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MSH2 and Hereditary Nonpolyposis Colorectal Cancer By Bobby Glenn Warren III MutS Homolog 2 DNA Mismatch Repair (MMR) Pathways MSH2 MSH6 MSH2 MutSα Cytoplasm Nuclear Envelope MSH3 MSH2 Larger insertion/deletion loops MutSβ Base mismatch repair and small insertion/deletion loops MMR deficiency (Mutations in the MSH2 gene) gives rise to Microsatellite Instability Loss of MSH2 function increases mutation frequencies by two to three magnitudes MSH2 MSH6 MSH2 MutSα Cytoplasm Nuclear Envelope MSH3 MSH2 Larger insertion/deletion loops MutSβ Base mismatch repair and small insertion/deletion loops Lynch Syndrome HPNCC is another term for MSH2 Hereditary Nonpolyposis Colorectal Cancer (HNPCC) MSH2 and HNPCC Summary • MSH2 is required for DNA mismatch repair (MMR) which repairs base pair mismatches and insertion/deletion loops. • The loss of MMR, in this case via loss of MSH2, causes an accumulation of mutations. • An accumulation of mutations leads to tumorigenesis. • Cells dividing more rapidly, such as epithelial cells, will most likely develop cancer first. • Since colon epithelial cells divide very rapid, they are the first and most common cancer associated with MMR deficiency. References • Ls Gentics HPNCC. (n.d.). Retrieved March 31, 2015, from http://www.lynch-syndromeuk.org/ls_genetics_.html • MSH2 gene. (n.d.). Retrieved March 31, 2015, from http://ghr.nlm.nih.gov/gene/MSH2 • SMH.COM - Understanding Lynch Syndrome. (n.d.). Retrieved March 31, 2015, from http://www.smh.com/p.aspx?p=525 • Tomasetti, C. (2015). Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science, 347(6217), 78-81.