Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is the most common of the hereditary colon cancer syndromes and is believed to account for 3% to 5% of all colorectal cancers.40 Henry T. Lynch, M.D., described the features of this syndrome in 1966 while conducting familial colorectal cancer studies.41 A variety of names followed, but the term Lynch syndrome was first used in 1984 to help clarify the disease and to honor Dr Lynch’s work.41
It is now known that Lynch syndrome results from an inherited mutation in one of the mismatch repair (MMR) genes. Normally, MMR genes produce proteins that identify and correct base-pairing mismatches that can occur during DNA replication. Consequently, a mutation that inactivates an MMR gene leads to accumulation of other mutations which significantly increases the likelihood of developing cancer. Mutations that disrupt the function of MMR genes (mutations in MLH1, MSH2, MSH6, EPCAM and PMS2) have been linked to Lynch syndrome.42,43
It has been known that germline mutations in MLH1, MSH2 and MSH6 account for the majority of detected mutations in families with Lynch syndrome.44 More recently it has been discovered that PMS2 and EPCAM also play an important role in Lynch syndrome.
As one of the four primary mismatch repair genes associated with Lynch syndrome, the functional importance of PMS2 has been clear, but its total contribution to Lynch syndrome was historically considered to be quite low. More recent studies suggest that the prevalence of PMS2 mutations is comparable to MSH6, with as much as 15% of all Lynch syndrome attributable to PMS2.
The EPCAM gene is a recently discovered contributor to Lynch syndrome, accounting for an estimated 1-3% of all detectable Lynch syndrome mutations. Studies indicate that large deletions in the end of this gene, which is located directly “upstream” of MSH2, can lead to a loss of MSH2 expression and result in Lynch syndrome.
MYH-associated polyposis (MAP) is caused by mutations in the mutY homolog (MYH) gene. MAP is inherited in an autosomal recessive manner. Individuals with MAP have mutations in both of their MYH genes (one from each parent, often referred to as “biallelic MYH mutations”). Patients often have no family history of colon cancer or polyps in parents (although siblings may be affected).83 The The MYH gene is an important part of the base excision repair (BER) pathway, which allows for repair of DNA mutations caused by oxidative damage to cells. MAP is believed to account for approximately 1% of all colorectal cancers. MAP can cause patients to develop colorectal cancer even in the absence of colon polyposis.280