What is Lynch syndrome (LS)?

Updated: Jun 06, 2020
  • Author: Jaime Shalkow, MD, FACS; Chief Editor: Cameron K Tebbi, MD  more...
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Lynch syndrome (LS) accounts for 2-4% of all diagnosed cases of colorectal cancer (CRC). It is characterized by a relatively young age of onset (45 years) and predominantly right-sided colon cancer, but it has been identified in children aged 9-13 years. The lifetime risk of LS-associated colorectal cancer is 52-82%. [7]

Patients with LS develop polyps that advance from adenoma to carcinoma more rapidly than in sporadic cases (2-3 years versus 8-10 years) and have a lifetime risk of CRC of 70%.

Forty percent of CRC cases in patients with LS are diagnosed before age 40 years. Histologically, these colonic tumors are often mucinous, high grade, poorly differentiated, and right sided, with large numbers of tumor-infiltrating lymphocytes. [3]  

DNA mismatch repair (MMR) is defective in this syndrome. MMR promotes genomic stability by correcting acid-base and small insertion/deletion loops that form during DNA replication. [7]

LS is caused by germline mutation in a mismatch DNA repair gene (human MutL homolog 1 [MLH1], human MutS homolog 2 [MSH2], human MutL homolog 6 [MSH6], human postmeiotic segregation increased 2 [PMS2], or epithelial cell adhesion molecule [EpCAM]), leading to microsatellite instability. Mutations in hMSH2 and hMLH1 account for up to 70-90% of defects identified in families with LS, mutations in MSH6 are found in 10-14% of defects, and mutations in PMS2 are found in 15% of defects. LS caused by mutations in MSH2 or MLH1 may present earlier than that caused by mutations in MSH6.

The resulting changes in sequence length, known as microsatellite instability, are a hallmark of LS. Microsatellite instability is associated with a favorable prognosis and has important implications for therapeutics in CRC.

Affected individuals often manifest café-au-lait spots, central nervous system tumors, and hematologic malignancies. Consanguinity is often noted in affected families, and parents of affected children rarely experience LS-related malignancy.

Few data on prophylactic colectomy for patients with LS are available. Carriers of a hereditary nonpolyposis colon cancer mutation rarely develop CRC in the first 2 decades of life. Prophylactic colectomy may be appropriate for patients whose colons are technically difficult to evaluate by colonoscopy, those who cannot or will not comply with screening recommendations, those with severe psychological distress resulting from fear of developing CRC, or patients with a family history of early-onset CRC. [39]  MMR deficiency is not exclusive for LS-associated tumors, as it has been found in 15-20% of sporadic CRC cases. [18]

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