The MLH1 gene provides instructions for a protein that acts as a “proofreader” for our DNA, correcting errors that arise during DNA replication. This process ensures the accurate transmission of genetic information. Mutations in this gene can disrupt this function, leading to significant health implications.
The Role of the MLH1 Gene
The primary function of the MLH1 gene lies within the DNA Mismatch Repair (MMR) system, which serves as a cellular “spell-checker.” When DNA replicates, occasional errors, known as mismatches, can occur in the newly synthesized strand. The MLH1 protein, in conjunction with other proteins like MSH2, MSH6, and PMS2, forms a complex that identifies and corrects these replication errors. This intricate machinery works by detecting mismatched base pairs or small loops of extra DNA, then coordinating the removal of the incorrect section and its replacement with the correct sequence. This continuous repair activity is particularly important in cells that divide frequently, as they are at a higher risk of accumulating DNA replication errors.
Association with Lynch Syndrome
A direct connection exists between a faulty MLH1 gene and Lynch syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC). This hereditary disorder increases an individual’s predisposition to various types of cancer. Inherited mutations in the MLH1 gene are among the most common causes of Lynch syndrome. These uncorrected DNA errors accumulate over time as cells divide, leading to alterations in other genes that regulate cell growth and division. This accumulation of genetic mistakes drives the increased cancer risk seen in individuals with Lynch syndrome.
Increased Cancer Risks
Individuals with an inherited MLH1 mutation face a substantially increased lifetime risk for several types of cancer compared to the general population. Colorectal cancer and endometrial cancer are the most commonly associated malignancies. For men with an MLH1 mutation, the lifetime risk of developing colorectal cancer ranges from approximately 40% to 80%, while for women, it is about 40% to 60%. This contrasts sharply with the general population’s lifetime risk of around 5%.
Women with an MLH1 mutation also have a significantly elevated lifetime risk of endometrial (uterine) cancer, estimated to be between 34% and 60%. Other cancers with increased risk include ovarian cancer (4% to 24%), stomach cancer (5% to 7%), small intestine cancer (3% to 10%), pancreatic cancer (1.4% to 4%), and urinary tract cancers (1% to 7%), encompassing bladder, ureter, and renal pelvis. The average age of diagnosis for these cancers in individuals with MLH1 mutations is often earlier than in the general population, for instance, around 44 years for colorectal cancer compared to 68-72 years in the general population.
Genetic Testing and Inheritance
Genetic testing plays a significant role in identifying individuals with an MLH1 mutation and Lynch syndrome. Testing is typically recommended for individuals with a personal or strong family history of Lynch-associated cancers, such as early-onset colorectal or endometrial cancer, or multiple family members affected across generations. This process involves analyzing a person’s DNA to identify specific pathogenic variants in the MLH1 gene.
MLH1 mutations are inherited in an autosomal dominant pattern. This means that an individual only needs to inherit one copy of the mutated MLH1 gene from either parent to have the condition and an increased cancer risk. A parent who carries an MLH1 mutation has a 50% chance of passing that mutated gene to each of their children, regardless of the child’s gender. Inheriting the mutation increases the risk, but does not guarantee cancer development.
Medical Management and Surveillance
Knowing about an MLH1 mutation allows for proactive medical management and surveillance to detect cancers early or reduce risk. Individuals with MLH1 mutations should discuss a personalized management plan with their healthcare provider.
Surveillance Protocols
Recommended protocols include starting colonoscopies at a younger age, typically between 20 to 25 years, or 2-5 years before the earliest colorectal cancer diagnosis in the family if it occurred before age 25. These colonoscopies are performed frequently, every 1-2 years, to identify and remove precancerous polyps. Daily aspirin may also be considered to reduce colorectal cancer risk. For women, surveillance for endometrial cancer may involve considering endometrial biopsies and transvaginal ultrasounds, typically starting around age 30-35, every 1-2 years.
Risk-Reducing Options
Risk-reducing surgeries are also an option for women who have completed childbearing, such as a total hysterectomy and bilateral salpingo-oophorectomy (removal of the uterus and ovaries/fallopian tubes). These procedures can significantly lower the risk of endometrial and ovarian cancers associated with the mutation.