{"entity":{"id":"paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014","kind":"paper","name":"Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer","aka":[],"tldr":"The prostate cancers with a broken proofreading system usually break it by tearing the gene apart rather than by switching it off, which is the opposite of what happens in bowel cancer.","summary":"A hypermutated subtype of advanced prostate cancer had been described but its prevalence and mechanism were not characterised. Of 60 advanced prostate cancers examined, 7, 12%, were hypermutated, and all of the hypermutated cancers had mismatch repair gene mutations and microsatellite instability. The mutations were frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 epigenetic silencing, identifying both parallels and differences with the mechanisms of hypermutation in other microsatellite instability-associated cancers.","asOf":"2026-09-25","links":[{"label":"Pritchard et al., Nat Commun 2014: complex MSH2 and MSH6 rearrangements in hypermutated microsatellite-unstable advanced prostate cancer (60 cancers)","url":"https://doi.org/10.1038/ncomms5988"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25255306/"}],"tags":[],"related":[],"cancers":["prostate","prostate-mcrpc"],"sections":[],"technologies":["wes-wgs","cgp"],"targets":["msh2","msh6","mmr"],"drugs":[],"companies":[],"institutions":[],"pathways":["mismatch-repair-msi","ddr"],"terms":["msi","lynch-syndrome","tmb"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-communications"],"dependsOn":[],"notes":[],"journal":"Nature Communications","year":2014,"doi":"10.1038/ncomms5988","pmid":"25255306","authors":"Pritchard CC, Morrissey C, Kumar A, et al.","paperType":"basic","findings":["Seven of 60 advanced prostate cancers hypermutated, 12%.","All hypermutated cancers had mismatch repair gene mutations and microsatellite instability.","Complex MSH2 or MSH6 structural rearrangements rather than MLH1 promoter methylation."],"whatItMeans":"It matters for how the test is done. A mismatch repair assay designed around the colorectal mechanism, looking for MLH1 promoter methylation and simple mutations, can miss the prostate mechanism entirely, which is one reason microsatellite instability was under-recognised in this disease for so long.","caveats":["Sixty advanced cancers, so the 12% is imprecise and higher than the 3.1% found in a much larger prospectively sequenced series.","Rapid-autopsy and research material.","Structural rearrangements are hard to call on short-read panel data, so this mechanism is still under-detected."],"changedPractice":false,"participants":60},"route":"/key-papers/paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014/","neighbours":{"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"},{"id":"msh2","kind":"target","name":"MSH2","route":"/targets/msh2/"},{"id":"msh6","kind":"target","name":"MSH6","route":"/targets/msh6/"}],"pathway":[{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/"},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"}],"term":[{"id":"lynch-syndrome","kind":"term","name":"Lynch syndrome","route":"/terms/lynch-syndrome/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"journal":[{"id":"nature-communications","kind":"journal","name":"Nature Communications","route":"/journals/nature-communications/"}],"biomarker":[{"id":"msi-high","kind":"biomarker","name":"MSI-high (microsatellite instability by PCR or sequencing)","route":"/biomarkers/msi-high/"}]}}