Apoptosis and mutation in the murine small intestine: loss of Mlh1- and Pms2-dependent apoptosis leads to increased mutation in vivo

MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice lacking MMR

“…We selected this approach both because it is well validated for assessing mutation frequencies in the context of loss of DNA repair activities (reviewed in Sansom and Clarke, 2000) and because it remains the only approach for scoring mutation frequencies in a physiological setting in situ. In accordance with our previous studies, we observed significant increases in mutation frequency at the Dlb-1b locus in both the Msh2-and Mlh1-deficient backgrounds (Toft et al, 1999;Sansom et al, 2001Sansom et al, , 2003a. When Msh2À/À Mbd4À/À and Mlh1À/À Mbd4À/À mice were compared to the single nulls, the mutation frequency was significantly higher than the Mbd4À/À mice (Pp0.03, Mann-Whitney), but was unchanged compared to the individual MMR mutants: Mlh1À/À (P ¼ 0.51, n ¼ 5, Mann-Whitney), Msh2À/À (P ¼ 0.24, n ¼ 5, MannWhitney).…”

Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance

“…Therefore, the MMR-deficient cells in the proximal colon of a Lynch syndrome patient may have a direct proliferative advantage that facilitates their clonal outgrowth. Moreover, MMR-deficient cells are more mutable than MMR-proficient cells by many different mutagenic compounds, including nitrosamines and food-derived heterocyclic amines, and other mutagens [Andrew et al, 1998; Borgdorff et al, 2006; Sansom et al, 2003; Smith-Roe et al, 2006]. For this reason, bile-induced and food-derived mutagens probably not only induce somatic mutation of the wild-type MMR allele and enhance clonal outgrowth of the resulting MMR-deficient enterocytes but, in addition, induce more mutations in oncogenes and tumor suppressor genes in these cells.…”

Non-Steroidal Anti-Inflammatory Drugs, DNA Repair and Cancer

“…Decreased expression of hMLH1 can alter hPMS2 stability and consequently, genetic integrity. Moreover, hMLH1 and hPMS2 can have a role in activating cell-cycle checkpoints and promoting apoptosis (Cejka et al, 2003;Davis et al, 1998;Ding et al, 2009;McDaid et al, 2009;Sansom et al, 2003;Yanamadala & Ljungman, 2003;Zhang et al, 1999). Thus, a functional DNA mismatch repair system prohibits expansion of cells containing DNA damage (Carethers et al, 1996;Papouli et al, 2004).…”