epithelial origin in colon cancers, and about 50% of the colon crypts in the epithelium within 10 cm adjacent to cancers (in the field defects from which the cancers likely arose) have reduced or absent expression of PMS2. Deficiencies in PMS2 in colon epithelium appear to mostly be due to epigenetic repression. In tumors classified as mismatch repair deficient and lacking, in a majority PMS2 expression is deficient because of lack of its pairing partner MLH1. Pairing of PMS2 with MLH1 stabilizes. The loss of MLH1 in sporadic cancers was due to epigenetic silencing caused by promoter methylation in 65 out of 66 cases. In 16 cancers Pms2 was deficient even though MLH1 protein expression was present. Of these 16 cases, no cause was determined for 10, but 6 were found to have a heterozygous germline mutation in Pms2, followed by likely loss of heterozygosity in the tumor. Thus only 6 of 119 tumors lacking expression for Pms2 (5%) were due to mutation of PMS2. Coordination with ERCC1 and ERCC4 (XPF) When PMS2 is reduced in colonic crypts in a field defect, it is most often associated with reduced expression of DNA repair enzymes ERCC1 and ERCC4 (XPF) as well (see images in this section). A deficiency in ERCC1 and/or ERCC4 (XPF) would cause DNA damage accumulation. Such excess DNA damage often leads to apoptosis. However, an added defect in PMS2 can inhibit this apoptosis. Thus, an added deficiency in PMS2 likely would be selected for in the face of the increased DNA damages when ERCC1 and/or ERCC4 (XPF) are deficient. When ERCC1 deficient Chinese hamster ovary cells were repeatedly subjected to DNA damage, of five clones derived from the surviving cells, three were mutated in Pms2. Progression to colon cancer ERCC1, PMS2 double mutant Chinese hamster ovary cells, when exposed to Ultraviolet light (a DNA damaging agent), showed a 7,375-fold greater mutation frequency than wild type Chinese hamster ovary cells, and a 967-fold greater mutation frequency than the cells defective in ERCC1, alone. Thus colonic cell deficiency in both ERCC1 and PMS2 causes genome instability. A similar genetically unstable situation is expected for cells doubly defective for PMS2 and ERCC4 (XPF). This instability would likely enhance progression to colon cancer by causing a mutator phenotype, and account for the presence of the cells doubly deficient in PMS2 and ERCC1 [or PMS2 and ERCC4 (XPF)] in field defects associated with