Mutator phenotype

Rampino N, Yamamoto H, Ionov Y, et al. Somatic frameshift mutations in theBax gene in colon cancers of the microsatellite mutator phenotype. Science 1997 275 967-969. 

These observations support the theory that, in an early stage of tumor formation, a mutation occurs in a repair system needed to maintain the integrity of the genome (Loeb, 1991, Loeb, 1998). Loss of the fimction of the repair system leads to a mutator phenotype a missing or ineffective DNA repair favors further accumulation of mutations and leads to an intrinsic instability of the genome. 

Loeb, L.A. Mutator phenotype may be required for multistage carcinogenesis (1991) Cancer Res 51, 3075-3079... 

Loeb, L.A. Cancer cells exhibit a mutator phenotype (1998) Adv Cancer Res 72, 25-56... 

Bielas JH, Loeb KR, Rubin BP et al. Human cancers express a mutator phenotype. Proc Natl Acad Sci USA 2006 103 18238-18242. 

Microsatellite instability (MSI) in the tumor caused by defeetive DNA mismateh repair has been associated with outeome to ehemotherapy (34). For example, a study of 320 Dukes B2 and C colon cancers treated with 5-FU therapy showed that MSI status was eorrelated with improved survival (p = O.OI) (35). MSI is also associated with a mutator phenotype that may lead to mutations in pharmaeogenetic markers, which would not be pieked up by screening the germline genome. 

Wu MS, Lee CW, Shun CT, Wang HP, Lee WJ, Chang MC, Sheu JC, Lin JT. Distinct clinicopathologic and genetic profiles in sporadic gastric cancer with different mutator phenotypes. Genes Chromosomes Cancer 2000 27 403-411. 

Conditional Mutation. Phenotype of the organism changes only under a specific condition called the restrictive condition, but remains normal under other conditions called the permissive condition. 

Patient Genotype Exon Mutation Mutation Phenotype RNA Splicing Aminoacid Substitution Ref... 

Mismatch DNA repair is critical in the maintenance of a stable genome. Inheritance of mutations in genes involved in mismatch DNA repair MSHl, MSH2, MSH6, PMSl, PMS2) can predispose to cancers of the brain, endometrium, ovaries, and bowel. Somatic mutations in these genes may also contribute to the mutator phenotype. 

Loeb LA (1994) Microsatellite instability marker of a mutator phenotype in cancer. Cancer Research 54 5059-5063. 

Microsatellite instability is found to be a common feature of nearly all tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) (4,16). The majority of HNPCC cases arise through germline mutations in two genes, hMSH2 and hMLHl on chromosomes 2 and 3, which encode the human homologs of bacterial mismatch repair genes, MutS and MutL (17,18). Cells which display microsatellite instability are termed as having an RER+ phenotype, which stands for replication error (5). Such RER+ tumor cells have been shown to have defects in mismatch repair and possess a mutator phenotype (19). 

The mutation and malfunction of key components of DNA repair and DNA damage checkpoints will lead to an increased mutational load on the cell and will favor the accumulation of further genetic changes. One hypothesis is that tumor cells acquire - at some state of the tumor development - a mutator phenotype, which is characterized by an increased mutation rate due to a malfunction of gene products responsible for the maintenance of genetic stability (see Section 14.1.5). 

Chiappini F, Gross-Goupil M, Saffroy R, et al. Microsatellite instability mutator phenotype in hepatocellular carcinoma in nonalcoholic and non-virally infected normal livers. Carcinogenesis. 2004 25 541-547. 

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