Our bodies are made of countless cells, and within each cell lies DNA, the blueprint for life. This genetic material is constantly being copied as cells divide, a process that is fundamental for growth and repair. While DNA replication is remarkably accurate, errors can occasionally occur during this copying process.
To maintain the integrity of our genetic information, cells possess sophisticated repair mechanisms. These systems act like internal “spell-checkers,” identifying and correcting mistakes in the DNA sequence. This vigilance ensures that the genetic instructions remain precise, safeguarding cellular function and overall health.
The Role of DNA Mismatch Repair Genes
The MLH1, MSH2, MSH6, and PMS2 genes are integral components of a cellular system known as DNA mismatch repair (MMR). These genes provide instructions for creating proteins that correct errors when DNA is duplicated.
The MSH2 and MSH6 proteins form a complex that acts as the initial error detector, recognizing mismatched DNA bases or small insertions and deletions. Once an error is identified, this complex recruits other proteins, including those produced by the MLH1 and PMS2 genes. The MLH1 protein pairs with PMS2 to form another complex that helps coordinate the repair process.
Together, these protein complexes work to remove the incorrect segment of DNA and replace it with the correct sequence. This repair process is important for maintaining the stability of our genome. By correcting these replication errors, the MMR system prevents the accumulation of mutations, which is important for healthy cell function and preventing disease.
When Mismatch Repair Goes Wrong
When mutations occur in the MLH1, MSH2, MSH6, or PMS2 genes, the DNA mismatch repair system becomes impaired. These mutations can lead to a faulty or non-functional repair mechanism, allowing errors to accumulate in the DNA over time. This accumulation can increase the risk of developing certain cancers.
The primary condition linked to mutations in these genes is Lynch Syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Lynch Syndrome is an inherited condition passed down in an autosomal dominant pattern, meaning a person only needs to inherit one mutated copy of the gene from a parent to have the syndrome. This syndrome significantly increases an individual’s lifetime risk of developing various cancers, often at younger ages than seen in the general population.
Cancers commonly associated with Lynch Syndrome include:
- Colorectal cancer
- Endometrial cancer in women
- Ovarian cancer
- Stomach cancer
- Small bowel cancer
- Urinary tract cancer
- Biliary tract cancer
- Brain tumors (such as glioblastoma)
- Sebaceous gland tumors
The specific cancer risks and their average ages of onset can vary depending on which of the four MMR genes is affected. For example, MLH1 and MSH2 mutations are associated with higher cancer risks and earlier onset compared to MSH6 and PMS2 mutations.
Genetic Testing and Health Management
Mutations in the MLH1, MSH2, MSH6, and PMS2 genes are identified through genetic testing, performed on a blood or saliva sample. This testing is recommended for individuals with a personal or family history suggestive of Lynch Syndrome, such as multiple relatives diagnosed with Lynch-associated cancers, particularly at young ages. Universal screening for Lynch Syndrome is implemented, where all newly diagnosed colorectal or endometrial cancers are tested for MMR deficiency.
A positive genetic test result indicates the presence of a pathogenic variant, signifying an increased cancer risk. Receiving such a diagnosis highlights the importance of genetic counseling, which provides individuals with information about their risks and implications for their health and family. Genetic counselors can also discuss the chance of passing the mutation to offspring, which is 50% for each child.
Health management for individuals with these mutations involves increased surveillance and preventative measures aimed at early cancer detection or prevention. For instance, colonoscopies are recommended every one to two years, starting at a younger age, between 20 and 25 years for MLH1 and MSH2 carriers, or 30-35 years for MSH6 and PMS2 carriers. Women with Lynch Syndrome may also consider regular endometrial cancer screening and, in some cases, risk-reducing surgeries like hysterectomy and removal of ovaries after childbearing is complete, around age 40.