The role of deficient mismatch repair system in Lynch syndrome and the increased risk of colorectal cancer
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Abstract
Over the years, the prevalence of colorectal cancer has increased, most significantly among young individuals, with colorectal cancer currently being the third leading cancer diagnosis in the world (Nfonsam et al., 2022). While many of the causes of colorectal cancer are unclear, there are some hereditary conditions that have been shown to put individuals at an increased risk. Around 30% of all colorectal cancers are due to inherited syndromes, with 2-5% being the result of known conditions (Zhang et al., 2015). The most prevalent known hereditary condition predisposing individuals to develop colorectal cancer is what is known as Lynch syndrome. Initially, Lynch syndrome was termed hereditary non-polyposis colorectal cancer (HNPCC) in order to distinguish it from the second most common inherited cancer syndrome, familial adenomatous polyposis (FAP) (Zhang et al., 2015). The term Lynch syndrome is now considered a more specific diagnosis than HNPCC and the words are no longer used synonymously. Lynch syndrome predisposes individuals not only to colorectal cancer, but also to a wide range of other cancers including gynecologic, gastrointestinal, genitourinary cancers as well as cancers of other organs (Biller & Creedon et al., 2022). It has been found that approximately 3% of individuals diagnosed with colorectal cancer have Lynch syndrome (Biller & Syngal et al., 2019). Lynch syndrome is the result of germline mutations in DNA mismatch repair genes (Yurgelun & Hampel, 2018). Analysis of individuals and families with Lynch syndrome found that patients had defects specifically in chromosomes 2, 3 and 7 (Zhang et al., 2015). The significance of these chromosomes was later discovered as it was found these chromosomes contained the DNA mismatch repair genes, MSH1, MSH2, MSH6, PSM1, and PMS2 (Zhang et al. 2015. Specifically, chromosome 2 was found to contain the genes MSH2, MSH6, and PSM2, chromosome 3 contained the gene MLH1, and chromosome 7 contained the gene PMS2 (Zhang et al., 2015). In addition to the four MMR genes, it was also found that germline deletions in the non-MMR gene EPCAM (Epithelial-cell adhesion molecule) can also result in Lynch syndrome due to EPCAM’s location upstream from the MMR gene MSH2 (Biller & Creedon et al., 2022). A deficient MMR system often results in the phenotype microsatellite instability (MSI) which is a strong diagnostic indicator of Lynch syndrome. The connection between Lynch syndrome and defects in mismatch repair genes have had important implications in the diagnosis and treatment of Lynch syndrome associated colorectal cancer.
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2024