MLH1 gene and cancer
The MLH1 gene plays a crucial role in the DNA mismatch repair process, which is essential for correcting errors that occur during DNA replication. Mutations in the MLH1 gene are significantly associated with hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, which predisposes individuals to various cancers, including colorectal, endometrial, and other types. Those with an MLH1 mutation face a markedly higher risk of developing colorectal cancer—between 45 to 60 percent—compared to a 4 percent risk in the general population. Similarly, their risk of endometrial cancer increases to 35 to 55 percent, versus a 3 percent risk for non-affected individuals.
In addition to hereditary cases, mutations in MLH1 can also be found in 10 to 20 percent of sporadic cancers, particularly those exhibiting microsatellite instability (MSI), a condition linked to further genomic mutations and cancer progression. Diagnostic tests, including DNA sequencing and immunohistochemical analysis of tumor tissue, can identify these mutations and assess the levels of MLH1 protein, which can influence cancer prognosis and treatment response. Consequently, individuals with MLH1 mutations are often advised to undergo regular cancer screenings, highlighting the gene's significant implications for cancer prevention and management.
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MLH1 gene and cancer
ALSO KNOWN AS: MutL homolog 1, colon cancer nonpolyposis type 2 (E. coli); HNPCC; FCC2; HNPCC2; mutL (E. coli) homolog 1 (colon cancer, nonpolyposis type 2), Hereditary Nonpolyposis Colorectal Cancer (HNPCC), Muir-Torre syndrome
DEFINITION: The MLH1 gene encodes a protein that is involved in deoxyribonucleic acid (DNA) mismatch repair.
Normal cellular function: When a cell divides, it must replicate its genetic material, which is contained within the DNA. During DNA replication, errors can be made that need to be corrected. The DNA mismatch repair machinery recognizes the errors and recruits other proteins to repair them. If errors are not corrected, mutations can affect the production or function of important proteins.
Relevance to cancer: MLH1 and MSH2, another gene part of the DNA mismatch repair machinery, are the two genes most frequently mutated in hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. Though rare, constitutional mismatch repair deficiency (CMMRD) also results from mutations in these genes. Inheriting mutations in either MLH1 or MSH2 predispose patients to develop many types of cancer, including colorectal, endometrial, kidney, prostate, bladder, bowel, brain, stomach, ovarian, and biliary duct cancers. Individuals with an MLH1 mutation have a 45 to 60 percent chance of being diagnosed with colorectal cancer in their lifetime compared to the 4 percent chance in the average population. Similarly, the lifetime risk of endometrial cancer is between 35 and 55 percent for individuals with MLH1 compared to an average individual's 3 percent risk. Mutations in DNA mismatch repair genes are also present in 10 to 20 percent of sporadic (noninherited) cancers.
Defects in mismatch repair proteins are correlated with tumors that show microsatellite instability (MSI). Microsatellites are regions of the genome that contain highly repetitive DNA sequences that are more likely to generate errors during DNA replication. If the DNA mismatch repair machinery does not correct these errors, this can lead to further mutations within the genome that may promote tumor formation and progression.
Diagnostic and genetic testing: Several tests can identify people with inherited mutations in mismatch repair genes and characterize the levels of these proteins in tumor cells, both of which have important clinical implications. DNA sequencing tests are available for both MLH1 and MSH2, the mismatch repair genes most commonly mutated in cancer. In addition to mutations in the genes themselves, other types of chromosome modifications can alter the levels at which the proteins produced by these genes are expressed within the cells. Therefore, immunohistochemical analysis of tissue samples can be used to detect how much of the mismatch repair proteins are being produced.
Clinical implications: Because mutations in MLH1 or MSH2 significantly increase the risk of developing cancer, patients carrying these mutations should undergo frequent screening for colon and endometrial cancer. In addition, levels of MLH1 and MSH2 protein within tumor cells can be prognostic indicators since differential protein levels are associated with differences in cancer progression, recurrence, and treatment response. For example, one study found that cells lacking MLH1 protein were more resistant to DNA damage-inducing than cells that contain MLH1.
Bibliography
"About Mutations in the MLH1 Gene." Memorial Sloan Kettering Cancer Center, 12 July 2023, www.mskcc.org/cancer-care/patient-education/about-mutations-mlh1-gene. Accessed 20 June 2024.
"Cancer Risk Associated with Inherited MLH1 Mutations." FORCE-Facing Our Risk of Cancer Empowered, 31 Dec. 2023, www.facingourrisk.org/info/hereditary-cancer-and-genetic-testing/hereditary-cancer-genes-and-risk/genes-by-name/mlh1/cancer-risk. Accessed 20 June 2024.
Milanizadeh, Saman, et al. "Molecular Analysis of Imperative Polymorphisms of MLH1 Gene in Sporadic Colorectal Cancer." Cancer Biomarkers, vol. 13, no. 6, 2013, pp. 427–32. doi:10.3233/CBM-140391.
"MLH1 Gene." MedlinePlus, medlineplus.gov/genetics/gene/mlh1. Accessed 20 June 2024.
Reeves, Stuart G., et al. "DNA Repair Gene Polymorphisms and Risk of Early Onset Colorectal Cancer in Lynch Syndrome." Cancer Epidemiology, vol. 36, no. 2, 2012, pp. 183–89. doi:10.1016/j.canep.2011.09.003.