Lynch Syndrome

Lynch Syndrome or hereditary nonpolyposis colorectal cancer (HNPCC), first characterised by Henry T. Lynch in 1966, is an inherited disorder with early age onset of different cancer in an affected individuals. The syndrome is caused by the germline mutations in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, and part of EPCAM) and results in high level of microsatellite instability (MSI) which confers an increased susceptibility to cancers.


It represents the most common inherited colorectal cancer (2%-4%) and endometrial cancer (2%-5%) in women. HNPCC is subdivided into Lynch syndrome I characterised by synchronous and metachronous colorectal cancer and Lynch syndrome II which, besides having a similar colonic phenotype, also has a high risk of endometrial, ovarian and other cancers. Individuals carrying germline genetic mutations in MMR genes have an increased risk of developing CRC by 70-80% compared to 2% of lifetime risk in the general population.


In women with Lynch syndrome, apart from colorectal cancer, they have more than 70% lifetime risk of developing endometrial cancer compared to 1,5% in general population. Colon cancer develops most frequently in the right side of the colon in patients with HNPCC, and for this reason, the symptoms remain silent for an extended period although the transition can occur within 30 months compared to 10 years in adenomatous polyps. Besides colorectal and endometrial cancer, these patients carry an increased risk of other tumours like ovarian, hepatobiliary tract, upper urinary tract, pancreatic, small bowls, skin, and brain.


Lynch Syndrome is characterised by an autosomal dominant mode of genetic transmission, i.e., a mutation in one of the cell’s two gene copies (allele) is sufficient to manifest the disorder. In patients with this syndrome, one of the two parents is a carrier (heterozygous) with a genetic mutation, and each couple's children have 50% chance of inheriting the mutation. However, the penetrance of the disease is incomplete: this means that not all individuals bearing a mutation will necessarily develop cancer.


Sporadic cases are described in which the mutation occurs ex novo, i.e., it is not inherited from the parents, and the disorder is first encountered in the affected individuals. Epigenetic germline mutation, also known as “germline epimutation,” in the promoter region of MLH1 and MHS2 genes have been identified in a small number of patients with clinical phenotype of Lynch syndrome. In this case, the MMR genes are normal, but one of the allele of the promoter region is highly methylated resulting in the inactivation of MMR genes. However, germline epimutation can revert to the normal function between generations because of the significant epigenetic reprogramming during the reproductive life cycle.


Screening for Lynch syndrome is advised in all patients with colorectal and endometrial cancer and can be detected either by PCR assays which analyses the microsatellite instability or by immunohistochemistry (IHC) which directly look for the expression MMR protein. MSI is found in approximately in 15% of all the CRC of which Lynch syndrome represents 3%. IHC testing is more advantageous to detect Lynch syndrome compared to the PCR analysis because the loss of a specific mismatch gene product (MLH1, MSH2, MSH6, and PMS2) can direct the patient to germline testing to that specific gene.


Once the mutated gene responsible for the disease is identified, one should know that even other family members are also at risk of developing the same disease and should be subjected to genetic testing. All mutations and CNVs in MLH1, MSH2, MSH6, PMS2, and part of EPCAM, which are syndrome-related genes, can be detected simultaneously using NGS.


The test for germline mutation in MMR gene is performed on an NGS platform within seven working days from a blood sampling (2 test tubes in EDTA).