a normal consequence of normal aging and the risk of<unk>  increases as a person gets older. The source and trigger of this age-related methylation is unknown. Approximately half of the genes that show age-related methylation changes are the same genes that have been identified to be involved in the development of<unk> . These findings may suggest a reason for age being associated with the increased risk of developing<unk> . Epigenetic reductions of DNA repair enzyme expression may likely lead to the genomic and epigenomic instability characteristic of cancer. As summarized in the articles Carcinogenesis and Neoplasm, for sporadic cancers in general, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene, but is much more frequently due to epigenetic alterations that reduce or silence expression of DNA repair genes. Epigenetic alterations involved in the development of<unk>  may affect a person's response to chemotherapy. Epigenomics Consensus molecular subtypes (CMS) classification of<unk>  was first introduced in 2015. CMS classification so far has been considered the most robust classification system available for<unk>  that has a clear biological interpretability and the basis for future clinical stratification and subtype-based targeted interventions. A novel Epigenome-based Classification (EpiC) of<unk>  was proposed in 2021 introducing 4 enhancer subtypes in people with<unk> . Chromatin states using 6 histone marks are characterized to identify EpiC subtypes. A combinatorial therapeutic approach based on the previously introduced consensus molecular subtypes (CMSs) and EpiCs could significantly enhance current treatment strategies.
Colorectal cancer
Irritable bowel syndrome
Anal cancer
Gastrointestinal cancer
Pancreatic cancer
Small intestine cancer
Colitis
Liver cancer