Hereditary non-polyposis

Non-steroidal anti-inflammatory agents, aspirin, and acetaminophen have been suggested for use in the prevention of different cancers, especially hereditary non-polyposis colon cancer.14 While there have been observational studies linked to a reduction of ovarian carcinoma risk, evidence is still lacking. Potential... 

Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, et al. Mutation in the DNA mismatch repair gene homologue hMLHl is associated with hereditary non-polyposis colon cancer. Nature 1994 368 258-61. 

Vasen HF, Mecldhi JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis CRC. (ICG-HNPCC). Dis Colon Rectum 1991 34 424-5. 

MSHl, MLH2, DNA mismatch repair hereditary non-polyposis... 

Lynch, H. M., Sinyrk, 1. C., Watson, R, Lanspa, I5 J.. Lynch, J. E. Lynch. R M-. Cavalieri, R. ].. and Boland, C R. 1993. Genetics, natural history, tumor spectrum, and pathology of hereditary non polyposis colorectal cancer An updated review. ( d.sfroe)itero/tigv 104 1535-1549. 

Hereditary non-polyposis colorectal cancer (HNPCC) is due to defects in mismatch repair (MMR) and thus to deficiencies in removing nucleotides mi-spaired by DNA polymerases as well as insertion/deletion loops (1-10 bases). This dramatically increases the mutation rate. The affected genes are MLHl (60%),MSH2 and MSH6. 

Muller, A., and R. Fishel. 2002. Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC). Cancer Invest. 20 102-109. 

The protein products of these genes play roles in DNA repair, recombination, and regulation of transcription. A second example, HNPCC (hereditary non-polyposis colorectal cancer), was previously introduced in Chapter 13. It results from inherited mutations in enzymes involved in the DNA mismatch repair system. 

The intruder elements undergo random, single base substitutions these mutations are frequent (one to 10/10 base pairs), heterogenous, and become clonal. Best known are these mutations in the hereditary non-polyposis colon cancer Lynch syndrome [2098]. These somatic point mutations appear as repetitive sequences, which are mismatch-repaired. While the initial mutations as oncogenic pathways were of definitive causative effect, the additional somatic point mutations occur... 

Mismatched bases produced during DNA replication are those not conforming to or A=T base pairing. They are identified and corrected in the new strand by the mismatch-repair enzyme complex . The mismatched nucleotides are identified and excised, and the gap filled by DNA polymerase. Mutations in this complex result in failure to correct mismatched base pairs and cause hereditary non-polyposis colorectal cancer (HNPCC). 

Umar A, Risinger Jl, Hawk ET, Barrett JC (2004) Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer 4 153-158... 

There are two major forms of heredifary susceptibility to colon cancer. Familial adenomatous polyposis is caused by defects in the ARC gene (see Chapter 32). The more common hereditary non-pol3rposis colorectal cancer (HNPCC), which includes many endometrial, stomach, and urinary tract tumors, results from defects in DNA mismatch repair. )) The proteins hMSH2 and hMSLl are homologs of the E.coli MutS and MutL (main text). 

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