Colon Cancer is not one disease \u2014 it is several different diseases that all look similar under the microscope, but got there by very different routes. Understanding these routes helps explain why some bowel cancers behave differently, respond to different treatments, and arise in different patients.
\nThere are three main roads to bowel cancer.<\/p>\n
Road 1 \u2014 The Classical Route (the most common)<\/strong> Road 2 \u2014 The Serrated Route<\/strong> Road 3 \u2014 Lynch Syndrome (the inherited route)<\/strong> Detecting MMR Deficiency: IHC versus Molecular MSI Testing<\/strong> The Bottom Line<\/strong> Quick Reference Glossary<\/strong> Reference: Guinney et al., Nature Medicine 2015 (Consensus Molecular Subtypes) | WHO Classification of Digestive System Tumours<\/p>\n","protected":false},"excerpt":{"rendered":" Colon Cancer is not one disease \u2014 it is several different diseases that all look similar under the microscope, but got there by very different routes. Understanding these routes helps explain why some bowel cancers behave differently, respond to different treatments, and arise in different patients. There are three main roads to bowel cancer. Road […]<\/p>\n","protected":false},"author":1119,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11192,290084,318392,1],"tags":[318395],"class_list":["post-137","post","type-post","status-publish","format-standard","hentry","category-cancer","category-gastro-intestinal-pathology","category-trainee","category-uncategorized","tag-gi"],"_links":{"self":[{"href":"https:\/\/blogs.imperial.ac.uk\/my-path\/wp-json\/wp\/v2\/posts\/137","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.imperial.ac.uk\/my-path\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.imperial.ac.uk\/my-path\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.imperial.ac.uk\/my-path\/wp-json\/wp\/v2\/users\/1119"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.imperial.ac.uk\/my-path\/wp-json\/wp\/v2\/comments?post=137"}],"version-history":[{"count":1,"href":"https:\/\/blogs.imperial.ac.uk\/my-path\/wp-json\/wp\/v2\/posts\/137\/revisions"}],"predecessor-version":[{"id":138,"href":"https:\/\/blogs.imperial.ac.uk\/my-path\/wp-json\/wp\/v2\/posts\/137\/revisions\/138"}],"wp:attachment":[{"href":"https:\/\/blogs.imperial.ac.uk\/my-path\/wp-json\/wp\/v2\/media?parent=137"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.imperial.ac.uk\/my-path\/wp-json\/wp\/v2\/categories?post=137"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.imperial.ac.uk\/my-path\/wp-json\/wp\/v2\/tags?post=137"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\nThis is the familiar “polyp to cancer” story. A conventional polyp (adenoma) develops in the lining of the bowel and, over 10\u201315 years, accumulates a series of faults in key genes \u2014 first APC, then KRAS, then TP53. Each fault gives the cells a further growth advantage until cancer develops.
\nThese cancers tend to be left-sided (descending colon and rectum) and are the ones most commonly detected by bowel cancer screening programmes.<\/p>\n
\nThis route starts from a different type of polyp \u2014 the sessile serrated lesion. These polyps are flat, pale, and easy to miss at colonoscopy, which is one reason this pathway is clinically important.
\nThe first genetic fault here is in a gene called BRAF. What happens next is unusual \u2014 instead of accumulating more gene mutations, the tumour takes an epigenetic shortcut.
\nWhat does epigenetic mean?
\nThink of genes as light switches. A genetic mutation breaks the switch permanently. An epigenetic change is different \u2014 it puts a piece of “sticky tape” over the switch, keeping it off without actually breaking it. The gene is still physically intact but cannot be read. This chemical silencing process uses methyl groups and is called methylation.
\nIn the serrated pathway, sticky tape is applied to the control switches of multiple genes simultaneously \u2014 a process called CIMP (CpG island methylator phenotype), or simply being “methylated”.
\nWhat happens next depends on which genes get silenced:
\n\u2022 If the sticky tape lands on MLH1 \u2014 the gene that proofreads and repairs DNA copying errors \u2014 the cell loses its ability to correct mistakes. Errors pile up rapidly in short repetitive DNA sequences called microsatellites. This is called microsatellite instability (MSI-H). These cancers have a very high number of mutations, attract a large immune response, tend to be right-sided, occur more often in older women, and respond very well to modern immunotherapy drugs.
\n\u2022 If the sticky tape does NOT silence MLH1, the cancer remains genomically stable (MSS). Paradoxically, this subgroup tends to behave more aggressively and does not respond to immunotherapy.
\nWhat about MSI-Low (MSI-L)?
\nYou will sometimes see a third category \u2014 MSI-Low (MSI-L) \u2014 in reports and papers. This means there is a small degree of microsatellite instability, more than a fully stable tumour but nowhere near the level seen in MSI-H. In practice, MSI-L is a borderline or intermediate result. Most MSI-L tumours behave biologically more like MSS cancers than MSI-H cancers \u2014 they do not carry the same good prognosis, do not respond to immunotherapy, and are not generally associated with Lynch syndrome. MSI-L is thought to reflect minor, incidental errors in DNA copying rather than a true failure of the mismatch repair system. In most clinical algorithms, MSI-L is grouped with MSS for treatment decisions.<\/p>\n
\nLynch syndrome also produces MSI-H cancers, but through a completely different mechanism. Here, a person is born with a faulty copy of one of the DNA repair genes. There is no sticky tape involved \u2014 the problem is hardwired into every cell of the body from conception.
\nHow is it inherited?
\nLynch syndrome follows an autosomal dominant pattern of inheritance. This means:
\n\u2022 Only one faulty copy of the gene is needed \u2014 inherited from one parent \u2014 to carry the syndrome. You do not need two faulty copies.
\n\u2022 Each child of an affected parent has a 50% chance of inheriting the faulty gene.
\n\u2022 It affects men and women equally.
\n\u2022 The faulty gene may have come from either the mother’s or father’s side of the family.
\nThe genes involved are the mismatch repair genes: MLH1, MSH2, MSH6, and PMS2. Carrying a faulty copy does not guarantee cancer \u2014 it raises the lifetime risk substantially (up to 70\u201380% for bowel cancer with MLH1\/MSH2 mutations) but is not inevitable. This is why Lynch families are offered regular surveillance colonoscopy.
\nLynch syndrome also increases the risk of cancers in other organs \u2014 particularly the womb (endometrium), ovary, stomach, urinary tract, and small bowel \u2014 because the same repair machinery operates throughout the body.
\nThe key distinction from the serrated pathway is that CIMP and BRAF mutation are absent in Lynch syndrome. Both arrive at MSI-H by different roads.<\/p>\n
\nIn routine clinical practice, there are two completely different laboratory methods used to detect defective DNA repair in bowel cancers. They measure different things, and it is important not to confuse them.
\nImmunohistochemistry (IHC) \u2014 looking at the proteins
\nIHC is a staining technique performed by the pathologist on the tumour tissue section. Antibodies are applied that specifically bind to the four MMR proteins \u2014 MLH1, MSH2, MSH6, and PMS2 \u2014 and a colour reaction shows whether each protein is present or absent in the tumour cell nuclei.
\nIn a normal tumour, all four proteins stain positively (present). If one or more proteins are lost, this indicates that the corresponding gene has been switched off or mutated \u2014 the cancer is said to show loss of MMR protein expression, or to be dMMR (deficient mismatch repair).
\nIHC has additional diagnostic value: the pattern of loss points towards the likely cause:
\n\u2022 Loss of MLH1 and PMS2 together \u2192 most likely sporadic (epigenetic silencing via CIMP, as in the serrated pathway). MLH1 methylation testing can confirm this.
\n\u2022 Loss of MSH2 and MSH6 together \u2192 strongly suggests Lynch syndrome (germline MSH2 mutation).
\n\u2022 Isolated loss of MSH6 or PMS2 \u2192 may indicate Lynch syndrome with a mutation in that specific gene.
\n\u2022 Loss of MLH1\/PMS2 in a younger patient, or without BRAF mutation \u2192 raises suspicion for Lynch syndrome even if MLH1 is lost.
\nIHC is widely available, inexpensive, fast, and gives results the pathologist can interpret directly from the slide. However, it tests for protein \u2014 it tells you the protein is missing but does not directly measure what is happening to the DNA.
\nMolecular MSI Testing \u2014 looking at the DNA directly
\nMolecular MSI testing (also called PCR-based MSI testing or next-generation sequencing MSI analysis) works at the DNA level. It directly measures the lengths of specific short repetitive DNA sequences \u2014 microsatellites \u2014 in the tumour compared to normal tissue. If these sequences are abnormally variable in length, the tumour is called MSI-H. If they are stable, it is called MSS.
\nThis test does not look at proteins at all. It confirms functionally that the DNA repair machinery has failed, regardless of which protein caused the problem or why.
\nSo which test does what?
\nThink of it this way:
\n\u2022 IHC asks: which MMR protein is missing from the tumour? It identifies the defective component and points towards the mechanism (sporadic vs Lynch).
\n\u2022 Molecular MSI testing asks: has the loss of that protein actually caused DNA repair failure? It confirms the functional consequence.
\n\u2022 The two tests usually agree \u2014 a tumour that is dMMR by IHC is almost always MSI-H by molecular testing, and vice versa. But there are occasional discordant cases where one test is positive and the other negative, which is why both may be used in complex or equivocal situations.
\n\u2022 IHC is the standard first-line test in most pathology laboratories because it is practical and gives mechanistic clues. Molecular MSI testing is used to confirm, for clinical trials, or when IHC results are equivocal.
\n\u2022 Neither test on its own tells you whether the MMR deficiency is due to Lynch syndrome (germline, inherited) or sporadic methylation \u2014 that question requires germline genetic testing of the patient’s blood DNA, ideally guided by the IHC pattern and MLH1 methylation status.<\/p>\n
\n\u2022 MSI (microsatellite instability) is the consequence \u2014 the end result of broken DNA repair, whatever the cause.
\n\u2022 MSI-H means the repair system has truly failed. MSI-L is a borderline finding that usually behaves like MSS and does not indicate Lynch syndrome.
\n\u2022 CIMP (methylation) is one mechanism that can cause MSI-H \u2014 by chemically silencing the MLH1 repair gene with sticky tape.
\n\u2022 The serrated pathway is the route \u2014 a distinct biological journey, starting from a different polyp, that frequently leads to CIMP and MSI-H.
\n\u2022 Lynch syndrome arrives at the same MSI-H destination by an entirely different, inherited road \u2014 a germline gene fault passed from parent to child with 50% probability.
\n\u2022 IHC and molecular MSI testing are complementary tools: IHC identifies which protein is lost and guides the search for the cause; molecular testing confirms that DNA repair has functionally failed.<\/p>\n
\nCIMP \u2014 CpG island methylator phenotype. The process of chemically silencing multiple genes simultaneously via methylation.
\ndMMR \u2014 Deficient mismatch repair. Detected by IHC as loss of one or more MMR proteins.
\nEpigenetic \u2014 Changes that affect gene activity without altering the DNA sequence itself.
\nIHC (Immunohistochemistry) \u2014 A staining technique that detects specific proteins in tissue sections using antibodies.
\nMethylation \u2014 Addition of methyl groups to gene promoters, acting like sticky tape over a switch to silence gene expression.
\nMMR \u2014 Mismatch repair. The cellular machinery that proofreads and corrects DNA copying errors.
\nMSI-H \u2014 Microsatellite instability-high. Confirms functional failure of DNA mismatch repair; high mutation burden; responds to immunotherapy.
\nMSI-L \u2014 Microsatellite instability-low. A borderline finding; behaves clinically like MSS; not associated with Lynch syndrome.
\nMSS \u2014 Microsatellite stable. Normal DNA repair function.
\nAutosomal dominant \u2014 Inheritance pattern where one faulty copy of a gene (from either parent) is sufficient to cause the condition; 50% transmission risk per child.
\nLynch syndrome \u2014 An inherited condition caused by a germline mutation in an MMR gene (MLH1, MSH2, MSH6, or PMS2), predisposing to bowel and other cancers.
\nBRAF \/ KRAS \/ APC \/ TP53 \u2014 Genes that when mutated drive cancer development along different pathways.<\/p>\n