{"entity":{"id":"lynch-syndrome","kind":"term","name":"Lynch syndrome","aka":[],"tldr":"Lynch syndrome is the most common inherited cancer syndrome: a faulty mismatch-repair gene raises lifetime bowel cancer risk to 40-80% and also endometrial and other cancers.","summary":"Germline MLH1, MSH2, MSH6, PMS2, or EPCAM variants; ~3% of CRC and 1 in ~280 people. Colonoscopy every 1-2 years from age 20-25, aspirin chemoprevention (CAPP2), and risk-reducing hysterectomy. Lynch tumours are dMMR and highly immunotherapy-responsive; frameshift neoantigen vaccines (Nous-209) aim at prevention.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Lynch_syndrome","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Lynch_syndrome"},{"label":"Win, Cancer Epidemiol Biomarkers Prev 2017: prevalence and penetrance of major genes and polygenes for colorectal cancer (5,744 families)","url":"https://doi.org/10.1158/1055-9965.epi-16-0693"},{"label":"Moller, Gut 2017: cancer incidence and survival in Lynch syndrome under surveillance, the Prospective Lynch Syndrome Database (1,942 carriers)","url":"https://doi.org/10.1136/gutjnl-2015-309675"},{"label":"Monahan, Gut 2020: BSG, ACPGBI and UKCGG guidelines for the management of hereditary colorectal cancer","url":"https://doi.org/10.1136/gutjnl-2019-319915"}],"tags":[],"related":[],"cancers":["colorectal","endometrial","msi-high-pdac","lynch-associated-colorectal-cancer","prostate"],"sections":[],"technologies":["germline-testing","chemoprevention","colorectal-screening"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["msi","germline-vs-somatic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-moreira-lynch-syndrome-identification-jama-2012","paper-ligtenberg-epcam-deletion-msh2-silencing-nat-genet-2009","paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019","paper-guedes-msh2-loss-primary-prostate-ccr-2017"],"journals":[],"dependsOn":[],"notes":["Colorectal cancer: 312 of 10,206 colorectal cancer probands (3.1%) carried a mismatch repair gene mutation, and testing every tumour found all of them against 87.8% for the Bethesda guidelines and 85.4% for the Jerusalem recommendations (Moreira 2012), which is the evidence behind universal testing. Where the four genes sequence clean, a 3' EPCAM deletion may be silencing MSH2 in cis (Ligtenberg 2009). The commonest false lead is sporadic MLH1 silencing by CIMP-associated promoter methylation, which is why BRAF V600E or methylation testing follows an MLH1-deficient result (Weisenberger 2006).","Penetrance differs by gene. Among 1,942 carriers followed prospectively under colonoscopic surveillance, the cumulative incidence of colorectal cancer by age 70 was 46 percent for MLH1, 35 percent for MSH2, 20 percent for MSH6 and 10 percent for PMS2, and cancers appeared from age 25 in MLH1 and MSH2 carriers but only from about 40 in MSH6 and PMS2 carriers; ten-year crude survival was 91 percent when the first cancer was colorectal (Moller 2017).","Population prevalence, from modelling 5,744 families: 1 in 279 people carry a mismatch repair variant (MLH1 1 in 1,946, MSH2 1 in 2,841, MSH6 1 in 758, PMS2 1 in 714), and 1 in 45 carry a MUTYH variant (Win 2017).","Prostate cancer: 7 of the 32 men found to have microsatellite instability-high or mismatch repair deficient prostate cancer in a 1,033-man prospectively sequenced series carried a pathogenic germline variant in a Lynch syndrome gene, 21.9%, so finding the tumour phenotype should prompt a germline test (Abida 2019); 3 of 12 men with MSH2 protein loss on a primary tumour had a germline MSH2 mutation (Guedes 2017)."],"category":"Genomics & genetics"},"route":"/terms/lynch-syndrome/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"early-onset-colorectal","kind":"cancer","name":"Early-onset colorectal cancer (under 50)","route":"/cancers/early-onset-colorectal/"},{"id":"endometrial","kind":"cancer","name":"Endometrial cancer","route":"/cancers/endometrial/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"localised-small-bowel-adenocarcinoma","kind":"cancer","name":"Localised small bowel adenocarcinoma (stage I to III, resected)","route":"/cancers/localised-small-bowel-adenocarcinoma/"},{"id":"lynch-associated-colorectal-cancer","kind":"cancer","name":"Lynch syndrome-associated colorectal cancer","route":"/cancers/lynch-associated-colorectal-cancer/"},{"id":"gastric-msi-high","kind":"cancer","name":"Microsatellite-unstable (MSI-high) gastric cancer","route":"/cancers/gastric-msi-high/"},{"id":"msi-high-pdac","kind":"cancer","name":"Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma","route":"/cancers/msi-high-pdac/"},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/"},{"id":"endometrial-mmr-deficient","kind":"cancer","name":"Mismatch-repair-deficient endometrial cancer","route":"/cancers/endometrial-mmr-deficient/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"small-bowel","kind":"cancer","name":"Small intestine cancer (small bowel adenocarcinoma)","route":"/cancers/small-bowel/"}],"technology":[{"id":"aspirin-cancer-prevention","kind":"technology","name":"Aspirin for cancer prevention and adjuvant therapy","route":"/technologies/aspirin-cancer-prevention/"},{"id":"chemoprevention","kind":"technology","name":"Chemoprevention & risk-reducing surgery","route":"/technologies/chemoprevention/"},{"id":"colorectal-screening","kind":"technology","name":"Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)","route":"/technologies/colorectal-screening/"},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"msi-mmr-testing","kind":"technology","name":"MSI and mismatch-repair testing","route":"/technologies/msi-mmr-testing/"}],"term":[{"id":"cimp","kind":"term","name":"CpG island methylator phenotype (CIMP)","route":"/terms/cimp/"},{"id":"familial-pancreatic-cancer","kind":"term","name":"Familial pancreatic cancer and inherited risk (who qualifies for surveillance)","route":"/terms/familial-pancreatic-cancer/"},{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"},{"id":"hereditary-cancer-syndromes","kind":"term","name":"Hereditary cancer syndromes","route":"/terms/hereditary-cancer-syndromes/"},{"id":"lynch-syndrome-testing-uk","kind":"term","name":"Lynch syndrome testing after bowel cancer, and what it means for the family","route":"/terms/lynch-syndrome-testing-uk/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"mlh1-promoter-methylation","kind":"term","name":"MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss)","route":"/terms/mlh1-promoter-methylation/"}],"paper":[{"id":"paper-capp2-aspirin-lynch-lancet-2020","kind":"paper","name":"CAPP2: two years of aspirin cuts bowel cancer in Lynch syndrome by more than a third over 10 years","route":"/key-papers/paper-capp2-aspirin-lynch-lancet-2020/"},{"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","route":"/key-papers/paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014/"},{"id":"paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","kind":"paper","name":"CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer","route":"/key-papers/paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006/"},{"id":"paper-lynch-frameshift-vaccine-ccr-2020","kind":"paper","name":"First trial of a vaccine against the shared neoantigens of mismatch-repair-deficient cancers","route":"/key-papers/paper-lynch-frameshift-vaccine-ccr-2020/"},{"id":"paper-wardell-biliary-drivers-germline-j-hepatol-2018","kind":"paper","name":"Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations","route":"/key-papers/paper-wardell-biliary-drivers-germline-j-hepatol-2018/"},{"id":"paper-ligtenberg-epcam-deletion-msh2-silencing-nat-genet-2009","kind":"paper","name":"Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1","route":"/key-papers/paper-ligtenberg-epcam-deletion-msh2-silencing-nat-genet-2009/"},{"id":"paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018","kind":"paper","name":"Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations","route":"/key-papers/paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018/"},{"id":"paper-moreira-lynch-syndrome-identification-jama-2012","kind":"paper","name":"Identification of Lynch syndrome among patients with colorectal cancer","route":"/key-papers/paper-moreira-lynch-syndrome-identification-jama-2012/"},{"id":"paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998","kind":"paper","name":"Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma","route":"/key-papers/paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998/"},{"id":"paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","kind":"paper","name":"Inherited DNA-repair gene mutations in men with metastatic prostate cancer","route":"/key-papers/paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016/"},{"id":"paper-guedes-msh2-loss-primary-prostate-ccr-2017","kind":"paper","name":"MSH2 loss in primary prostate cancer","route":"/key-papers/paper-guedes-msh2-loss-primary-prostate-ccr-2017/"},{"id":"paper-nicolosi-germline-variants-prostate-testing-guidelines-jama-oncol-2019","kind":"paper","name":"Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines","route":"/key-papers/paper-nicolosi-germline-variants-prostate-testing-guidelines-jama-oncol-2019/"},{"id":"paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019","kind":"paper","name":"Prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade","route":"/key-papers/paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019/"}],"institution":[{"id":"bowel-cancer-uk","kind":"institution","name":"Bowel Cancer UK","route":"/institutions/bowel-cancer-uk/"}],"person":[{"id":"john-burn","kind":"person","name":"John Burn","route":"/people/john-burn/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation","route":"/roadmaps/colorectal-roadmap/"}],"bottleneck":[{"id":"b-hereditary-risk","kind":"bottleneck","name":"Inherited risk is mostly unidentified","route":"/bottlenecks/b-hereditary-risk/"},{"id":"b-generic-repurposing","kind":"bottleneck","name":"No incentive to repurpose cheap drugs","route":"/bottlenecks/b-generic-repurposing/"},{"id":"b-prevention-adoption","kind":"bottleneck","name":"Prevention we already have is not deployed","route":"/bottlenecks/b-prevention-adoption/"}],"target":[{"id":"epcam","kind":"target","name":"EpCAM","route":"/targets/epcam/"},{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"},{"id":"wrn","kind":"target","name":"WRN helicase (MSI-high cancers)","route":"/targets/wrn/"}],"pathway":[{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"}],"drug":[{"id":"ventana-mmr-rxdx","kind":"drug","name":"VENTANA MMR RxDx Panel","route":"/drugs/ventana-mmr-rxdx/"}],"collection":[{"id":"force-facing-our-risk","kind":"collection","name":"FORCE: Facing Our Risk of Cancer Empowered","route":"/collections/force-facing-our-risk/"}]}}