The MSH2 gene plays a significant role in maintaining the integrity of our genetic material. It is one of several genes responsible for detecting and repairing errors in DNA. When a mutation occurs in the MSH2 gene, its repair function is impaired. This impairment has implications for an individual’s health, especially regarding cancer risk.
The Role of MSH2 in DNA Repair
The MSH2 gene is a component of the DNA mismatch repair (MMR) system, which acts as a cellular “spellchecker” for DNA. During cell division, DNA strands are copied, and errors, such as incorrect base pairings or small insertions and deletions, can occur. The MMR system, with MSH2 as a central component, identifies these mismatches and initiates their correction.
MSH2 works with other proteins, like MSH6, to form a complex that scans DNA for replication errors. Once an error is detected, the MMR system recruits other proteins to remove the incorrect segment and synthesize a new, accurate one. A mutation in the MSH2 gene means this repair mechanism is less effective or non-functional. This compromised repair leads to an accumulation of errors in the DNA, affecting genetic stability.
MSH2 Mutation and Lynch Syndrome
A mutation in the MSH2 gene is a primary cause of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). This inherited condition significantly increases an individual’s lifetime risk for developing various cancers, often at younger ages. The impaired DNA repair mechanism in Lynch syndrome allows DNA errors to persist and accumulate, increasing the likelihood of mutations in genes that control cell growth, leading to cancer development.
Individuals with an MSH2 mutation face an elevated risk for colorectal cancer, with lifetime risks estimated between 52% and 58%. These cancers can develop more rapidly, sometimes within one to two years from a polyp stage. Women with an MSH2 mutation also have an elevated risk for endometrial cancer, with estimates ranging from 25% to 60%.
Other cancers associated with MSH2 mutations and Lynch syndrome include ovarian cancer (4-12% lifetime risk) and stomach cancer (6-13% risk). Other associated cancers include:
Small intestine
Urinary tract
Hepatobiliary tract
Brain (e.g., glioblastoma)
Sebaceous skin growths
While the exact risks for these less common cancers may vary, their occurrence is a recognized feature of Lynch syndrome.
Understanding Inheritance and Genetic Counseling
MSH2 mutations are inherited in an autosomal dominant pattern. This means only one copy of the mutated gene, inherited from either parent, is sufficient to predispose an individual to Lynch syndrome. If a parent carries an MSH2 mutation, each child has a 50% chance of inheriting it. This inheritance pattern applies equally to males and females, and the condition does not skip generations.
Genetic counseling is recommended for individuals and families with a suspected or confirmed MSH2 mutation. A genetic counselor provides a risk assessment by reviewing personal and family medical histories, identifying patterns of associated cancers. They explain the implications of the inheritance pattern, discuss genetic testing options, and provide support for making informed decisions. This process helps families understand their risks and plan for appropriate screening and management strategies.
Screening and Management Strategies
For individuals with an MSH2 mutation, screening and management are recommended to detect cancers early or reduce their risk. Regular colonoscopies are a key part of surveillance, advised every one to two years starting between ages 20 and 25. Lynch syndrome-associated colorectal cancers can have a flat or non-polypoid morphology, making them harder to detect.
For women, endometrial surveillance is recommended, which may include annual pelvic examinations and endometrial sampling starting between ages 30 and 35. Risk-reducing surgeries such as prophylactic hysterectomy and bilateral salpingo-oophorectomy (removal of ovaries and fallopian tubes) may be considered around age 40. Other screenings, such as upper endoscopy for stomach and small intestine cancers, and urinalysis for urinary tract cancers, are also recommended based on individual risk and family history. Daily aspirin may be considered to reduce colorectal cancer risk.