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Lynch syndrome was first described by the American physician Henry T Lynch in and is a familial cancer condition that is almost always associated with the presence of a mono-allelic germline mutation in an MMR gene.

Neoplasms associated with Lynch syndrome 4 13 Inactivation of MMR genes occurs with MLH-1 and is a consequence of hypermethylation of the promoter sequence of the gene. Hypermethylation is a common biological process that comprises the addition of methyl groups —CH 3 to CpG islands.

Hypermethylation is a physiological process for controlling gene expression and many sites within the genome are methylated during cellular development and differentiation.

Hypermethylation of promoter sequences causes inactivation of the promoter and switches off the corresponding gene. Hypermethylation is usually a somatic process and within colorectal neoplasia, occurs commonly in the serrated pathway of carcinogenesis in association with BRAF mutations.

Constitutional hypermethylation can rarely occur and may be heritable in a Mendelian fashion, depending on the precise nature of MMR gene inactivation present. In clinical practice, dMMR may be detected at a genetic, protein or functional level. Diagnostic histopathologists will be most familiar with the use of immunohistochemistry IHC to demonstrate the presence of MMR proteins within tumour cell nuclei.

Due to MMR protein heterodimerism, the pattern of loss of expression of the four most commonly studied proteins provides useful clues to the most likely underlying genetic defect table 2. Some of the more commonly encountered difficulties in the interpretation of MMR protein expression are described in table 3.

However, heterogeneity of MMR protein expression may be encountered and manifests as a defined area of lost expression in the presence of retained stromal and inflammatory cell MMR protein staining—within a tumour that otherwise shows widespread expression of the protein s concerned. In this situation, an individual malignant gland can sometimes show zones of retained and lost MMR protein expression. Assuming that technical reasons for variations in staining intensity have been excluded, this heterogeneous staining implies the presence of a clonal somatic MMR gene mutation or localised hypermethylation process, that is, a mutation or genetic inactivation affecting only a small area of the tumour.

Importantly, it does not imply that a germline mutation is present. Commonly encountered difficulties in MMR protein immunohistochemistry interpretation. Microsatellites are non-coding DNA regions that are present throughout the genome and that—along with coding regions—are replicated imperfectly during cell division if there is dMMR.

However, if the index of suspicion for a germline MMR gene defect is high, for example, in a patient under investigation by a clinical genetics department for possible Lynch syndrome, they can both be applied to the same tumour. This approach can minimise the risk of missing dMMR—this could otherwise occur for example, due to the presence of a mutation that affects the function of an MMR protein but in which the enzyme is still demonstrable using IHC, or the presence of a defect in a different, rarely implicated MMR gene, for example.

Next generation sequencing is becoming more commonly used as an alternative method for detecting MSI. This is often as part of a broader panel for identifying somatic mutations and can be performed on formalin-fixed and paraffin-embedded tissue-derived DNA. This method may be better suited to large scale analyses and does not require the interrogation of matched normal tissue alongside the tumour sample. Formal genetic mutation analysis of germline DNA is the gold standard for identifying MMR gene mutations and if found, represent a powerful tool for screening family members.

However, sometimes rare or novel mutations are found and these can require correlation with IHC and MSI testing in order to assess whether they are likely to be pathogenic ie, disease-causing in nature. A germline MMR gene mutation confirming the diagnosis of Lynch syndrome is found in almost all patients with an appropriate family history and tumour characteristics suggesting the presence of such a mutation.

This can indicate the presence of a germline MLH-1 mutation but much more commonly occurs due to somatic MLH-1 inactivation associated with hypermethylation of its promoter sequence.

If a BRAF mutation is found, the tumour is most likely to be sporadic in nature and has probably developed along the serrated pathway. The presence of hypermethylation almost always indicates that the tumour is sporadic. The exception to this is constitutional hypermethylation that is, hypermethylation of germline DNA, representing a very rare cause of Lynch syndrome. This is because in these settings, they are likely to possess a germline MLH-1 mutation. This can provide an MMR status earlier in the patient pathway and rapid formalin fixation of small biopsy tissue fragments results in optimised antigen preservation and therefore minimised technical artefacts on IHC.

However, sometimes IHC on biopsies is not possible for example, if the biopsy shows features that are not diagnostic of adenocarcinoma, or if an emergency colorectal resection is performed without prior biopsy for example, due to bowel perforation or obstruction. In these situations, testing must instead be undertaken on resection material. Caution must be applied when interpreting MMR protein IHC in resection specimens from patients who have undergone neo-adjuvant therapy. Therefore, if loss of expression is found when examining a post-neoadjuvant therapy specimen, repeat MMR IHC on pretreatment biopsy material is required if this is available.

In colorectal neoplasia, while IHC and MSI testing for dMMR is usually undertaken on biopsy or resection material showing adenocarcinoma, useful information may sometimes be gained in patients under investigation for possible Lynch syndrome, via IHC performed on colorectal adenomas. This testing is sometimes requested by clinical genetics departments, for individuals from possible Lynch syndrome families who have had colorectal adenomas removed but who do not have CRC.

Loss of MMR protein expression can be seen in morphologically normal colonic mucosa in patients with Lynch syndrome but is only very exceptionally seen in individuals without this condition. This phenomenon can provide useful supporting evidence for the presence of Lynch syndrome, particularly in patients where germline MMR gene mutation analysis is inconclusive. Additional funding was not provided for pathology laboratories to support this development.

Individual patient consent is not required for this screening process, unless and until direct testing for a germline mutation is needed. Implementation of these guidelines also requires a well-defined pathway for the further investigation of MLHdeficient CRC and a reliable mechanism for ensuring that patients in whom screening suggests the presence of Lynch syndrome are appropriately referred to clinical genetics departments. In , NICE introduced similar guidelines for patients with endometrial cancer.

In CRC, the presence of dMMR is associated with a better stage-adjusted prognosis compared with MMR-proficient tumours, but a reduced likelihood of response to certain conventional chemotherapy regimens, for example, 5-fluorouracil 5-FU. In contrast, patients with endometrial cancer showing dMMR may show an improved response to adjuvant radiotherapy.

The introduction of immunotherapy has improved clinical outlook within a range of cancers and the number of cancer types in which immunotherapy has been shown to be of benefit is ever-increasing. The presence of dMMR leads to an increased mutational burden and the generation of novel peptide sequences by cancer cells, representing an enhanced range of epitopes that are potentially recognisable by the host immune system.

Therefore, tumours with dMMR may respond more favourably to immunotherapy than those lacking this feature. MMR proteins play a critical role in DNA repair and therefore help protect against the accrual of sporadic mutations and the development of neoplasia. Nowadays, a detailed understanding of the biology of dMMR is essential not only for the identification of inherited predisposition to cancer but also for guiding oncologists with treatment choices associated with both conventional chemotherapy and novel immunotherapies.

Funding The author has not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Provenance and peer review Not commissioned; externally peer reviewed. Skip to main content. Log in via OpenAthens. Log in using your username and password For personal accounts OR managers of institutional accounts. Forgot your log in details? Register a new account?

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DNA mismatch repair proteins: scientific update and practical guide. Statistics from Altmetric. DNA genes neoplasm immunohistochemistry colorectal neoplasms carcinoma Mismatch repair proteins and their function Mismatch repair MMR proteins are essential for repairing DNA errors eg, point mutations that are generated during DNA replication. Table 1 Neoplasms associated with Lynch syndrome 4 13 View this table: View inline View popup. Table 3 Commonly encountered difficulties in MMR protein immunohistochemistry interpretation.

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WebA deficient MMR (dMMR) system leads to accumulations of mismatches, insertions, and deletion in microsatellite repetitive sequences, resulting in microsatellite Missing: nuance · meaning. WebNuance Healthcare Service Community. Home; News and Events; MoreMissing: meaning. WebdMMR. Mismatch-repair Deficient Mismatch Repair. Research, Translational Medicine, Medical. Research, Translational Medicine, Medical. Vote. 2. Vote. dMMR. Deficient Missing: nuance.