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home - Colon - Colorectal and Anal Cancer - Lynch Syndrome Written by Dr Sebastian Zeki
Knowledge

Knows the pathology of benign and malignant tumours of the colon
and rectum
Has awareness of the molecular genetics of colorectal
carcinogenesis and the adenoma-carcinoma sequence
Knows the range of predisposing conditions including inherited
syndromes and acquired colonic diseases
Knows the range of clinical presentation and the means of
diagnosis, investigation, management and follow-up
Knows the strategy for prevention including procedures for
screening

Skills
Uses clinical assessment and selects investigations to reach a rapid
conclusion as to whether a patient might have colorectal cancer and
arranges timely investigation.
Refers the patient to the multi-disciplinary team CbD, mini-CEX,

Behaviours
Shows ability to react to possible diagnosis of malignancy in a timely
manner

Communicates with patient and family in a sympathetic and
understanding manner, explains next steps, involves other health
professionals (including the GP) as appropriate

Lynch Syndrome

Lynch syndrome (=hereditary nonpolyposis colorectal cancer) Most common of the inherited colon cancer susceptibility syndromesIt accounts for 2 to 3 % of all colon cancer cases and similarly is responsible for about 2 % of uterine cancer M M R M u t a t i o n AD CRCInitial colorectal cancer diagnosis is about 45 years, compared to around age 65 for sporadic CRC Lifetime risk of 70% Ovarian (mean age 50), Upper urologic tractGastricSmall bowel, Biliary/pancreaticSkin (sebaceous adenomas and carcinomas and keratoacanthomas),Brain cancers. Amsterdam II Criteria:-"3-2-1 rule" (3 affected members, 2 generations, 1 under age 50).Not sensitive enough.3or>3 relatives with HNPCC-assoc. cancers (colorectal cancer, cancer of the endome-trium, small bowel, ureter, or renal pelvis), one of whom is a FDR of the other 2 and in whom FAP has been excluded. Lynch syndrome-associated cancers involving at least two generations.In which one or more cancers were diagnosed before the age of 50.Bethesda guidelines —= List of criteria that suggest Lynch syndrome in a patient with colon cancer If meet criteria, do MSI testing, and if positive, do germline MMR testing (by IHC for protein, and then for specific mutations)If positive MMR, need family testing and genetic counsellingHigh sensitivity, but low specificityPredictive models —Leiden model /MMRpro model /PREMM model MSI testingby PCR or IHC- IHC can detect PMS2 and MLH6 which PCR cannot Positive (90%) Positive Negative MMR testing (by IHC for protein, and then for specific mutations) Genetic counselling and family testing Probable hypermethyla-tion of MLH1 MLH1 by IHC Tests for methylation of MLH1 or BRAF mutational testing to identify the sporadic microsatellite unstable cancers. Positive Negative Probable undetectable MMR mutation and therefore presumed Lynch syndrome Mismatch Repair Genes:hMSH2 (human MutS homolog 2)-chromosome 2p16.hMLH1 (human MutL homolog 1)- chromosome 3p21. hPMS1 and hPMS2 (human postmeiotic segregation 1 and 2) chromosomes 2q31 and 7p22, respectively.hMSH6 (human MutS homolog 6) chromosome 2p16. hMLH3, a mismatch repair gene that interacts with MLH1, although mutations in this gene have not yet been found in HNPCC. MutL-alpha-heterodimer of MLH1 and PMS2MutL-beta-MLH1/PMS1 heterodimer,MutL-gamma-MLH1/MLH3 heterodimer MutS-alpha- MSH2 and MSH6 heterodimerMutS-beta-MSH2/MSH3 heterodimer Mismatch recognition proteins Mismatch repair proteins Microsatellite instability Leads to Mutations in MSH2 or MLH1 are thought to account for about 90 % MSH6 mutations are thought to account for most of the remainderPMS2 mutations have been described in relatively few Lynch families.The overall cancer risk (about 80 %) and the colorectal cancer risk (50 to 70 %) is similar in MLH1 and MSH2 familiesMSH2 families- Higher risk of endometrial and other extracolonic cancersFamilies with MSH6 and possibly PMS2 mutations have later age of cancer diagnosis and a lower penetrance compared to MLH1 and MSH2 families. Cancer 2-3yrs 70 % of Lynch CRC proximal to the splenic flexure vs 40% in sporadic Evolve from adenomasAdenomas are larger, flatter and more likely to have high grade dysplasia/ villous architectureCan have intense lymphocytic infiltrate Extracolonic cancers in Lynch syndrome70% are females- Endometrial carcinoma is predominant.Cancers of ovary, stomach, small bowel, pancreas, hepatobiliary system, renal pelvis, and ureter are known associations.Prostate and breast may be partly associated but it is unclear.The cumulative risk is related to the specific MMR mutation. More commonly poorly differentiatedMore commonly mucinous than sporadic CRCBetter 5 yr survival rates Muir-Torre and Turcot variants of Lynch syndrome Muir-Torre (Lynch syndrome with associated sebaceous tumours, cutaneous keratoacanthomas, and visceral carcinomas).Turcot syndrome (Lynch syndrome with associated brain tumours, typically gliomas). Identification Of Patients With Lynch Syndrome: Written by Dr Sebastian Zeki

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