MSH genes and cancer
MSH genes are a group of genes that play a crucial role in DNA mismatch repair, a process essential for correcting errors that occur during DNA replication. When these genes mutate, they can significantly increase an individual’s risk of developing various types of cancer, including hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome. Defects in the mismatch repair system result in heightened mutation rates—up to 1,000 times higher than normal—which can lead to cancer if critical genes regulating cell growth are affected.
One of the most well-known MSH genes, MSH2, is frequently mutated in HNPCC, leading to a predisposition for cancers such as bowel, bladder, prostate, and stomach cancer. Additionally, mutations in MSH3 and MSH6 can also contribute to cancer risk, though less commonly. For example, 40% of women with MSH6 mutations develop endometrial cancer. Diagnostic tools like DNA sequencing and immunohistochemical analysis help identify these mutations and monitor tumor characteristics, which can inform treatment approaches. Understanding the role of MSH genes in cancer can guide preventative screenings and influence treatment strategies, as tumors with high microsatellite instability (MSI) can exhibit distinct behaviors and responses to therapies.
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MSH genes and cancer
ALSO KNOWN AS: MSH MutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); HNPCC; HNPCC1; MSH3 mutS homolog 3 (E. coli); DUP; divergent upstream protein; mismatch repair protein 1; MRP1; MSH4 mutS homolog 4 (E. coli); MSH5 mutS homolog 5 (E. coli); MSH6 mutS homolog 6 (E. coli); GTBP; MSH2‗HUMAN
DEFINITION: MSH genes are a class of genes normally involved in deoxyribonucleic acid (DNA) mismatch repair. However, they can mutate and increase an individual's risk of developing some types of cancer.
Normal cellular function: DNA mismatch repair is the process whereby errors in DNA replication are recognized and repaired by proteins in the cell. If the mismatch repair machinery is defective, either by mutation of the genes encoding the proteins or by altering the expression levels of the proteins, errors are no longer repaired.
Relevance to cancer: Cells with defects in DNA mismatch repair show mutation rates one hundred to one thousand times higher than normal cells. Most mutations may not have adverse effects, but if mutations are made in genes required to regulate cell growth and proliferation, this can lead to cancer. A readout of this increased mutation rate is microsatellite instability (MSI). Microsatellites are repetitive DNA sequences prone to replication errors, and cells that are defective in mismatch repair show variability in the length of these sequences.
One of these genes, MSH2, is among the most frequently mutated genes in hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome. Inheriting a mutation in this gene causes a genetic predisposition to bowel, bladder, prostate, and stomach cancer. In addition, MSH genes are often mutated in noninherited forms of cancer, such as skin cancer and ovarian cancer. The MSH genes MSH3 and MSH6 may also mutate and play a role in cancer development, but at a lower frequency than MSH2. Forty percent of women with MSH6 gene mutations develop endometrial cancer, and 10 percent develop ovarian cancer.
Diagnostic and genetic testing: Several tests are available to monitor the status of the mismatch repair machinery, which can provide diagnostic and prognostic information. DNA sequencing of the MSH2 gene can be done to look for mutations that can predispose patients to cancer. Protein levels can be measured by immunohistochemical analysis of tissue samples, and tests to monitor the MSI status of tumor cells can also be performed.
Clinical implications: Because they strongly predispose people to develop cancer, patients carrying mutations in mismatch repair genes should undergo frequent colonoscopy procedures and screenings for endometrial cancers. In addition, levels of mismatch repair proteins and MSI status can be strong predictors of tumor progression and prognosis. For example, although tumors that show high MSI tend to be aggressive, the outcome is usually favorable. Further, cells defective in mismatch repair are less sensitive to platinum-based chemotherapy and methylating agents, which both work by inducing DNA damage.
Bibliography
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"Cancer Risk Associated with Inherited MSH2 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/msh2/cancer-risk. Accessed 20 June 2024.
"Cancer Risk Associated with Inherited MSH6 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/msh6/cancer-risk. Accessed 20 June 2024.
"Lynch Syndrome and HNPCC." Cleveland Clinic, 9 Dec. 2022, my.clevelandclinic.org/health/diseases/17195-lynch-syndrome-and-hnpcc. Accessed 20 June 2024.
"MSH2 Gene." MedlinePlus, 2020, medlineplus.gov/genetics/gene/msh2. 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.