The four genes—MLH1, MSH2, MSH6, and PMS2—encode proteins that are components of the cell’s DNA Mismatch Repair (MMR) system. This system functions as a molecular proofreader, correcting errors that occur during DNA replication. When a person inherits a mutation in one of these genes, the MMR system is compromised, leading to Lynch Syndrome. This inherited defect significantly increases the lifetime risk of developing several types of cancer, most notably colorectal and endometrial cancers, often at a younger age.
The Mechanism of DNA Mismatch Repair
The DNA Mismatch Repair system acts as a quality control mechanism, scanning newly synthesized DNA strands for errors missed by the DNA polymerase enzyme. These errors primarily include single base-pair mismatches and small insertion or deletion loops that occur when the replication machinery slips on repetitive DNA sequences. The proteins encoded by MLH1, MSH2, MSH6, and PMS2 work together in specific pairs to perform this repair process.
The process begins with recognition, primarily handled by MutS-like complexes. The MSH2 protein forms a heterodimer with MSH6 (known as MutS $\alpha$), which is responsible for recognizing single base-pair mismatches and small insertion-deletion loops. Once the mismatch is identified, this complex binds tightly to the error site, triggering the recruitment of the next component.
The second stage involves the MutL-like complexes, which coordinate the rest of the repair process. The MLH1 protein pairs with PMS2 to form the MutL $\alpha$ heterodimer, which is recruited to the site of the MSH2/MSH6 complex. The MLH1/PMS2 complex then identifies the newly synthesized strand containing the error. In human cells, this identification is facilitated by single-strand breaks in the new DNA.
After the MLH1/PMS2 complex marks the erroneous strand, its endonuclease function cuts the DNA backbone near the mismatch. An exonuclease then excises the segment of the new strand containing the error, creating a gap. Finally, a DNA polymerase fills this gap with the correct sequence, using the original strand as a template, and DNA ligase seals the final break, completing the repair.
Consequences of Gene Failure: Hereditary Cancer Risk
Failure in any of the four MMR genes means the cell loses its ability to correct replication errors, a state referred to as Mismatch Repair Deficiency (dMMR). This failure leads to a massive accumulation of mutations, known as Microsatellite Instability (MSI). Microsatellites are short, repetitive DNA sequences prone to polymerase slippage errors, and their instability is a hallmark of MMR deficiency.
The accumulation of these errors, particularly in genes that control cell growth and death, drives the transformation of normal cells into cancerous ones. Lynch Syndrome, caused by inherited mutations in these genes, is the most common form of hereditary colorectal cancer. The lifetime risk of developing colorectal cancer varies significantly by the specific gene involved, with carriers of MLH1 and MSH2 mutations facing the highest risk, often between 40% and 60%.
The spectrum of associated cancers is broad and gene-dependent. MLH1 and MSH2 mutations confer a high risk of endometrial cancer, often exceeding 40% in women. Other associated cancers include ovarian, gastric, small bowel, pancreatic, hepatobiliary tract, and urinary tract cancers. Individuals with MSH6 and PMS2 mutations generally face a lower overall cancer risk and a later average age of cancer onset compared to those with MLH1 or MSH2 mutations.
Detecting MMR Gene Changes
Identifying MMR system failure typically involves a two-step process, starting with the tumor tissue to determine if the repair proteins are functional. The first diagnostic tool is Immunohistochemistry (IHC), a technique that uses specific antibodies to stain and visualize the presence of the MLH1, MSH2, MSH6, and PMS2 proteins within the cell nuclei. A functioning MMR system shows positive staining for all four proteins.
A deficient MMR system is indicated by the absence of staining for one or more proteins, known as loss of expression. The pattern of protein loss often predicts the underlying germline mutation. For instance, loss of MSH2 almost always causes MSH6 to be lost as well, while loss of MLH1 typically results in the loss of its partner, PMS2. This IHC result guides the next phase of testing, determining if the deficiency is inherited or sporadic.
If protein loss is detected, the second step is germline genetic testing, which involves sequencing a patient’s DNA, usually from a blood or saliva sample. This test looks for a mutation in the MMR genes to confirm a diagnosis of Lynch Syndrome. Not all MMR deficiencies are inherited; for example, the loss of MLH1 and PMS2 can sometimes be caused by a sporadic event called MLH1 promoter hypermethylation, which is not passed down through families. Confirming a germline mutation guides the patient’s long-term management and screening for family members.
Clinical Surveillance and Risk Reduction Strategies
Once an inherited MMR gene mutation is confirmed, an intensive cancer surveillance plan is implemented to detect cancers at their earliest stages. For colorectal cancer, the primary surveillance tool is colonoscopy, which begins at an earlier age and with greater frequency than for the general population. For carriers of MLH1 and MSH2 mutations, colonoscopies are typically initiated between ages 20 and 25, and performed every one to two years due to the high and early risk.
For MSH6 and PMS2 carriers, who face a lower and later risk, surveillance may begin later (ages 30 to 35) and be performed at longer intervals, such as every three years. Surveillance for extracolonic cancers, such as stomach and upper urinary tract cancers, is also recommended. This often involves annual urinalysis and upper endoscopy, especially in families with a history of these cancer types.
For women, the high lifetime risk of endometrial and ovarian cancer often makes prophylactic surgery a preferred risk reduction strategy. While endometrial surveillance through transvaginal ultrasound and biopsy can be offered, risk-reducing hysterectomy and bilateral salpingo-oophorectomy (removal of the uterus, tubes, and ovaries) are often recommended after childbearing is complete. Chemoprevention with daily low-dose aspirin has been shown to reduce the incidence of colorectal cancer and may be discussed as an additional risk reduction strategy.