The MSH2 gene provides instructions for a protein central to maintaining genetic integrity. This protein is a major component of the cellular machinery that identifies and corrects errors occurring during cell division. Without a functioning MSH2 protein, DNA repair mechanisms fail, allowing mistakes to accumulate rapidly. This breakdown creates a pathway for the development of hereditary cancer.
The Role of MSH2 in DNA Repair
The MSH2 protein acts as a molecular proofreader within the Mismatch Repair (MMR) system, correcting errors in newly synthesized DNA. DNA replication is imperfect, often incorporating incorrect base pairs or creating small loops of extra or missing genetic material. MSH2 is the “M” in the MMR system, partnering with other proteins to scan the DNA helix for these imperfections.
MSH2 forms complexes, or dimers, to perform surveillance. It primarily partners with MSH6 to create MutS\(alpha\), which recognizes single base pair mismatches and small insertion or deletion loops. MSH2 provides stability to this complex.
MSH2 also pairs with MSH3 to form MutS\(beta\), which detects larger insertion or deletion loops. Once a complex identifies an error, it recruits other MMR proteins to excise the faulty section and synthesize a corrected DNA sequence, preserving the cell’s genetic blueprint.
How MSH2 Mutations Lead to Cancer
A mutation in the MSH2 gene compromises the MSH2 protein, crippling the Mismatch Repair system. When the protein is non-functional or missing, the cell loses its ability to correct replication errors, leading to genomic instability. DNA mistakes that would normally be fixed are instead passed on to daughter cells.
The direct consequence of a failed MMR system is Microsatellite Instability (MSI). Microsatellites are short, repetitive DNA sequences prone to errors during replication. In a healthy cell, MSH2 complexes quickly repair any expansion or contraction of these sequences.
When MSH2 is mutated, accumulating errors change the length of these microsatellites. This increased mutation rate accelerates the accumulation of mutations in other genes controlling cell growth and division. Over time, these additional mutations drive the process of tumor formation.
MSH2 and Lynch Syndrome
MSH2 gene mutations are a significant cause of Lynch syndrome, previously known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Lynch syndrome is the most common inherited cause of colorectal cancer. Individuals inheriting a non-working copy of MSH2 have an increased lifetime risk for several types of cancer.
Lynch syndrome follows an autosomal dominant inheritance pattern, meaning only one copy of the mutated MSH2 gene is needed to have the condition. Each child of an affected parent has a 50% chance of inheriting the pathogenic variant. Although the cancer risk is elevated, not everyone who inherits the mutation will develop cancer.
The spectrum of associated cancers primarily includes colorectal and endometrial (uterine) cancer, the most common Lynch-associated malignancies. MSH2 carriers also face increased risk of developing extra-colonic cancers, such as stomach, ovarian, urinary tract, and small bowel cancers. Genetic counseling and specialized screening protocols are important for those with a confirmed MSH2 mutation.
Screening and Genetic Testing for MSH2 Mutations
Genetic testing for MSH2 mutations occurs in two settings: on tumor tissue and on germline DNA. Tumor testing is often the first step, where a pathologist examines cancer cells for the presence of the MSH2 protein. Immunohistochemistry (IHC) staining can reveal the protein’s absence in the tumor, suggesting a defect in the MMR pathway.
If IHC shows loss of MSH2 expression, or if the tumor shows high Microsatellite Instability (MSI-H), Lynch syndrome is highly probable. The next step is germline genetic testing, typically a blood or saliva test, to confirm an inherited MSH2 mutation. Testing is recommended for individuals with a strong family history of Lynch-associated cancers or those diagnosed with colorectal or endometrial cancer before age 50.
For confirmed MSH2 carriers, the focus shifts to cancer prevention and early detection through specialized surveillance. Standard guidelines recommend MSH2 carriers begin screening colonoscopies every one to two years, starting between ages 20 and 25. Women are also advised to consider screening for endometrial and ovarian cancer, which may involve transvaginal ultrasound or endometrial sampling.