The MSH2 gene plays an important role in maintaining the stability of our genetic information. It is one of several genes responsible for ensuring our DNA is accurate. Understanding MSH2’s function provides insight into how our bodies safeguard against disease and what happens when these mechanisms are compromised.
MSH2’s Role in Cellular Health
The MSH2 gene provides instructions for making a protein that is part of the DNA mismatch repair (MMR) system. This system functions like a cellular proofreader, constantly scanning our DNA for mistakes that occur during DNA replication, the process where our cells make copies of their genetic material. When a new DNA strand is created, sometimes the wrong building blocks are paired, forming a “mismatch.”
The MSH2 protein works with other proteins, notably MSH6, to form a complex known as hMutS alpha. This complex is responsible for recognizing these mismatched bases or small loops of extra DNA that arise during replication. Once an error is identified, the MMR system, with MSH2 as an important component, tags the incorrect section, allowing other cellular machinery to remove and replace it. This correction process maintains genomic stability, preventing the accumulation of errors, or mutations, that disrupt normal cell function.
MSH2 and Inherited Cancer Syndromes
When the MSH2 gene contains a mutation, the instructions for making the MSH2 protein are flawed, causing the DNA mismatch repair system to malfunction. Without a properly working MSH2 protein, DNA replication errors are not corrected, leading to an accumulation of mutations. This increased mutation rate raises an individual’s lifetime risk of developing certain cancers.
A non-functional MSH2 gene is linked to Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). Lynch syndrome is passed down in an autosomal dominant pattern, meaning inheriting one mutated copy from either parent increases cancer risk. While carrying an MSH2 mutation increases risk, it does not guarantee cancer development; a “second hit” or additional mutation in the remaining healthy copy of the gene is needed for cancer to arise.
Individuals with MSH2 mutations have an elevated lifetime risk for various cancers. Colorectal cancer and endometrial (uterine) cancer are among the most common, often appearing at younger ages than in the general population. For example, the lifetime risk of colorectal cancer for MSH2 mutation carriers ranges from 33-52%, with an average onset around 44 years, significantly higher and earlier than the general population (4.1% risk, onset 68-72 years). For female MSH2 carriers, endometrial cancer risk is 21-57%, with average onset around 47-48 years, compared to 3.1% risk and onset around 60 years in the general population.
Beyond colorectal and endometrial cancers, MSH2 mutations also increase the risk for other cancers, including:
- Ovarian cancer (lifetime risk 8-38%, average onset 43 years)
- Gastric (stomach) cancer (0.2-9% lifetime risk)
- Small bowel cancer
- Urinary tract cancers (2.2-28% lifetime risk for kidney/ureter, 4.4-12.8% for bladder)
- Brain cancer
- Pancreatic cancer
- Hepatobiliary tract cancer (affecting the liver, bile ducts, and gallbladder)
- Sebaceous gland tumors (skin cancers, sometimes part of Muir-Torre syndrome)
Specific cancer risks can vary based on factors like age, gender, precise mutation, and individual and family health history.
Detecting MSH2-Related Conditions
Identifying MSH2 mutations involves several methods to identify a compromised DNA mismatch repair system. Genetic testing is a primary approach, analyzing a blood or saliva sample for specific changes (germline mutations) within the MSH2 gene. This testing directly confirms an inherited mutation predisposing an individual to Lynch syndrome.
Tumor testing methods also provide clues for an underlying MSH2 defect. Immunohistochemistry (IHC) examines tumor tissue for the presence or absence of specific proteins, including the MSH2 protein. If MSH2 protein is not detected in tumor cells, it indicates the gene may not be functioning correctly, prompting further germline genetic testing. Another tumor-based test is microsatellite instability (MSI) testing. Microsatellites are repetitive DNA sequences prone to errors when the MMR system is faulty. High levels of instability in these microsatellites within a tumor can signal a defective mismatch repair system, potentially due to an MSH2 mutation, leading to recommendations for genetic counseling and germline testing.
Living with MSH2-Associated Risks
For individuals identified with an MSH2 mutation, proactive management strategies address the increased cancer risks. These strategies often involve heightened cancer surveillance, meaning more frequent and specialized screenings than those recommended for the general population. For instance, individuals with MSH2 mutations begin colonoscopies at an earlier age and undergo them more often, sometimes every one to two years starting from age 25.
Women with MSH2 mutations receive increased endometrial and ovarian cancer screenings, which may include regular pelvic exams, transvaginal ultrasounds, and endometrial biopsies. Depending on the specific risk profile and family history, additional screenings like upper endoscopies to examine the stomach and small intestine, or urinalysis to check for blood in the urine, may be recommended. These enhanced surveillance protocols aim to detect any potential cancers at their earliest, most treatable stages.
Family cascade testing is an important aspect of living with an MSH2 mutation. Since MSH2 mutations are inherited, blood relatives (parents, siblings, and children) each have a 50% chance of carrying the same mutation. Genetic counseling provides comprehensive information about the mutation, personalized cancer risk assessments, and guidance on testing for at-risk family members. While less common than for some other hereditary cancer genes, risk-reducing surgeries, such as prophylactic removal of the uterus or ovaries, may be discussed in specific circumstances, particularly if childbearing is complete.