free full access: Familial colorectal cancer risk: ESMO Clinical Practice Guidelines — Ann Oncol

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Lynch syndrome

prevalence and penetrance of mismatch-repair gene mutations

Lynch syndrome is the most common hereditary colorectal cancer (CRC) syndrome and it accounts for ∼1%–3% of all CRC burden. The syndrome is transmitted with an autosomal dominant pattern and it is associated with mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. These alterations lead to tumour DNA instability at microsatellites (MSI) and foster inactivating mutations in tumour suppressors containing microsatellites (i.e. TGF-βRII and BAX). Mutations in the MMR genes may lead to loss of expression of the corresponding protein and be detected by immunohistochemistry (IHC) techniques.

Overall, mutation carriers mainly have an increased risk of CRC (lifetime 30%–70%) and endometrial cancer (lifetime 30%–60%). Other extracolonic tumours observed at increased risk (lifetime 5%–15%) are urinary tract, small intestine, ovary, gastric, pancreas, biliary tract, brain and sebaceous gland tumours. A genotype–phenotype correlation has been observed in which MLH1 mutation carriers are at higher risk of young onset CRC cancer, MSH2 at higher risk of extracolonic cancers, MSH6 at increased risk of endometrial cancer and PMS2 carriers show a lower lifetime absolute risk of CRC and endometrial cancer (15%–20%) compared with other mutation carriers.

The name Turcot syndrome refers to patients with MMR gene mutations and brain tumours, and the name Muir–Torre syndrome to patients with cutaneous gland tumours (keratoacanthomas, sebaceous adenomas or adenocarcinomas)......cont'd