Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a hereditary cancer syndrome that increases the risk of developing several types of cancer. It is caused by mutations in specific genes involved in DNA mismatch repair (MMR). Individuals with Lynch syndrome have a higher lifetime risk of developing colorectal cancer, as well as an increased risk of other cancers.
Lynch syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of Lynch syndrome include:
- Increased Risk of Colorectal Cancer: Individuals with Lynch syndrome have a significantly elevated risk of developing colorectal cancer, often at an earlier age than the general population.
- Increased Risk of Other Cancers: Lynch syndrome is also associated with an increased risk of other cancers, including endometrial (uterine) cancer, ovarian cancer, stomach cancer, small intestine cancer, kidney cancer, and certain types of cancer affecting the urinary tract.
- Autosomal Dominant Inheritance: Lynch syndrome follows an autosomal dominant pattern of inheritance. This means that a person with a mutation in one of the Lynch syndrome-associated genes has a 50% chance of passing the mutation to each of their children.
- Young Age at Cancer Onset: Cancers associated with Lynch syndrome often occur at a younger age than sporadic (non-inherited) cancers.
- Microsatellite Instability: Lynch syndrome-related tumors often exhibit microsatellite instability (MSI), which results from defective DNA mismatch repair.
- Specific Genes Involved: Lynch syndrome is most commonly associated with mutations in the following MMR genes: MLH1, MSH2, MSH6, and PMS2. Variants in the EPCAM gene can also lead to Lynch syndrome.
- Screening and Surveillance: Individuals with Lynch syndrome and their family members may undergo more intensive cancer screening and surveillance programs to detect cancers at an early, more treatable stage. This may include colonoscopies, endometrial biopsies, and other imaging studies.
- Genetic Testing and Counseling: Genetic testing can identify mutations in Lynch syndrome-associated genes. Genetic counseling is integral to Lynch syndrome management, helping individuals understand their risk, make informed decisions, and facilitate testing for at-risk family members.
Management of Lynch syndrome involves a combination of surveillance, risk reduction strategies, and, in some cases, preventive surgeries. Regular follow-up with healthcare professionals specializing in cancer genetics is essential for individuals with Lynch syndrome.
Identifying Lynch syndrome in affected individuals and their families allows for proactive measures to reduce cancer risks and improve outcomes through early detection and intervention.
More Information
Lynch syndrome (LS) was the first familial oncologic syndrome discovered and one of the most common hereditary cancers associated with an increased risk of colorectal cancer (CRC), endometrial cancer, and other malignancies not classically linked to LS, such as soft tissue sarcoma, germ cell tumors, mesothelioma, melanoma, and CNS tumors, among others.
In cells, the DNA mismatch repair (MMR) system consists of sequential steps of DNA damage recognition, removal, and synthesis at the mismatched site that ensures that DNA fidelity is preserved.
The prevalence of Lynch syndrome in the general population is around 0.35%. It is estimated that approximately one in 700 to 750 people may carry a variant in one of the PMS2 and MSH6 genes. One in 1900 to 2800 people might have a copy of some mutation in MLH1 or MSH2, the two most frequently altered MMR genes in patients with non-polyposis CRC.
Most affected LS patients inherit a germline mutation in one of the 4 MMR genes, which are MLH1, MSH2, MSH6, and PMS2. In LS patients, additional somatic mutations usually occur that inactivate the remaining functional copy of the MMR gene affected by the germline mutation. There is a fifth gene that we did not analyze here, which has been linked to LS. This gene is not an MMR gene. It is known as EPCAM and encodes for epithelial cell adhesion molecules. EPCAM mutations appear to be the least common, accounting for less than 10% of LS cases.
This analysis includes about 700 pathogenic variants in total of the MLH1, MSH2, MSH6, and PMS2 genes, whose pathogenicity was defined by the group of experts constituting the International Society for Gastrointestinal Hereditary Cancer and/or are classified as potentially pathogenic in the ClinVar database.
LS follows an autosomal dominant inheritance pattern, which means that a pathogenic variant in the aforementioned MMR genes may increase the risk of developing the syndrome. The risk of developing LS-related cancers in carriers of pathogenic MMR mutations depends on the mutated gene. For example, mutations in MLH1 and MSH2 markedly increase the risk of CRC. The average risk of CRC in men with MLH1 and MSH2 mutations up to 75 years of age is 57% and 51%, respectively; women have a 48% and 47% risk of CRC if they carry a pathogenic mutation in MLH1 or MSH2, respectively). On the other hand, MSH6 and PMS2 mutations have a minor impact on predisposition to CRC and other LS-related malignancies (~20% and ~10% of MSH6 and PMS2 carriers, respectively, develop CRC before the age of 75 years). The overall risk of cancer up to age 75 years is also higher in MLH1 or MSH2 carriers (~70-85%) compared to the risk in MSH6 carriers (60%) and PMS2 carriers (~20%).
The prevalence of LS varies by population, and more than 50 founder mutations have been identified. A founder mutation is a genetic variant that is highly prevalent in a specific geographic/cultural isolate group. In the MLH1 gene, c.112A>C (p.Asn38His) is a founder mutation of Dutch origin. This variant reduces the activity and expression of the MLH1 protein. Another MLH1 variant is c.454-1G>A, which is more frequent in eastern Finland.
The variant c.545+3A>G has been observed in Italy, in the Quebec region (Canada), where it was introduced by Italian ancestors, and in Brazil (Ponti et al., 2015). Another mutation that possibly had a founder effect in Italy is c.731G>A (p.Gly244Asp), which results in the substitution of a glycine, highly conserved in all vertebrates, by aspartic acid at codon 244 of the MLH1 protein.
Regarding the MSH2 gene, we include the study of 4 variants that could have a founder effect in different geographical areas: c.942+3A>T (rs19393922376) (Newfoundland, Canada), c.1165C>T (rs587779075) (Quebec, Canada), c.1906G>C, and c.2063T>G (rs63749993) (Tenerife Island, Spain).
Lynch syndrome genetic testing analyzes the 273 most frequent pathogenic mutations of the MLH1 gene, the 203 most frequent pathogenic mutations of the MSH2 gene, the 154 most frequent pathogenic mutations of the MSH6 gene, and the 66 most frequent pathogenic mutations of the PMS2 gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
