PMS genes and cancer
PMS genes, specifically PMS1 and PMS2, are crucial components of the cellular mismatch repair system responsible for correcting errors that occur during DNA replication. These genes play a significant role in maintaining genetic integrity; however, mutations in PMS1 and PMS2 can lead to hereditary nonpolyposis colorectal cancer (HNPCC) and increase the risk of various cancers, including colorectal, ovarian, and endometrial cancers. Individuals with mutations in these genes often exhibit a higher mutation rate in their cells, known as a mutator phenotype, which contributes to cancer development by disrupting normal cell growth and death mechanisms.
The clinical implications of PMS gene mutations are significant, making it vital for at-risk individuals to undergo genetic testing and regular cancer screenings. Studies indicate that those with a PMS2 mutation have markedly elevated risks of developing colorectal and endometrial cancers compared to the general population. Additionally, understanding the status of mismatch repair proteins in tumors can inform treatment strategies and prognosis, as their levels may influence the effectiveness of certain chemotherapies. Overall, PMS genes are integral to cancer risk assessment and management, highlighting the importance of genetic awareness in cancer prevention.
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PMS genes and cancer
ALSO KNOWN AS:PMS1 postmeiotic segregation increased 1 (Saccharomyces cerevisiae); postmeiotic segregation increased (S. cerevisiae) 1; PMS2 postmeiotic segregation increased 2 (S. cerevisiae); postmeiotic segregation increased (S. cerevisiae) 2
DEFINITION: PMS genes, PMS1 and PMS2, encode proteins that are part of the cellular mismatch repair machinery that corrects errors made during deoxyribonucleic acid (DNA) replication. Defects in mismatch repair proteins are seen in hereditary nonpolyposis colorectal cancer, or HNPCC.
Normal cellular function: Each time a cell divides, it must faithfully replicate its genetic material contained within the DNA. Due to the inherent properties of the replication machinery, several mutations are made each time the genome is replicated. These mutations are rarely permanent, though, because of the action of a set of proteins that recognize and repair DNA damage. One type of repair mechanism is called the mismatch repair pathway.
Role in cancer: Individuals who inherit a mutation in one of the mismatch repair genes are strongly predisposed to developing certain types of cancer, including colorectal, ovarian, and endometrial. Other common cancers include stomach, bladder, pancreatic, and prostate. MLH1 and MSH2 are the most commonly mutated genes in this pathway, but PMS1 and PMS2 are also mutated in some cases of hereditary nonpolyposis colorectal cancer. Cells with defects in mismatch repair proteins have a mutator phenotype; that is, because the machinery that normally corrects errors is compromised, the frequency of mutations is significantly higher than in normal cells. These cells are more likely to accumulate mutations within genes critical for limiting cell growth and proliferation and inducing cell death when damage has been done to the DNA, which are characteristics of cancer cells.
Clinical implications: Because inheriting a mutation in one of the DNA mismatch repair genes significantly predisposes an individual to developing cancer, it is important to identify at-risk individuals so that they can be frequently screened for tumors. In studies, individuals with the PMS2 gene mutation were more than five times more likely to develop colorectal cancer. The lifetime risk of endometrial cancer rose from 3 percent in the general population to between 13 and 26 percent in patients with a PMS2 gene mutation. People with a strong family history of early-onset colorectal cancer are urged to undergo genetic testing to identify mutations in the mismatch repair genes. Once a tumor has formed, the levels of mismatch repair proteins can provide insight into the patient’s prognosis and cancer progression. In addition, knowing the levels of mismatch repair proteins within tumor cells can have implications for the method of treatment that is prescribed. Although the effects vary based on tumor type, there have been data showing that the state of the mismatch repair machinery can affect the efficacy of certain types of chemotherapeutic agents. For example, patients with ovarian cancer resulting from defective mismatch repair show higher levels of cancer recurrence following treatment with cisplatin.
Bibliography
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“Genetics of Breast and Gynecologic Cancers (PDQ®).” National Cancer Institute, 4 Apr. 2024, www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq. Accessed 29 June 2024.
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