From the Guidelines
Lynch Syndrome is a hereditary cancer predisposition disorder caused by germline mutations in DNA mismatch repair (MMR) genes, primarily MLH1, MSH2, MSH6, PMS2, and EPCAM, which normally function to identify and repair errors that occur during DNA replication. The genetic basis of Lynch Syndrome involves mutations in these genes, leading to a defective DNA mismatch repair system, genomic instability, and an increased risk of developing certain cancers 1. The primary genes involved are MLH1, MSH2, MSH6, PMS2, and EPCAM, with MLH1 and MSH2 mutations accounting for approximately 70-80% of Lynch Syndrome cases, while MSH6 and PMS2 mutations are less common 1. EPCAM mutations cause Lynch Syndrome through a unique mechanism - deletions in EPCAM can lead to inactivation of the adjacent MSH2 gene 1. The syndrome follows an autosomal dominant inheritance pattern, meaning that inheriting just one defective copy of any of these genes from either parent is sufficient to cause the condition.
Some key points about the genetic basis of Lynch Syndrome include:
- The genes involved in Lynch Syndrome are MLH1, MSH2, MSH6, PMS2, and EPCAM 1
- MLH1 and MSH2 mutations account for approximately 70-80% of Lynch Syndrome cases 1
- EPCAM mutations cause Lynch Syndrome through a unique mechanism - deletions in EPCAM can lead to inactivation of the adjacent MSH2 gene 1
- The syndrome follows an autosomal dominant inheritance pattern 1
- This genetic defect results in a significantly increased lifetime risk of colorectal cancer (up to 80%), endometrial cancer in women (up to 60%), and elevated risks for cancers of the ovary, stomach, small intestine, urinary tract, and other organs 1.
The most recent and highest quality study, published in 2024, provides the most up-to-date information on the genetic basis of Lynch Syndrome and its associated cancer risks 1. The identification of Lynch Syndrome is important for individuals with cancer and their families, as it allows for early detection and prevention of cancer through surveillance and heightened attention to symptoms.
From the Research
Genetic Basis of Lynch Syndrome
The genetic basis of Lynch syndrome is attributed to mutations in the following genes:
- MLH1
- MSH2
- MSH6
- PMS2
- EPCAM
Key Findings
- Lynch syndrome is an autosomal dominant disease caused by germline variants in one of the four mismatch repair genes or the EPCAM gene 2, 3.
- The syndrome is characterized by a high lifetime risk of colorectal, endometrial, gastric, ovarian, hepatobiliary, brain, and other cancers 2, 3.
- Mutations in MLH1 and MSH2 account for approximately 90% of Lynch syndrome cases, while MSH6 and PMS2 account for around 10% 4.
- The molecular characterization of Lynch syndrome is crucial for defining the syndrome and providing predictive information on cancer risks 4.
- Recent developments in high-throughput technologies and computational prediction tools may improve the assessment of variants of unknown significance in Lynch syndrome 5.
Molecular Mechanisms
- Loss-of-function variants in the MLH1, MSH2, MSH6, and PMS2 genes disrupt the DNA mismatch repair system, leading to a detrimental increase in the cellular mutational burden and cancer development 5.
- The treatment prospects for Lynch syndrome rely heavily on early diagnosis, which is inextricably linked to correct clinical interpretation of individual variants 5.