The MSH2 gene is a component of our genetic blueprint, providing instructions for a protein that helps maintain the stability of our DNA. Understanding the MSH2 gene is important for comprehending how DNA integrity is maintained and what can happen when this process is disrupted.
Role of MSH2 in DNA Repair
The MSH2 gene produces a protein that is a key part of the mismatch repair (MMR) system, which functions like a “spell checker” for our DNA. During DNA replication, when cells divide, errors can occur as new DNA strands are made. The MSH2 protein works with other proteins, such as MSH6, to form a complex that identifies these mistakes, specifically mismatched base pairs or small insertions and deletions.
Once an error is detected, the MSH2 complex signals other proteins to remove the incorrect DNA section. This allows for the insertion of the correct DNA sequence, effectively “proofreading” and fixing the mistake. This continuous error correction by the MMR system, involving MSH2, prevents the accumulation of mutations that could otherwise lead to abnormal cell growth and disease.
MSH2 Gene Mutations and Lynch Syndrome
When the MSH2 gene undergoes a mutation, its ability to produce a functional protein is compromised, meaning the DNA mismatch repair system cannot properly correct errors that arise during DNA replication. These unrepaired DNA errors then accumulate over time within cells, potentially altering the activity of other genes that regulate cell growth and division.
This accumulation of mutations significantly increases an individual’s risk of developing various cancers, a condition primarily known as Lynch Syndrome. Lynch Syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is an inherited disorder that predisposes individuals to specific types of cancer. Cancers commonly associated with Lynch Syndrome due to MSH2 mutations include colorectal and endometrial cancers, but also others like ovarian, stomach, small intestine, and urinary tract cancers.
Hereditary Cancer Risk
MSH2 gene mutations are passed down through families in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered MSH2 gene from either parent to have an increased risk of cancer. Each child of a parent with an MSH2 mutation has a 50% chance of inheriting the mutation.
Individuals with an MSH2 mutation have elevated lifetime risks for several cancers. These include significantly increased risks for colorectal cancer (30-50% lifetime risk) and endometrial cancer (20-50% lifetime risk for women). Ovarian cancer risk is also elevated (up to 38%). Other cancers with increased risk include stomach, small intestine, liver, bile duct, kidney/ureter, bladder, prostate, and brain cancers. Having an MSH2 mutation increases cancer risk but does not guarantee cancer development.
Genetic Testing and Clinical Management
MSH2 mutations are identified through genetic testing, typically performed using a blood sample or tumor tissue. Genetic testing is often considered for individuals with a personal or family history suggestive of Lynch Syndrome, such as multiple relatives with Lynch-associated cancers, cancers diagnosed at younger ages (e.g., before age 50), or multiple primary cancers in one individual. Tumor testing for mismatch repair deficiency or microsatellite instability can also indicate the need for germline genetic testing.
For individuals who test positive for an MSH2 mutation, specific surveillance and management strategies are recommended to mitigate cancer risk:
Regular colonoscopies are advised every 1-2 years, typically starting between ages 20-25, or 2-5 years before the earliest colorectal cancer diagnosis in the family if it occurred before age 25.
Women may consider annual endometrial biopsies or transvaginal ultrasounds, though the benefit of these specific screenings for reducing mortality is not fully established.
Risk-reducing surgeries, such as prophylactic hysterectomy and bilateral salpingo-oophorectomy, may be considered after childbearing is complete for women.
Daily aspirin therapy has been shown to reduce colorectal cancer risk in individuals with Lynch Syndrome, though the optimal dose and timing are still being researched.